Title:
Genetic Markers for Assessing Risk of Developing Schizophrenia
Kind Code:
A1


Abstract:
This document provides methods and materials related to genetic markers of schizophrenia (SZ). For example, this document provides methods for using such genetic markers to assess risk of developing schizophrenia.



Inventors:
Ramsey, Timothy Lynn (Shelbyville, KY, US)
Brennan, Mark David (Jeffersonville, IN, US)
Application Number:
12/612585
Publication Date:
05/13/2010
Filing Date:
11/04/2009
Assignee:
SUREGENE LLC (Louisville, KY, US)
Primary Class:
Other Classes:
435/6.12, 514/211.13, 514/220, 514/546
International Classes:
A61K33/00; A61K31/22; A61K31/551; A61K31/554; C12Q1/68
View Patent Images:
Related US Applications:



Other References:
Stefansson, Hreinn et al. Large recurrent microdeletions assoicated with schizophrenia. Nautre 9/11/2008 Vol 455 pages 232-237
Sturmey, Peter et al. The PAS-ADD Checklist: independent replication of its psychometric properties in a community sample BJP 2005 Vol 186 319-323
Schmidt et al. Discover Magazine July 22, 2008 http://discovermagazine.com/2008/aug/22-can-schizophrenia-be-cured-before-it-starts
Wang et al. Cold Spring Harb Protoc Vol 3 Issue 6, June 2008
Primary Examiner:
HANEY, AMANDA MARIE
Attorney, Agent or Firm:
FISH & RICHARDSON P.C. (BO) (MINNEAPOLIS, MN, US)
Claims:
What is claimed is:

1. A method of determining risk of developing schizophrenia (SZ) in a human subject, the method comprising: determining the identity of at least one allele of a single nucleotide polymorphism (SNP) listed in Table 1; and comparing the identity of the allele in the subject with a reference allele, wherein the reference allele is associated with a known risk of developing SZ; and wherein the presence of an allele in the subject that is the same as the reference allele that is associated with the known risk of developing SZ indicates the risk that the subject will develop SZ.

2. A method of determining risk of developing SZ in a human subject, the method comprising: determining the copy number of at least one single nucleotide polymorphism (SNP) listed in Table 2 or 3; and comparing the copy number of the SNP in the subject with a reference copy number, wherein the reference copy number is associated with a known risk of developing SZ; and wherein the presence of a copy number of the SNP in the subject that is the same as a reference copy number that is associated with SZ indicates that the risk that the subject will develop SZ.

3. The method of claim 1 or 2, wherein determining the identity or copy number of an allele comprises obtaining a sample comprising DNA from the subject, and determining identity or copy number of the nucleotide at the polymorphic site.

4. The method of claim 3, wherein determining the identity of the nucleotide comprises contacting the sample with a probe specific for a selected allele of the polymorphism, and detecting the formation of complexes between the probe and the selected allele of the polymorphism, wherein the formation of complexes between the probe and the test marker indicates the presence of the selected allele in the sample.

5. The method of claim 4, wherein determining the identity of an allele comprises determining the identity of the nucleotide at position 31 of one of SEQ ID NOs: 1-1025.

6. The method of claim 3, wherein determining the copy number of an allele comprises contacting the sample with a probe specific for a selected allele, detecting the formation of complexes between the probe and the selected allele of the polymorphism, and quantifying the complexes, wherein the quantification of the complexes indicates the copy number of the selected allele in the sample.

7. The method of claim 6, wherein the probe comprises a fluorescent label, and quantifying the complexes comprises detecting intensity of emission from the label.

8. The method of claim 2, wherein determining the copy number of an allele comprises detecting the absence or duplication of the allele in the subject.

9. The method of claim 1 or 2, wherein the subject is a patient having or suspected of having SZ.

10. The method of claim 1 or 2, wherein the subject has one or more risk factors associated with SZ.

11. The method of claim 8, wherein the risk factors associated with SZ include one or more of: a relative afflicted with SZ; and a genetically based phenotypic trait associated with risk for a SZ.

12. The method of claim 1 or 2, wherein the subject has exhibited or exhibits symptoms of psychosis.

13. The method of claim 1 or 2, further comprising selecting or excluding a subject for enrollment in a clinical trial based on the identity of the allele.

14. The method of claim 1 or 2, further comprising stratifying a subject population for analysis of a clinical trial based on the identity of the allele in the subjects.

15. The method of claim 1 or 2, further comprising confirming a diagnosis of a SZ using psychometric instruments.

16. The method of claim 1, further comprising selecting a treatment for SZ if an allele in the subject is the same as a reference allele associated with SZ.

17. The method of claim 2, further comprising selecting a treatment for SZ if the copy number of the allele in the subject is the same as a reference copy number associated with SZ.

18. The method of claim 14 or 15, further comprising administering the selected treatment to the subject.

19. The method of claim 14 or 15, wherein the treatment comprises one or more of an anti-psychotic drug, an anti-depressant drug, anti-anxiety drug, mood stabilizer, selective serotonin reuptake inhibitor (SSRI), psychotherapy, or a stimulant.

20. The method of claim 1 or 2, further comprising recording the identity of the allele in a tangible medium.

21. The method of claim 1 or 2, wherein the tangible medium comprises a computer-readable disk, a solid state memory device, or an optical storage device.

22. The method of claim 1, wherein the single nucleotide polymorphism (SNP) is at position 31 of a sequence selected from the group consisting of SEQ ID NO:656, 665, 248, 639, 25, 494, 700, and 691.

23. The method of claim 2, wherein the single nucleotide polymorphism (SNP) is at position 31 of a sequence selected from the group consisting of SEQ ID NO:665, 314, 679, 597, 523, 619, 402, 677, 586, 558, 664, 87, 851, and 500.

Description:

CLAIM OF PRIORITY

This application is a continuation of International Patent Application Serial No. PCT/US2009/058487, filed Sep. 25, 2009, which claims the benefit of U.S. Provisional Application Ser. No. 61/100,176, filed on Sep. 25, 2008, which are incorporated by reference in their entirety herein.

FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

The U.S. Government has certain rights in this invention pursuant to Grant Nos. R43 MH078437, N01 MH900001, and MH074027, awarded by the National Institutes of Health.

TECHNICAL FIELD

This invention relates to genetic markers of schizophrenia (SZ). For example, methods of using such genetic markers for assessing risk of developing SZ are provided.

BACKGROUND

The schizophrenia spectrum disorders include schizophrenia (SZ), schizotypal personality disorder (SPD), and/or schizoaffective disorder (SD). Schizophrenia (SZ) is considered a clinical syndrome, and is probably a constellation of several pathologies. Substantial heterogeneity is seen between cases, which is thought to reflect multiple overlapping etiologic factors, including both genetic and environmental contributions. SD is characterized by the presence of affective (depressive or manic) symptoms and schizophrenic symptoms within the same, uninterrupted episode of illness. SPD is characterized by a pervasive pattern of social and interpersonal deficits marked by acute discomfort with, and reduced capacity for, close relationships as well as by cognitive or perceptual distortions and eccentricities of behavior, beginning by early adulthood and present in a variety of contexts.

Various genes and chromosomes have been implicated in etiology of SZ. Many studies have suggested the presence of one or more important genes relating to SZ on most or all of the autosomes (Williams et al., Hum. Mol. Genet. 8:1729-1739 (1999); Fallin et al., Am. J. Hum. Genet. 77:918-936 (2005); ; Badner et al., Mol. Psychiatry. 7:405-411 (2002); Cooper-Casey et al., Mol. Psychiatry. 10:651-656 (2005); Devlin et al., Mol. Psychiatry. 7:689-694 (2002); Fallin et al., Am. J. Hum. Genet. 73:601-611 (2003); Jablensky, Mol. Psychiatry. 11: 815-836 (2006); Kirov et al., J. Clin. Invest. 115:1440-1448 (2005); Norton et al., Curr. Opin. Psychiatry 19:158-164 (2006); Owen et al., Mol. Psychiatry. 9:14-27 (2004)). However, none of these prior studies have used high resolution genetic association methods to systematically compare genes involved in SZ. Neither have any of these studies demonstrated that genetic polymorphisms in the genes defined herein are important, in particular in the genetic etiology of SZ.

Due to the severity of these disorders, especially the negative impact of a psychotic episode on a patient, and the diminishing recovery after each psychotic episode, there is a need to more conclusively identify individuals who have or are at risk of developing schizophrenia (SZ), schizotypal personality disorder (SPD), or schizoaffective disorder (SD), for example, to confirm clinical diagnoses, to allow for prophylactic therapies, to determine appropriate therapies based on their genotypic subtype, and to provide genetic counseling for prospective parents with a history of the disorder.

SUMMARY

This disclosure provides methods for determining a subject's risk of developing schizophrenia based on detecting variations in genes involved in a number of pathways including: glutamate signaling and metabolism, cell adhesion, cytoskeletal architecture, vesicle formation, and trafficking, G-protein coupled receptors, carrier proteins and transporters, cell cycle modulators, neuronal development, calcium/calmodulin signaling, neuropeptide signaling, and several additional genes identified by virtue of their interaction with genes in high impact pathways and their expression in the central nervous system. This disclosure also provides methods and materials relating to determining the genetic risk of developing an SSD (e.g., SZ). For example, the allelic and genotypic variants identified as described herein can be used for assessing genetic risk. Specifically, the invention includes methods for assessing genetic risk based on evaluation of 1025 exemplary SNPs relating to SZ risk. Additionally, the specific SNPs can be used to capture copy number variation related to SZ risk. The allelic and genotypic variants thus identified can be used for assessing genetic risk.

In one aspect, this document features methods for determining risk of developing schizophrenia (SZ) in a human subject. Methods can include determining the identity of at least one allele of a single nucleotide polymorphism (SNP) listed in Table 1 (e.g., at nucleotide 31 of SEQ ID NO:656, 665, 248, 639, 25, 494, 700, or 691); and comparing the identity of the allele in the subject with a reference allele, wherein the reference allele is associated with a known risk of developing SZ; and wherein the presence of an allele in the subject that is the same as the reference allele that is associated with the known risk of developing SZ indicates the risk that the subject will develop SZ.

In another aspect, this document features methods for determining risk of developing SZ in a human subject. Methods can include: determining the copy number of at least one single nucleotide polymorphism (SNP) listed in Table 2 (e.g, at nucleotide 31 of SEQ ID NO:665, 314, 679, 597, 523, 619, 402) or Table 3 (e.g., at nucleotide 31 of SEQ ID NO:677, 586, 558, 664, 87, 851, or 500); and comparing the copy number of the SNP in the subject with a reference copy number, wherein the reference copy number is associated with a known risk of developing SZ; and wherein the presence of a copy number of the SNP in the subject that is the same as a reference copy number that is associated with SZ indicates that the risk that the subject will develop SZ.

Determining the identity or copy number of an allele can include obtaining a sample comprising DNA from the subject, and determining identity or copy number of the nucleotide at the polymorphic site. Determining the identity of the nucleotide can include contacting the sample with a probe specific for a selected allele of the polymorphism, and detecting the formation of complexes between the probe and the selected allele of the polymorphism, wherein the formation of complexes between the probe and the test marker indicates the presence of the selected allele in the sample. Determining the identity of an allele can include determining the identity of the nucleotide at position 31 of one of SEQ ID NOs: 1-1025. Determining the copy number of an allele can include contacting the sample with a probe specific for a selected allele, detecting the formation of complexes between the probe and the selected allele of the polymorphism, and quantifying the complexes, wherein the quantification of the complexes indicates the copy number of the selected allele in the sample. A probe can include a fluorescent label, and quantifying the complexes comprises detecting intensity of emission from the label. Determining the copy number of an allele can include detecting the absence or duplication of the allele in the subject. A subject can be a patient having or suspected of having SZ. A subject can have one or more risk factors associated with SZ. Risk factors associated with SZ can include one or more of: a relative afflicted with SZ; and a genetically based phenotypic trait associated with risk for a SZ. A subject can have exhibited or exhibits symptoms of psychosis. Methods can further include selecting or excluding a subject for enrollment in a clinical trial based on the identity of the allele. Methods can further include stratifying a subject population for analysis of a clinical trial based on the identity of the allele in the subjects. Methods can further include confirming a diagnosis of a SZ using psychometric instruments. Methods can further include selecting a treatment for SZ if an allele in the subject is the same as a reference allele associated with SZ. Methods can further include selecting a treatment for SZ if the copy number of the allele in the subject is the same as a reference copy number associated with SZ. Methods can further include administering the selected treatment to the subject. A treatment can include one or more of an anti-psychotic drug, an anti-depressant drug, anti-anxiety drug, mood stabilizer, selective serotonin reuptake inhibitor (SSRI), psychotherapy, or a stimulant. Methods can further include recording the identity of the allele in a tangible medium. A tangible medium can include a computer-readable disk, a solid state memory device, or an optical storage device.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used to practice the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

DETAILED DESCRIPTION

This document provides methods for assessing genetic risk for developing SSDs based on evaluation of single nucleotide polymorphisms (SNPs) for genes relating to SSDs including schizophrenia (SZ), schizotypal personality disorder (SPD), and schizoaffective disorder (SD). As described herein, bioinformatic and genetic analyses provided evidence of association of the disclosed SNPs and haplotypes SZ. Specific allelic and copy number variants identified herein can be used to assess genetic risk.

DEFINITIONS

As used herein, an “allele” is one of a pair or series of genetic variants of a polymorphism at a specific genomic location. An “SZ risk allele” is an allele that is associated with increased risk of developing SZ. An “SZ allele” is an allele that is statistically associated with a diagnosis of SZ.

As used herein, “genotype” refers to the diploid combination of alleles for a given genetic polymorphism. A homozygous subject carries two copies of the same allele and a heterozygous subject carries two different alleles.

As used herein, “genetic model” refers to the manner in which an allele influences risk or differential diagnosis. In a “dominant model” the allele impacts the clinical state to the same extent whether present in one copy or two copies, i.e., whether homozygous or heterozygous. In a “recessive model” the allele impacts the clinical state only when homozygous. In an “additive model” the allele impacts the clinical state in proportion to the number of copies present, i.e., the homozygous state has twice the impact of the heterozygous state.

As used herein, a “haplotype” is one or a set of signature genetic changes (polymorphisms) that are normally grouped closely together on the DNA strand, and are usually inherited as a group; the polymorphisms are also referred to herein as “markers.” A “haplotype” as used herein is information regarding the presence or absence of one or more genetic markers in a given chromosomal region in a subject. A haplotype can consist of a variety of genetic markers, including indels (insertions or deletions of the DNA at particular locations on the chromosome); single nucleotide polymorphisms (SNPs) in which a particular nucleotide is changed; microsatellites; and minisatellites.

Microsatellites (sometimes referred to as a variable number of tandem repeats or VNTRs) are short segments of DNA that have a repeated sequence, usually about 2 to 5 nucleotides long (e.g., CACACA), that tend to occur in non-coding DNA. Changes in the microsatellites sometimes occur during the genetic recombination of sexual reproduction, increasing or decreasing the number of repeats found at an allele, changing the length of the allele. Microsatellite markers are stable, polymorphic, easily analyzed and occur regularly throughout the genome, making them especially suitable for genetic analysis.

“Copy number variation” (CNV), as used herein, refers to variation from the normal diploid condition for a gene or polymorphism. Individual segments of human chromosomes can be deleted or duplicated such that the subject's two chromosome carry fewer than two copies of the gene or polymorphism (a deletion or deficiency) or two or more copies (a duplication).

“Linkage disequilibrium” refers to when the observed frequencies of haplotypes in a population does not agree with haplotype frequencies predicted by multiplying together the frequency of individual genetic markers in each haplotype.

The term “chromosome” as used herein refers to a gene carrier of a cell that is derived from chromatin and comprises DNA and protein components (e.g., histones). The conventional internationally recognized individual human genome chromosome numbering identification system is employed herein. The size of an individual chromosome can vary from one type to another with a given multi-chromosomal genome and from one genome to another. In the case of the human genome, the entire DNA mass of a given chromosome is usually greater than about 100,000,000 base pairs. For example, the size of the entire human genome is about 3×109 base pairs.

The term “gene” refers to a DNA sequence in a chromosome that codes for a product (either RNA or its translation product, a polypeptide). A gene contains a coding region and includes regions preceding and following the coding region (termed respectively “leader” and “trailer”). The coding region is comprised of a plurality of coding segments (“exons”) and intervening sequences (“introns”) between individual coding segments.

The term “probe” refers to an oligonucleotide. A probe can be single stranded at the time of hybridization to a target. As used herein, probes include primers, i.e., oligonucleotides that can be used to prime a reaction, e.g., a PCR reaction.

The term “label” or “label containing moiety” refers in a moiety capable of detection, such as a radioactive isotope or group containing same, and nonisotopic labels, such as enzymes, biotin, avidin, streptavidin, digoxygenin, luminescent agents, dyes, haptens, and the like. Luminescent agents, depending upon the source of exciting energy, can be classified as radioluminescent, chemiluminescent, bioluminescent, and photoluminescent (including fluorescent and phosphorescent). A probe described herein can be bound, e.g., chemically bound to label-containing moieties or can be suitable to be so bound. The probe can be directly or indirectly labeled.

The term “direct label probe” (or “directly labeled probe”) refers to a nucleic acid probe whose label after hybrid formation with a target is detectable without further reactive processing of hybrid. The term “indirect label probe” (or “indirectly labeled probe”) refers to a nucleic acid probe whose label after hybrid formation with a target is further reacted in subsequent processing with one or more reagents to associate therewith one or more moieties that finally result in a detectable entity.

The terms “target,” “DNA target,” or “DNA target region” refers to a nucleotide sequence that occurs at a specific chromosomal location. Each such sequence or portion is preferably at least partially, single stranded (e.g., denatured) at the time of hybridization. When the target nucleotide sequences are located only in a single region or fraction of a given chromosome, the term “target region” is sometimes used. Targets for hybridization can be derived from specimens which include, but are not limited to, chromosomes or regions of chromosomes in normal, diseased or malignant human cells, either interphase or at any state of meiosis or mitosis, and either extracted or derived from living or postmortem tissues, organs or fluids; germinal cells including sperm and egg cells, or cells from zygotes, fetuses, or embryos, or chorionic or amniotic cells, or cells from any other germinating body; cells grown in vitro, from either long-term or short-term culture, and either normal, immortalized or transformed; inter- or intraspecific hybrids of different types of cells or differentiation states of these cells; individual chromosomes or portions of chromosomes, or translocated, deleted or other damaged chromosomes, isolated by any of a number of means known to those with skill in the art, including libraries of such chromosomes cloned and propagated in prokaryotic or other cloning vectors, or amplified in vitro by means well known to those with skill; or any forensic material, including but not limited to blood, or other samples.

The term “hybrid” refers to the product of a hybridization procedure between a probe and a target.

The term “hybridizing conditions” has general reference to the combinations of conditions that are employable in a given hybridization procedure to produce hybrids, such conditions typically involving controlled temperature, liquid phase, and contact between a probe (or probe composition) and a target. Conveniently and preferably, at least one denaturation step precedes a step wherein a probe or probe composition is contacted with a target. Guidance for performing hybridization reactions can be found in Ausubel et al., Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. (2003), 6.3.1-6.3.6. Aqueous and nonaqueous methods are described in that reference and either can be used. Hybridization conditions referred to herein are a 50% formamide, 2×SSC wash for 10 minutes at 45° C. followed by a 2×SSC wash for 10 minutes at 37° C.

Calculations of “identity” between two sequences can be performed as follows. The sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second nucleic acid sequence for optimal alignment and non-identical sequences can be disregarded for comparison purposes). The length of a sequence aligned for comparison purposes is at least 30% (e.g., at least 40%, 50%, 60%, 70%, 80%, 90% or 100%) of the length of the reference sequence. The nucleotides at corresponding nucleotide positions are then compared. When a position in the first sequence is occupied by the same nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.

The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. In some embodiments, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package, using a Blossum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5.

As used herein, the term “substantially identical” is used to refer to a first nucleotide sequence that contains a sufficient number of identical nucleotides to a second nucleotide sequence such that the first and second nucleotide sequences have similar activities. Nucleotide sequences that are substantially identical are at least 80% (e.g., 85%, 90%, 95%, 97% or more) identical.

The term “nonspecific binding DNA” refers to DNA which is complementary to DNA segments of a probe, which DNA occurs in at least one other position in a genome, outside of a selected chromosomal target region within that genome. An example of nonspecific binding DNA comprises a class of DNA repeated segments whose members commonly occur in more than one chromosome or chromosome region. Such common repetitive segments tend to hybridize to a greater extent than other DNA segments that are present in probe composition.

As used herein, the term “stratification” refers to the creation of a distinction between subjects on the basis of a characteristic or characteristics of the subjects. Generally, in the context of clinical trials, the distinction is used to distinguish responses or effects in different sets of patients distinguished according to the stratification parameters. In some embodiments, stratification includes distinction of subject groups based on the presence or absence of particular markers or haplotypes described herein. The stratification can be performed, e.g., in the course of analysis, or can be used in creation of distinct groups or in other ways.

Methods of Diagnoses and Evaluation of Risk

Described herein are a variety of methods for determining susceptibility to an SSD (e.g., SZ). “Susceptibility” does not necessarily mean that the subject will develop an SSD (e.g., SZ), but rather that the subject is, in a statistical sense, more likely to develop SZ than an average member of the population, i.e., has an increased risk of developing an SSD (e.g., SZ). As used herein, susceptibility to an SSD exists if the subject has a genetic variation, e.g., an allele or CNV, associated with an increased risk of an SSD (e.g., SZ) as described herein. Ascertaining whether the subject has such an allele or CNV is included in the concept of diagnosing susceptibility to an SSD (e.g., SZ) as used herein. Such determination is useful, for example, for purposes of diagnosis, treatment selection, and genetic counseling. Thus, the methods described herein can include obtaining a haplotype associated with an increased risk of an SSD (e.g., SZ) as described herein for the subject.

As used herein, “determining the identity of an allele” or “determining copy number” includes obtaining information regarding the identity, number, presence or absence of one or more specific alleles or SNPs in a subject. Determining the identity of an allele or determining copy number can, but need not, include obtaining a sample comprising DNA from a subject, and/or assessing the identity, copy number, presence or absence of one or more genetic markers in the sample. The individual or organization who performs the determination need not actually carry out the physical analysis of a sample from a subject; the methods can include using information obtained by analysis of the sample by a third party. Thus the methods can include steps that occur at more than one site. For example, a sample can be obtained from a subject at a first site, such as at a health care provider, or at the subject's home in the case of a self-testing kit. The sample can be analyzed at the same or a second site, e.g., at a laboratory or other testing facility.

Determining the identity of an allele or copy number of a SNP can also include or consist of reviewing a subject's medical history, where the medical history includes information regarding the identity, copy number, presence or absence of one or more alleles or SNPs in the subject, e.g., results of a genetic test.

In some embodiments, to determine the identity of an allele or copy number/presence/absence of an allele or genotype described herein, a biological sample that includes nucleated cells (such as blood, a cheek swab or mouthwash) is prepared and analyzed for the copy number, presence or absence of preselected markers. Such diagnoses may be performed by diagnostic laboratories, or, alternatively, diagnostic kits can be manufactured and sold to health care providers or to private individuals for self-diagnosis. Diagnostic or prognostic tests can be performed as described herein or using well known techniques, such as described in U.S. Pat. No. 5,800,998.

Results of these tests, and optionally interpretive information, can be returned to the subject, the health care provider or to a third party payor. The results can be used in a number of ways. The information can be, e.g., communicated to the tested subject, e.g., with a prognosis and optionally interpretive materials that help the subject understand the test results and prognosis. The information can be used, e.g., by a health care provider, to determine whether to administer a specific drug, or whether a subject should be assigned to a specific category, e.g., a category associated with a specific disease endophenotype, or with drug response or non-response. The information can be used, e.g., by a third party payer such as a healthcare payer (e.g., insurance company or HMO) or other agency, to determine whether or not to reimburse a health care provider for services to the subject, or whether to approve the provision of services to the subject. For example, the healthcare payer may decide to reimburse a health care provider for treatments for SZ if the subject has SZ or has an increased risk of developing SZ. The presence or absence of the allele or genotype in a patient may be ascertained by using any of the methods described herein.

Alleles and Genotypes Associated with SSDs

This document provides methods for diagnosing and assessing genetic risk based on evaluation of single nucleotide polymorphisms (SNPs) for genes relating to SZ-spectrum disorders including schizophrenia (SZ), schizotypal personality disorder (SPD) and schizoaffective disorder (SD). Tables 1-3 and Table A list specific exemplary SNPs that can be used to capture significant haplotype variation in these genes. One of skill in the art will appreciate that additional variants can be identified via TDT using families with multiple affected individuals (such as those collected CCGS) and verified by Case/Control comparisons, e.g., using the methods and markers presented herein. Using the SNP markers described herein, one can determine the alleles, copy number, genotypes or haplotypes in these genes relating to diagnosis or genetic risk of developing SZ. This information can then be used to determine risk of developing SZ, or for making a diagnosis of SZ. The allelic and genotypic variants thus identified can be used for diagnosis and for assessing genetic risk.

In some embodiments, the methods can include determining the presence of a haplotype that includes one or more polymorphisms near D22S526 and/or the polymorphisms in the Sult4a1 gene and/or polymorphisms within 1 linkage disequilibrium unit (LDU) of these markers, e.g., as described in U.S. Pat. Pub. No. US2006/0177851, incorporated herein in its entirety.

Linkage Disequilibrium Analysis

Linkage disequilibrium (LD) is a measure of the degree of association between alleles in a population. One of skill in the art will appreciate that haplotypes involving markers in LD with the polymorphisms described herein can also be used in a similar manner to those described herein. Methods of calculating LD are known in the art (see, e.g., Morton et al., Proc. Natl. Acad. Sci. USA 98(9):5217-21 (2001); Tapper et al., Proc. Natl. Acad. Sci. USA 102(33):11835-11839 (2005); Maniatis et al., Proc. Natl. Acad. Sci. USA 99:2228-2233 (2002)). Thus, in some cases, the methods can include analysis of polymorphisms that are in LD with a polymorphism described herein. Methods are known in the art for identifying such polymorphisms; for example, the International HapMap Project provides a public database that can be used, see hapmap.org, as well as The International HapMap Consortium, Nature 426:789-796 (2003), and The International HapMap Consortium, Nature 437:1299-1320 (2005). Generally, it will be desirable to use a HapMap constructed using data from individuals who share ethnicity with the subject. For example, a HapMap for African Americans would ideally be used to identify markers in LD with an exemplary marker described herein for use in genotyping a subject of African American descent.

Alternatively, methods described herein can include analysis of polymorphisms that show a correlation coefficient (r2) of value ≧0.5 with the markers described herein. Results can be obtained from on line public resources such as HapMap.org on the World Wide Web. The correlation coefficient is a measure of LD, and reflects the degree to which alleles at two loci (for example, two SNPs) occur together, such that an allele at one SNP position can predict the correlated allele at a second SNP position, in the case where r2 is >0.5.

Identifying Additional Genetic Markers

In general, genetic markers can be identified using any of a number of methods well known in the art. For example, numerous polymorphisms in the regions described herein are known to exist and are available in public databases, which can be searched using methods and algorithms known in the art. Alternately, polymorphisms can be identified by sequencing either genomic DNA or cDNA in the region in which it is desired to find a polymorphism. According to one approach, primers are designed to amplify such a region, and DNA from a subject is obtained and amplified. The DNA is sequenced, and the sequence (referred to as a “subject sequence” or “test sequence”) is compared with a reference sequence, which can represent the “normal” or “wild type” sequence, or the “affected” sequence. In some embodiments, a reference sequence can be from, for example, the human draft genome sequence, publicly available in various databases, or a sequence deposited in a database such as GenBank. In some embodiments, the reference sequence is a composite of ethnically diverse individuals.

In general, if sequencing reveals a difference between the sequenced region and the reference sequence, a polymorphism has been identified. The fact that a difference in nucleotide sequence is identified at a particular site that determines that a polymorphism exists at that site. In most instances, particularly in the case of SNPs, only two polymorphic variants will exist at any location. However, in the case of SNPs, up to four variants may exist since there are four naturally occurring nucleotides in DNA. Other polymorphisms, such as insertions and deletions, may have more than four alleles.

The methods described herein can also include determining the presence or absence of other markers known or suspected to be associated with risk of bipolar disorder (BD) and/or SZ, or differentially inherited in BD versus SZ. In some embodiments, the methods include determining the presence or absence of one or more other markers that are or may be associated with BD or SZ, e.g., in one or more genes, e.g., e.g., as described in WO 2009/092032, WO 2009/089120, WO 2009/082743, US2006/0177851, and US2009/0012371 incorporated herein in their entirety. See also, e.g., OMIM entry no. 181500 (SCZD).

Methods of Determining the Identity of an Allele or Obtaining a Genotype

The methods described herein include determining the identity, copy number, presence, or absence of alleles or genotypes associated with diagnosis or risk of developing SZ. In some embodiments, an association with SZ is determined by the statistical likelihood of the presence of an allele or genotype in an individual with SZ, e.g., an unrelated individual or a first or second-degree relation of the subject, and optionally the statistical likelihood of the absence of the same allele, copy number, or genotype in an unaffected reference individual, e.g., an unrelated individual or a first or second-degree relation of the subject. Thus the methods can include obtaining and analyzing a sample from one or more suitable reference individuals.

Samples that are suitable for use in the methods described herein contain genetic material, e.g., genomic DNA (gDNA). Genomic DNA is typically extracted from biological samples such as blood or mucosal scrapings of the lining of the mouth, but can be extracted from other biological samples including urine or expectorant. The sample itself will typically consist of nucleated cells (e.g., blood or buccal cells) or tissue removed from the subject. The subject can be an adult, child, fetus, or embryo. In some embodiments, the sample is obtained prenatally, either from a fetus or embryo or from the mother (e.g., from fetal or embryonic cells in the maternal circulation). Methods and reagents are known in the art for obtaining, processing, and analyzing samples. In some embodiments, the sample is obtained with the assistance of a health care provider, e.g., to draw blood. In some embodiments, the sample is obtained without the assistance of a health care provider, e.g., where the sample is obtained non-invasively, such as a sample comprising buccal cells that is obtained using a buccal swab or brush, or a mouthwash sample.

In some cases, a biological sample may be processed for DNA isolation. For example, DNA in a cell or tissue sample can be separated from other components of the sample. Cells can be harvested from a biological sample using standard techniques known in the art. For example, cells can be harvested by centrifuging a cell sample and resuspending the pelleted cells. The cells can be resuspended in a buffered solution such as phosphate-buffered saline (PBS). After centrifuging the cell suspension to obtain a cell pellet, the cells can be lysed to extract DNA, e.g., gDNA. See, e.g., Ausubel et al., 2003, supra. The sample can be concentrated and/or purified to isolate DNA. All samples obtained from a subject, including those subjected to any sort of further processing, are considered to be obtained from the subject. Routine methods can be used to extract genomic DNA from a biological sample, including, for example, phenol extraction. Alternatively, genomic DNA can be extracted with kits such as the QIAamp® Tissue Kit (Qiagen, Chatsworth, Calif.) and the Wizard® Genomic DNA purification kit (Promega). Non-limiting examples of sources of samples include urine, blood, and tissue.

The copy number, absence or presence of an allele or genotype associated SZ as described herein can be determined using methods known in the art. For example, gel electrophoresis, capillary electrophoresis, size exclusion chromatography, sequencing, and/or arrays can be used to detect the presence or absence of the allele or genotype. Amplification of nucleic acids, where desirable, can be accomplished using methods known in the art, e.g., PCR. In one example, a sample (e.g., a sample comprising genomic DNA), is obtained from a subject. The DNA in the sample is then examined to identify or detect the presence of an allele or genotype as described herein. The allele or genotype can be identified or determined by any method described herein, e.g., by sequencing or by hybridization of the gene in the genomic DNA, RNA, or cDNA to a nucleic acid probe, e.g., a DNA probe (which includes cDNA and oligonucleotide probes) or an RNA probe. The nucleic acid probe can be designed to specifically or preferentially hybridize with a particular polymorphic variant.

Other methods of nucleic acid analysis can include direct manual sequencing (Church and Gilbert, Proc. Natl. Acad. Sci. USA 81:1991-1995 (1988); Sanger et al., Proc. Natl. Acad. Sci. USA 74:5463-5467 (1977); Beavis et al., U.S. Pat. No. 5,288,644); automated fluorescent sequencing; single-stranded conformation polymorphism assays (SSCP) (Schafer et al., Nat. Biotechnol. 15:33-39 (1995)); clamped denaturing gel electrophoresis (CDGE); two-dimensional gel electrophoresis (2DGE or TDGE); conformational sensitive gel electrophoresis (CSGE); denaturing gradient gel electrophoresis (DGGE) (Sheffield et al., Proc. Natl. Acad. Sci. USA 86:232-236 (1989)); denaturing high performance liquid chromatography (DHPLC, Underhill et al., Genome Res. 7:996-1005 (1997)); infrared matrix-assisted laser desorption/ionization (IR-MALDI) mass spectrometry (WO 99/57318); mobility shift analysis (Orita et al., Proc. Natl. Acad. Sci. USA 86:2766-2770 (1989)); restriction enzyme analysis (Flavell et al., Cell 15:25 (1978); Geever et al., Proc. Natl. Acad. Sci. USA 78:5081 (1981)); quantitative real-time PCR (Raca et al., Genet Test 8(4):387-94 (2004)); heteroduplex analysis; chemical mismatch cleavage (CMC) (Cotton et al., Proc. Natl. Acad. Sci. USA 85:4397-4401 (1985)); RNase protection assays (Myers et al., Science 230:1242 (1985)); use of polypeptides that recognize nucleotide mismatches, e.g., E. coli mutS protein; allele-specific PCR, and combinations of such methods. See, e.g., Gerber et al., U.S. Patent Publication No. 2004/0014095 which is incorporated herein by reference in its entirety.

Sequence analysis can also be used to detect specific polymorphic variants. For example, polymorphic variants can be detected by sequencing exons, introns, 5′ untranslated sequences, or 3′ untranslated sequences. A sample comprising DNA or RNA is obtained from the subject. PCR or other appropriate methods can be used to amplify a portion encompassing the polymorphic site, if desired. The sequence is then ascertained, using any standard method, and the presence of a polymorphic variant is determined. Real-time pyrophosphate DNA sequencing is yet another approach to detection of polymorphisms and polymorphic variants (Alderborn et al., Genome Research 10(8):1249-1258 (2000)). Additional methods include, for example, PCR amplification in combination with denaturing high performance liquid chromatography (dHPLC) (Underhill et al., Genome Research 7(10):996-1005 (1997)).

In order to detect polymorphisms and/or polymorphic variants, it will frequently be desirable to amplify a portion of genomic DNA (gDNA) encompassing the polymorphic site. Such regions can be amplified and isolated by PCR using oligonucleotide primers designed based on genomic and/or cDNA sequences that flank the site. PCR refers to procedures in which target nucleic acid (e.g., genomic DNA) is amplified in a manner similar to that described in U.S. Pat. No. 4,683,195, and subsequent modifications of the procedure described therein. Generally, sequence information from the ends of the region of interest or beyond are used to design oligonucleotide primers that are identical or similar in sequence to opposite strands of a potential template to be amplified. See e.g., PCR Primer: A Laboratory Manual, Dieffenbach and Dveksler, (Eds.); McPherson et al., PCR Basics: From Background to Bench (Springer Verlag, 2000); Mattila et al., Nucleic Acids Res., 19:4967 (1991); Eckert et al., PCR Methods and Applications, 1:17 (1991); PCR (eds. McPherson et al., IRL Press, Oxford); and U.S. Pat. No. 4,683,202. Other amplification methods that may be employed include the ligase chain reaction (LCR) (Wu and Wallace, Genomics 4:560 (1989), Landegren et al., Science 241:1077 (1988), transcription amplification (Kwoh et al., Proc. Natl. Acad. Sci. USA 86:1173 (1989)), self-sustained sequence replication (Guatelli et al., Proc. Nat. Acad. Sci. USA 87:1874 (1990)), and nucleic acid based sequence amplification (NASBA). Guidelines for selecting primers for PCR amplification are well known in the art. See, e.g., McPherson et al., PCR Basics: From Background to Bench, Springer-Verlag, 2000. A variety of computer programs for designing primers are available, e.g., ‘Oligo’ (National Biosciences, Inc, Plymouth Minn.), MacVector (Kodak/IBI), and the GCG suite of sequence analysis programs (Genetics Computer Group, Madison, Wis. 53711).

In some cases, PCR conditions and primers can be developed that amplify a product only when the variant allele is present or only when the wild type allele is present (MSPCR or allele-specific PCR). For example, patient DNA and a control can be amplified separately using either a wild type primer or a primer specific for the variant allele. Each set of reactions is then examined for the presence of amplification products using standard methods to visualize the DNA. For example, the reactions can be electrophoresed through an agarose gel and the DNA visualized by staining with ethidium bromide or other DNA intercalating dye. In DNA samples from heterozygous patients, reaction products would be detected in each reaction.

Real-time quantitative PCR can also be used to determine copy number. Quantitative PCR permits both detection and quantification of specific DNA sequence in a sample as an absolute number of copies or as a relative amount when normalized to DNA input or other normalizing genes. A key feature of quantitative PCR is that the amplified DNA product is quantified in real-time as it accumulates in the reaction after each amplification cycle. Methods of quantification can include the use of fluorescent dyes that intercalate with double-stranded DNA, and modified DNA oligonucleotide probes that fluoresce when hybridized with a complementary DNA.

The first report of extensive copy number variation (CNV) in the human genome used intensity analysis of microarray data to document numerous examples of genes that vary in copy number (Redon et al., Nature 444(7118):444-54 (2006)). Subsequent studies have shown that certain copy number variants are associated with complex genetic diseases such as SZ (Walsh et al., Science 320(5875):539-43 (2008); and Stone et al., Nature 455(7210):237-41 (2008)).

In some embodiments, a peptide nucleic acid (PNA) probe can be used instead of a nucleic acid probe in the hybridization methods described above. PNA is a DNA mimetic with a peptide-like, inorganic backbone, e.g., N-(2-aminoethyl)glycine units, with an organic base (A, G, C, T or U) attached to the glycine nitrogen via a methylene carbonyl linker (see, e.g., Nielsen et al., Bioconjugate Chemistry, The American Chemical Society, 5:1 (1994)). The PNA probe can be designed to specifically hybridize to a nucleic acid comprising a polymorphic variant conferring susceptibility to or indicative of the presence of, for example, SZ.

In some cases, allele-specific oligonucleotides can also be used to detect the presence of a polymorphic variant. For example, polymorphic variants can be detected by performing allele-specific hybridization or allele-specific restriction digests. Allele specific hybridization is an example of a method that can be used to detect sequence variants, including complete haplotypes of a subject (e.g., a mammal such as a human). See Stoneking et al., Am. J. Hum. Genet. 48:370-382 (1991); and Prince et al., Genome Res. 11:152-162 (2001). An “allele-specific oligonucleotide” (also referred to herein as an “allele-specific oligonucleotide probe”) is an oligonucleotide that is specific for particular a polymorphism can be prepared using standard methods (see Ausubel et al., Current Protocols in Molecular Biology, supra). Allele-specific oligonucleotide probes typically can be approximately 10-50 base pairs, preferably approximately 15-30 base pairs, that specifically hybridizes to a nucleic acid region that contains a polymorphism. Hybridization conditions are selected such that a nucleic acid probe can specifically bind to the sequence of interest, e.g., the variant nucleic acid sequence. Such hybridizations typically are performed under high stringency as some sequence variants include only a single nucleotide difference. In some cases, dot-blot hybridization of amplified oligonucleotides with allele-specific oligonucleotide (ASO) probes can be performed. See, for example, Saiki et al., Nature (London) 324:163-166 (1986).

In some embodiments, allele-specific restriction digest analysis can be used to detect the existence of a polymorphic variant of a polymorphism, if alternate polymorphic variants of the polymorphism result in the creation or elimination of a restriction site. Allele-specific restriction digests can be performed in the following manner. A sample containing genomic DNA is obtained from the individual and genomic DNA is isolated for analysis. For nucleotide sequence variants that introduce a restriction site, restriction digest with the particular restriction enzyme can differentiate the alleles. In some cases, polymerase chain reaction (PCR) can be used to amplify a region comprising the polymorphic site, and restriction fragment length polymorphism analysis is conducted (see Ausubel et al., Current Protocols in Molecular Biology, supra). The digestion pattern of the relevant DNA fragment indicates the presence or absence of a particular polymorphic variant of the polymorphism and is therefore indicative of the presence or absence of susceptibility to SZ. For sequence variants that do not alter a common restriction site, mutagenic primers can be designed that introduce a restriction site when the variant allele is present or when the wild type allele is present. For example, a portion of a nucleic acid can be amplified using the mutagenic primer and a wild type primer, followed by digest with the appropriate restriction endonuclease.

In some embodiments, fluorescence polarization template-directed dye-terminator incorporation (FP-TDI) is used to determine which of multiple polymorphic variants of a polymorphism is present in a subject (Chen et al., Genome Research 9(5):492-498 (1999)). Rather than involving use of allele-specific probes or primers, this method employs primers that terminate adjacent to a polymorphic site, so that extension of the primer by a single nucleotide results in incorporation of a nucleotide complementary to the polymorphic variant at the polymorphic site.

In some cases, DNA containing an amplified portion may be dot-blotted, using standard methods (see Ausubel et al., Current Protocols in Molecular Biology, supra), and the blot contacted with the oligonucleotide probe. The presence of specific hybridization of the probe to the DNA is then detected. Specific hybridization of an allele-specific oligonucleotide probe (specific for a polymorphic variant indicative of susceptibility to an SSD (e.g., SZ)) to DNA from the subject is indicative of susceptibility to an SSD (e.g., SZ).

The methods can include determining the genotype of a subject with respect to both copies of the polymorphic site present in the genome. For example, the complete genotype may be characterized as −/−, as −/+, or as +/+, where a minus sign indicates the presence of the reference or wild type sequence at the polymorphic site, and the plus sign indicates the presence of a polymorphic variant other than the reference sequence. If multiple polymorphic variants exist at a site, this can be appropriately indicated by specifying which ones are present in the subject. Any of the detection means described herein can be used to determine the genotype of a subject with respect to one or both copies of the polymorphism present in the subject's genome.

Methods of nucleic acid analysis to detect polymorphisms and/or polymorphic variants can include, e.g., microarray analysis. Hybridization methods, such as Southern analysis, Northern analysis, or in situ hybridizations, can also be used (see Ausubel et al., Current Protocols in Molecular Biology, eds., John Wiley & Sons (2003)). To detect microdeletions, fluorescence in situ hybridization (FISH) using DNA probes that are directed to a putatively deleted region in a chromosome can be used. For example, probes that detect all or a part of a microsatellite marker can be used to detect microdeletions in the region that contains that marker.

In some embodiments, it is desirable to employ methods that can detect the presence of multiple polymorphisms (e.g., polymorphic variants at a plurality of polymorphic sites) in parallel or substantially simultaneously. Oligonucleotide arrays represent one suitable means for doing so. Other methods, including methods in which reactions (e.g., amplification, hybridization) are performed in individual vessels, e.g., within individual wells of a multi-well plate or other vessel may also be performed so as to detect the presence of multiple polymorphic variants (e.g., polymorphic variants at a plurality of polymorphic sites) in parallel or substantially simultaneously according to certain embodiments.

Nucleic acid probes can be used to detect and/or quantify the presence of a particular target nucleic acid sequence within a sample of nucleic acid sequences, e.g., as hybridization probes, or to amplify a particular target sequence within a sample, e.g., as a primer. Probes have a complimentary nucleic acid sequence that selectively hybridizes to the target nucleic acid sequence. In order for a probe to hybridize to a target sequence, the hybridization probe must have sufficient identity with the target sequence, i.e., at least 70% (e.g., 80%, 90%, 95%, 98% or more) identity to the target sequence. The probe sequence must also be sufficiently long so that the probe exhibits selectivity for the target sequence over non-target sequences. For example, the probe will be at least 20 (e.g., 25, 30, 35, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900 or more) nucleotides in length. In some embodiments, the probes are not more than 30, 50, 100, 200, 300, 500, 750, or 1000 nucleotides in length. Probes are typically about 20 to about 1×106 nucleotides in length. Probes include primers, which generally refers to a single-stranded oligonucleotide probe that can act as a point of initiation of template-directed DNA synthesis using methods such as PCR (polymerase chain reaction), LCR (ligase chain reaction), etc., for amplification of a target sequence.

The probe can be a test probe such as a probe that can be used to detect polymorphisms in a region described herein (e.g., polymorphisms as described herein). For example, the probe can hybridize to an allele described herein. In some embodiments, the probe can bind to another marker sequence associated with SZ, SPD, SD or BD as described herein.

Control probes can also be used. For example, a probe that binds a less variable sequence, e.g., repetitive DNA associated with a centromere of a chromosome, can be used as a control. Probes that hybridize with various centromeric DNA and locus-specific DNA are available commercially, for example, from Vysis, Inc. (Downers Grove, Ill.), Molecular Probes, Inc. (Eugene, Oreg.), or from Cytocell (Oxfordshire, UK). Probe sets are available commercially such from Applied Biosystems, e.g., the Assays-on-Demand SNP kits Alternatively, probes can be synthesized, e.g., chemically or in vitro, or made from chromosomal or genomic DNA through standard techniques. For example, sources of DNA that can be used include genomic DNA, cloned DNA sequences, somatic cell hybrids that contain one, or a part of one, human chromosome along with the normal chromosome complement of the host, and chromosomes purified by flow cytometry or microdissection. The region of interest can be isolated through cloning, or by site-specific amplification via the polymerase chain reaction (PCR). See, for example, Nath and Johnson, Biotechnic. Histochem. 73(1):6-22 (1998); Wheeless et al., Cytometry 17:319-326 (1994); and U.S. Pat. No. 5,491,224.

In some embodiments, the probes are labeled, e.g., by direct labeling, with a fluorophore, an organic molecule that fluoresces after absorbing light of lower wavelength/higher energy. A directly labeled fluorophore allows the probe to be visualized without a secondary detection molecule. After covalently attaching a fluorophore to a nucleotide, the nucleotide can be directly incorporated into the probe with standard techniques such as nick translation, random priming, and PCR labeling. Alternatively, deoxycytidine nucleotides within the probe can be transaminated with a linker. The fluorophore then is covalently attached to the transaminated deoxycytidine nucleotides. See, e.g., U.S. Pat. No. 5,491,224.

Fluorophores of different colors can be chosen such that each probe in a set can be distinctly visualized. For example, a combination of the following fluorophores can be used: 7-amino-4-methylcoumarin-3-acetic acid (AMCA), TEXAS RED™ (Molecular Probes, Inc., Eugene, Oreg.), 5-(and-6)-carboxy-X-rhodamine, lissamine rhodamine B, 5-(and-6)-carboxyfluorescein, fluorescein-5-isothiocyanate (FITC), 7-diethylaminocoumarin-3-carboxylic acid, tetramethylrhodamine-5-(and-6)-isothiocyanate, 5-(and-6)-carboxytetramethylrhodamine, 7-hydroxycoumarin-3-carboxylic acid, 6-[fluorescein 5-(and-6)-carboxamido]hexanoic acid, N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a diaza-3-indacenepropionic acid, eosin-5-isothiocyanate, erythrosin-5-isothiocyanate, and CASCADE™ blue acetylazide (Molecular Probes, Inc., Eugene, Oreg.). Fluorescently labeled probes can be viewed with a fluorescence microscope and an appropriate filter for each fluorophore, or by using dual or triple band-pass filter sets to observe multiple fluorophores. See, for example, U.S. Pat. No. 5,776,688. Alternatively, techniques such as flow cytometry can be used to examine the hybridization pattern of the probes. Fluorescence-based arrays are also known in the art.

In other embodiments, the probes can be indirectly labeled with, e.g., biotin or digoxygenin, or labeled with radioactive isotopes such as 32P and 3H. For example, a probe indirectly labeled with biotin can be detected by avidin conjugated to a detectable marker. For example, avidin can be conjugated to an enzymatic marker such as alkaline phosphatase or horseradish peroxidase. Enzymatic markers can be detected in standard colorimetric reactions using a substrate and/or a catalyst for the enzyme. Catalysts for alkaline phosphatase include 5-bromo-4-chloro-3-indolylphosphate and nitro blue tetrazolium. Diaminobenzoate can be used as a catalyst for horseradish peroxidase.

In another aspect, this document features arrays that include a substrate having a plurality of addressable areas, and methods of using them. At least one area of the plurality includes a nucleic acid probe that binds specifically to a sequence comprising a polymorphism listed in Tables 1-3 or Table A, and can be used to detect the absence or presence of said polymorphism, e.g., one or more SNPs, microsatellites, minisatellites, or indels, as described herein, to determine or identify an allele or genotype. For example, the array can include one or more nucleic acid probes that can be used to detect a polymorphism listed in Tables 1-3 or Table A. In some embodiments, the array further includes at least one area that includes a nucleic acid probe that can be used to specifically detect another marker associated with SZ or one associated with BD as described herein or known in the art. In some embodiments, the probes are nucleic acid capture probes.

Generally, microarray hybridization is performed by hybridizing a nucleic acid of interest (e.g., a nucleic acid encompassing a polymorphic site) with the array and detecting hybridization using nucleic acid probes. In some cases, the nucleic acid of interest is amplified prior to hybridization. Hybridization and detecting are generally carried out according to standard methods. See, e.g., Published PCT Application Nos. WO 92/10092 and WO 95/11995, and U.S. Pat. No. 5,424,186. For example, the array can be scanned to determine the position on the array to which the nucleic acid hybridizes. The hybridization data obtained from the scan is typically in the form of fluorescence intensities as a function of location on the array.

Arrays can be formed on substrates fabricated with materials such as paper, glass, plastic (e.g., polypropylene, nylon, or polystyrene), polyacrylamide, nitrocellulose, silicon, optical fiber, or any other suitable solid or semisolid support, and can be configured in a planar (e.g., glass plates, silicon chips) or three dimensional (e.g., pins, fibers, beads, particles, microtiter wells, capillaries) configuration. Methods for generating arrays are known in the art and include, e.g., photolithographic methods (see, e.g., U.S. Pat. Nos. 5,143,854; 5,510,270; and 5,527,681), mechanical methods (e.g., directed-flow methods as described in U.S. Pat. No. 5,384,261), pin-based methods (e.g., as described in U.S. Pat. No. 5,288,514), and bead-based techniques (e.g., as described in PCT US/93/04145). The array typically includes oligonucleotide hybridization probes capable of specifically hybridizing to different polymorphic variants. Oligonucleotide probes that exhibit differential or selective binding to polymorphic sites may readily be designed by one of ordinary skill in the art. For example, an oligonucleotide that is perfectly complementary to a sequence that encompasses a polymorphic site (i.e., a sequence that includes the polymorphic site, within it or at one end) will generally hybridize preferentially to a nucleic acid comprising that sequence, as opposed to a nucleic acid comprising an alternate polymorphic variant.

Oligonucleotide probes forming an array may be attached to a substrate by any number of techniques, including, without limitation, (i) in situ synthesis (e.g., high-density oligonucleotide arrays) using photolithographic techniques; (ii) spotting/printing at medium to low density on glass, nylon or nitrocellulose; (iii) by masking, and (iv) by dot-blotting on a nylon or nitrocellulose hybridization membrane. Oligonucleotides can be immobilized via a linker, including by covalent, ionic, or physical linkage. Linkers for immobilizing nucleic acids and polypeptides, including reversible or cleavable linkers, are known in the art. See, for example, U.S. Pat. No. 5,451,683 and WO98/20019. Alternatively, oligonucleotides can be non-covalently immobilized on a substrate by hybridization to anchors, by means of magnetic beads, or in a fluid phase such as in microtiter wells or capillaries. Immobilized oligonucleotide probes are typically about 20 nucleotides in length, but can vary from about 10 nucleotides to about 1000 nucleotides in length.

Arrays can include multiple detection blocks (i.e., multiple groups of probes designed for detection of particular polymorphisms). Such arrays can be used to analyze multiple different polymorphisms. Detection blocks may be grouped within a single array or in multiple, separate arrays so that varying conditions (e.g., conditions optimized for particular polymorphisms) may be used during the hybridization. For example, it may be desirable to provide for the detection of those polymorphisms that fall within G-C rich stretches of a genomic sequence, separately from those falling in A-T rich segments. General descriptions of using oligonucleotide arrays for detection of polymorphisms can be found, for example, in U.S. Pat. Nos. 5,858,659 and 5,837,832. In addition to oligonucleotide arrays, cDNA arrays may be used similarly in certain embodiments.

The methods described herein can include providing an array as described herein; contacting the array with a sample (e.g., a portion of genomic DNA that includes at least a portion of a human chromosome) and/or optionally, a different portion of genomic DNA (e.g., a portion that includes a different portion of a human chromosome, e.g., including another region associated with SZ), and detecting binding of a nucleic acid from the sample to the array. Optionally, the method includes amplifying nucleic acid from the sample, e.g., genomic DNA that includes a portion of a human chromosome described herein, and, optionally, a region that includes another region associated with SZ, prior to or during contact with the array.

In some aspects, the methods described herein can include using an array that can ascertain differential expression patterns or copy numbers of one or more genes in samples from normal and affected individuals (see, e.g., Redon et al., Nature 444(7118):444-54 (2006)). For example, arrays of probes to a marker described herein can be used to measure polymorphisms between DNA from a subject having an SSD (e.g., SZ), and control DNA, e.g., DNA obtained from an individual that does not have SZ, SPD, or SD, and has no risk factors for an SSD (e.g., SZ). Since the clones on the array contain sequence tags, their positions on the array are accurately known relative to the genomic sequence. Different hybridization patterns between DNA from an individual afflicted with an SSD (e.g., SZ) and DNA from a normal individual at areas in the array corresponding to markers in human chromosome 4p and/or 22q as described herein, and, optionally, one or more other regions associated with an SSD (e.g., SZ), are indicative of a risk of SZ. Methods for array production, hybridization, and analysis are described, e.g., in Snijders et al., Nat. Genetics 29:263-264 (2001); Klein et al., Proc. Natl. Acad. Sci. USA 96:4494-4499 (1999); Albertson et al., Breast Cancer Research and Treatment 78:289-298 (2003); and Snijders et al., “BAC microarray based comparative genomic hybridization,” in: Zhao et al. (eds), Bacterial Artificial Chromosomes: Methods and Protocols, Methods in Molecular Biology, Humana Press, 2002.

In another aspect, this document provides methods of determining the absence or presence of a haplotype associated with SZ as described herein, using an array described above. The methods can include providing a two dimensional array having a plurality of addresses, each address of the plurality being positionally distinguishable from each other address of the plurality having a unique nucleic acid capture probe, contacting the array with a first sample from a test subject who is suspected of having or being at risk for SZ, and comparing the binding of the first sample with one or more references, e.g., binding of a sample from a subject who is known to have an SSD (e.g., SZ), and/or binding of a sample from a subject who is unaffected, e.g., a control sample from a subject who neither has, nor has any risk factors for an SSD (e.g., SZ). In some embodiments, the methods can include contacting the array with a second sample from a subject who has an SSD (e.g., SZ); and comparing the binding of the first sample with the binding of the second sample. In some embodiments, the methods can include contacting the array with a third sample from a cell or subject that does not have SZ and is not at risk for SZ; and comparing the binding of the first sample with the binding of the third sample. In some embodiments, the second and third samples are from first or second-degree relatives of the test subject. In the case of a nucleic acid hybridization, binding with a capture probe at an address of the plurality, can be detected by any method known in the art, e.g., by detection of a signal generated from a label attached to the nucleic acid.

Communicating a Diagnosis or Risk Assessment

This document also provides methods and materials to assist medical or research professionals in determining whether or not a subject has or is at risk for developing an SSD (e.g., SZ). Medical professionals can be, for example, doctors, nurses, medical laboratory technologists, and pharmacists. Research professionals can be, for example, principle investigators, research technicians, postdoctoral trainees, and graduate students. A professional can be assisted by (1) determining whether specific polymorphic variants are present in a biological sample from a subject, and (2) communicating information about polymorphic variants to that professional.

After information about specific polymorphic variants is reported, a medical professional can take one or more actions that can affect patient care. For example, a medical professional can record information in the patient's medical record regarding the patient's risk of developing an SSD (e.g., SZ). In some cases, a medical professional can record information regarding risk assessment, or otherwise transform the patient's medical record, to reflect the patient's current medical condition. In some cases, a medical professional can review and evaluate a patient's entire medical record and assess multiple treatment strategies for clinical intervention of a patient's condition.

A medical professional can initiate or modify treatment after receiving information regarding a patient's diagnosis of or risk of developing an SSD (e.g., SZ), for example. In some cases, a medical professional can recommend a change in therapy. In some cases, a medical professional can enroll a patient in a clinical trial for, by way of example, detecting correlations between a haplotype as described herein and any measurable or quantifiable parameter relating to the outcome of the treatment as described above.

A medical professional can communicate information regarding a patient's diagnosis of risk of developing an SSD (e.g., SZ) to a patient or a patient's family. In some cases, a medical professional can provide a patient and/or a patient's family with information regarding an SSD (e.g., SZ) and diagnosis or risk assessment information, including treatment options, prognosis, and referrals to specialists. In some cases, a medical professional can provide a copy of a patient's medical records to a specialist.

A research professional can apply information regarding a subject's diagnosis of or risk of developing an SSD (e.g., SZ) to advance scientific research. For example, a researcher can compile data on wild specific polymorphic variants. In some cases, a research professional can obtain a subject's haplotype as described herein to evaluate a subject's enrollment, or continued participation, in a research study or clinical trial. In some cases, a research professional can communicate information regarding a subject's diagnosis of or risk of developing an SSD (e.g., SZ) to a medical professional. In some cases, a research professional can refer a subject to a medical professional.

Any appropriate method can be used to communicate information to another person (e.g., a professional). For example, information can be given directly or indirectly to a professional. For example, a laboratory technician can input a patient's polymorphic variant haplotype as described herein into a computer-based record. In some cases, information is communicated by making an physical alteration to medical or research records. For example, a medical professional can make a permanent notation or flag a medical record for communicating the risk assessment to other medical professionals reviewing the record. In addition, any type of communication can be used to communicate the risk assessment information. For example, mail, e-mail, telephone, and face-to-face interactions can be used. The information also can be communicated to a professional by making that information electronically available to the professional. For example, the information can be communicated to a professional by placing the information on a computer database such that the professional can access the information. In addition, the information can be communicated to a hospital, clinic, or research facility serving as an agent for the professional.

Articles of Manufacture

Also provided herein are articles of manufacture comprising a probe that hybridizes with a region of human chromosome as described herein and can be used to detect a polymorphism described herein. For example, any of the probes for detecting polymorphisms described herein can be combined with packaging material to generate articles of manufacture or kits. The kit can include one or more other elements including: instructions for use; and other reagents such as a label or an agent useful for attaching a label to the probe. Instructions for use can include instructions for diagnostic applications of the probe for making a diagnosis of or assessing risk of an SSD (e.g., SZ) in a method described herein. Other instructions can include instructions for attaching a label to the probe, instructions for performing in situ analysis with the probe, and/or instructions for obtaining a sample to be analyzed from a subject. In some cases, the kit can include a labeled probe that hybridizes to a region of human chromosome as described herein.

The kit can also include one or more additional reference or control probes that hybridize to the same chromosome or another chromosome or portion thereof that can have an abnormality associated with a particular endophenotype. A kit that includes additional probes can further include labels, e.g., one or more of the same or different labels for the probes. In other embodiments, the additional probe or probes provided with the kit can be a labeled probe or probes. When the kit further includes one or more additional probe or probes, the kit can further provide instructions for the use of the additional probe or probes. Kits for use in self-testing can also be provided. Such test kits can include devices and instructions that a subject can use to obtain a biological sample (e.g., buccal cells, blood) without the aid of a health care provider. For example, buccal cells can be obtained using a buccal swab or brush, or using mouthwash.

Kits as provided herein can also include a mailer (e.g., a postage paid envelope or mailing pack) that can be used to return the sample for analysis, e.g., to a laboratory. The kit can include one or more containers for the sample, or the sample can be in a standard blood collection vial. The kit can also include one or more of an informed consent form, a test requisition form, and instructions on how to use the kit in a method described herein. Methods for using such kits are also included herein. One or more of the forms (e.g., the test requisition form) and the container holding the sample can be coded, for example, with a bar code for identifying the subject who provided the sample.

Databases and Reports

Also provided herein are databases that include a list of polymorphisms as described herein, and wherein the list is largely or entirely limited to polymorphisms identified as useful for determining a diagnosis or susceptibility to an SSD (e.g., SZ) as described herein. The list is stored, e.g., on a flat file or computer-readable medium. The databases can further include information regarding one or more subjects, e.g., whether a subject is affected or unaffected, clinical information such as endophenotype, age of onset of symptoms, any treatments administered and outcomes (e.g., data relevant to pharmacogenomics, diagnostics or theranostics), and other details, e.g., about the disorder in the subject, or environmental or other genetic factors. The databases can be used to detect correlations between a particular haplotype and the information regarding the subject.

The methods described herein can also include the generation of reports, e.g., for use by a patient, care giver, payor, or researcher, that include information regarding a subject's response allele(s), and optionally further information such as treatments administered, treatment history, medical history, predicted response, and actual response. The reports can be recorded in a tangible medium, e.g., a computer-readable disk, a solid state memory device, or an optical storage device.

Engineered Cells

Also provided herein are engineered cells that harbor one or more polymorphism described herein, e.g., one or more polymorphisms associated with an SSD (e.g., SZ), e.g., a SNP or CNV. Such cells are useful for studying the effect of a polymorphism on physiological function, and for identifying and/or evaluating potential therapeutic agents such as anti-psychotics for the treatment of an SSD (e.g., SZ).

As one example, included herein are cells in which one of the various alleles of the genes described herein has been re-created that is associated with an increased risk of an SSD (e.g., SZ). Methods are known in the art for generating cells, e.g., by homologous recombination between the endogenous gene and an exogenous DNA molecule introduced into a cell, e.g., a cell of an animal. In some cases, the cells can be used to generate transgenic animals using methods known in the art.

The cells are preferably mammalian cells (e.g., neuronal type cells) in which an endogenous gene has been altered to include a polymorphism as described herein. Techniques such as targeted homologous recombinations, can be used to insert the heterologous DNA as described in, e.g., Chappel, U.S. Pat. No. 5,272,071; WO 91/06667, published in May 16, 1991.

EXAMPLES

The invention is further described in the following examples, which do not limit the scope of the invention described in the claims.

Example 1

Alleles Associated with Risk of Developing Schizophrenia

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), a large federally funded clinical trial designed to assess the efficacy of antipsychotics in a real world setting, is a valuable resource for determining the role of genes in drug response (Stroup et al., Schizophr. Bull. 29:15-31 (2003); Lieberman et al., N. Engl. J. Med. 353:1209-1223 (2005)). As part of the CATIE trial, SNP genotyping was performed for roughly half of the trial participants (Sullivan et al., Mol. Psychiatry. 13:570-584 (2008)). When combined with disease status, PANSS scores, and clinical drug response data, the genotyping data allows the identification of genetic variants (e.g., SNPs) that are statistically associated with specific responses to selected treatments.

The design of the CATIE study has been described in detail by others (see, e.g., Stroup et al., Schizophr. Bull. 29:15-31 (2003); Lieberman et al., N. Engl. J. Med. 353:1209-1223 (2005)). Briefly, 1460 subjects were randomly assigned one of several antipsychotics and those who did not respond or chose to quit their current medication were re-randomized to another drug. Details regarding SNP genotyping and quality control have been recently published (Sullivan et al., Mol. Psychiatry. 13:570-584 (2008)).

Genotype and phenotype data for the CATIE trial were made available to qualified researchers through the NIMH Center for Collaborative Genetic Studies on Mental Disorders. Data for 417 patients with schizophrenia and 419 unaffected controls self reported as having exclusively European ancestry were evaluated. This same patient population was described in a recent study by Sullivan and coworkers, which confirmed that there is no hidden stratification in the sample (Sullivan et al., Mol. Psychiatry. 13:570-584 (2008)).

For the CATIE study, individual cases were diagnosed as having SZ based on DSM-III/IV criteria.

To determine the influence of specific alleles on likelihood of having schizophrenia, case/control association using the PLINK 1.03 whole genome analysis toolset developed by Purcell and coworkers (Purcell et al., Am. J. Hum. Genet. 81:559-575 (2007)). For dichotomous comparisons of affected vs. unaffected individuals, PLINK calculates P values for the allele-specific chi-squared test and the odds ratio (OR; or relative risk) associated with the minor allele.

Table 1 lists alleles and genotypes influencing a diagnosis of SZ. 1170 SZ cases, and 1378 neurologically normal controls were used to identify these alleles. Test 1 lists gene, SEQ ID, NCBI RS #, allele, frequency of allele in cases, p-value, and Odds ratio for cases versus controls.

Example 2

Copy Number Variants (CNVs) that Contribute to Risk of SZ

Genotyping and phenotype data were obtained from the Genetic Analysis Information Network (GAIN) Database found at ncbi.nlm.nih.gov through dbGaP, at accession number PHS000017.v1.p1. Genotypes and associated phenotype data for the GAIN Genome-Wide Association Study of Schizophrenia were provided by P. Gejman, and genotyping of these samples was provided through the Genetic Association Information Network (GAIN). Golden Helix's SVS 7.0 was used to determine the Copy Number Variation at SNP for the genes of interest. Briefly, GAIN determine SNP and CNV variation for the samples using the Affymetrix 6.0 SNP and CNV array. Probes were hybridized to the array and the intensity of the signal recorded. These raw intensity values were imported into the SVS using the import function of the program. Then CNV status was determined using the following protocol. For the present example, 1170 SZ patients and 1378 neurologically normal controls were used to identify SNPS that can detect CNV regions influencing SZ risk.

Table 2 lists SNPs and associated genes, deletions of which alter the likelihood of SZ diagnosis. P-values were calculated from Chi-square values at each SNP. Odds Ratios were calculated by comparing the frequency of a CNV in cases versus controls using the formula (Casefreq*(1−Controlfreq))/(Controlfreq*(1−Casefreq)).

Table 3 lists SNPs and associated genes, duplications of which event that alter the likelihood of SZ diagnosis. P-values were calculated from Chi-square values at each SNP. Odds Ratios were calculated by comparing the frequency of a CNV in cases versus controls using the formula (Casefreq*(1−Controlfreq))/(Controlfreq*(1−Casefreq)).

Other Embodiments

It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

TABLE 1
Alleles influencing likelihood of schizophrenia diagnosis
GeneSeq IDNCBI RS#AlleleFrequencyPOdds Ratio
PIK3CD111121472A0.14560.02300001.40
RP1-21O18.1210803343G0.01560.03243003.20
AGBL4-C1ORF16532153324G0.40000.00509501.33
AGBL4-C1ORF16541934368C0.29000.01066001.33
AGBL4-C1ORF16556667780C0.35970.02038001.27
AGBL4-C1ORF16564285747C0.38930.00326901.35
AGBL4-C1ORF16573121522A0.34010.02240001.27
AGBL4-C1ORF165812043418T0.38780.00586101.33
AGBL4-C1ORF16593122291T0.42340.01755001.27
SCP2107546714T0.13600.02319001.41
LRP8115174A0.36630.00448800.75
LRP8122297660A0.38290.01124000.78
LRP8132297657A0.35210.02760000.80
PRKACB146701486A0.24760.01575001.33
PRKACB152642186G0.23500.04008001.28
CGN161573129T0.13650.00798400.70
OLFML2B1712025136C0.27920.00025071.52
DPT181018453C0.50480.00533901.32
SEC16B19943762A0.08590.00977800.66
SEC16B204652279A0.08590.01417000.67
MR1213845422A0.19330.00524100.72
LAMC1226424888A0.42530.00244700.74
LAMC1232274984C0.42340.00325100.75
LAMC1242027085A0.42460.00442300.76
KCNK2252841598G0.51880.00004221.51
KCNK22610779634T0.34840.00323301.36
KCNK2272123331G0.38140.03518001.25
KCNK22817024179C0.18590.03301001.33
KCNK2294655272A0.52030.01447001.27
KCNK23010779647T0.38040.00956301.31
KCNK2316684084G0.31230.04044001.25
KCNK23210779651C0.31400.04535001.25
KCNK23310494994A0.25300.01966001.31
ESRRG341984137C0.43320.01880000.79
ESRRG3512037068C0.17450.02641001.36
ESRRG3612033378A0.17110.04777001.31
GNG437508208G0.38640.04032001.23
RYR2382169902A0.07350.01021000.64
RYR239515474C0.22000.02372001.32
RYR2404659819T0.45690.00947800.78
FMN2411542400G0.47090.03877000.82
RGS742191735A0.42940.04960001.22
PLD5432036407C0.32540.03402001.26
C2ORF4644182971C0.27460.02137001.30
C2ORF46453102945C0.17230.00560101.47
C2ORF46462562011C0.18190.01601001.38
KCNF1471317761A0.36230.00311201.36
KCNF1484669647T0.22650.03781001.29
KCNF1494669651T0.18500.03881001.32
ASXL2509309437T0.20330.00097171.54
CRIM1514670549T0.46060.04189001.22
CRIM1522049367A0.30650.03010001.27
CRIM1533770876C0.43180.03749001.23
CRIM1543755197A0.30380.00377200.74
CRIM15511681392T0.29950.01252000.77
HAAO563816182A0.27450.00540101.37
PLEKHH25717414362A0.23070.00384101.43
PRKCE586732900T0.45220.01365001.28
PRKCE594953270G0.46770.03078001.24
FBXO1160874869G0.50240.02755001.24
PSME461805404C0.26800.00590700.74
PSME46210183655T0.38620.03642000.81
PSME46317045488G0.23390.00557700.73
ACYP2646721970A0.21380.00073300.68
CCDC85A6510460558A0.27090.00025750.68
AAK1662871965T0.43200.02143001.26
AAK1673821277G0.41150.01562001.28
AAK1686546534T0.30670.04518001.24
AAK1696712370C0.29900.01700001.30
AAK17012713679G0.37770.00485001.34
AAK17110779953G0.30620.03173001.26
AAK17212471316G0.43790.00687801.31
CTNNA27717339556C0.31660.00129701.43
CTNNA2782861914G0.32700.00429601.36
CTNNA2792060393A0.45450.00488901.32
CTNNA28017018905C0.09140.00242501.80
NAP58510176860C0.21290.02477000.77
LRP1B862171107A0.30430.02994001.27
LRP1B8710496906A0.36290.00149000.73
LRP1B8810183142T0.52910.00169301.36
LRP1B891369542T0.48300.00645301.31
LRP1B9012623563A0.41490.01924000.79
LRP1B9113382235G0.06630.00811000.62
KYNU9210176234A0.36420.02816000.80
KYNU936429997C0.39260.02937000.81
KYNU943816193A0.19810.04853001.29
KIF5C954667369C0.36180.04197000.81
CACNB49613421383T0.18850.01513000.75
CACNB49712693235C0.22970.01159000.75
FMNL2982164402G0.25300.01778000.77
FMNL2994664114T0.28170.00026340.68
FMNL210017327752A0.23800.00513500.73
FMNL21012346182G0.33290.01276000.78
FMNL210210497108C0.11580.01382000.70
FMNL210310497111A0.12080.01918000.72
FMNL210411682487C0.33410.01278000.78
PKP41052528593A0.31620.02888000.80
PKP41062711035C0.06600.04444000.69
SCN7A10711900439A0.31250.02478000.79
CERKL10810490688T0.34250.03152001.25
CERKL109895901A0.34810.03662001.24
PDE1A1103769794C0.18240.04445000.78
PARD3B1117559302T0.29900.01174000.77
NRP211213396083C0.47600.04403001.22
PIP5K311310497899T0.03230.04212001.95
CNTN611517038701G0.06490.00032312.43
CNTN41161502582T0.19930.02145001.34
CNTN411713092590G0.30070.01091000.77
CNTN411817194455T0.36590.01142000.78
CNTN41191551997C0.28760.01799000.78
ITPR11214685803A0.46390.04563001.22
IRAK21226804954A0.42940.01492001.28
ATP2B212313100027T0.07850.00231800.60
ATP2B21249860273T0.07040.01529000.65
SLC6A61252241780C0.19010.03166000.77
SLC6A61262304510G0.14320.02097000.74
DAZL127890640A0.15940.00066431.65
DAZL1284234537C0.15160.00710201.49
ARPP-21129735353A0.44530.02801001.25
ARPP-2113011920715T0.44710.04148001.23
STAC13117035045T0.20410.01464000.75
STAC1324678878C0.35560.02786000.80
ULK41337627972A0.48090.03971001.22
ULK413411129908G0.51320.02768001.24
ULK41357618902G0.30370.01921001.30
ULK41369878069G0.37230.04961001.22
ULK41371495696C0.45660.04490001.22
ZNF16713813081859G0.28760.03957000.80
CACNA2D313917054677A0.20050.00698701.42
FLNB14012632456A0.28520.01658001.31
FHIT14213320646A0.45230.00198501.37
FHIT1437631246T0.44870.00342801.34
FHIT1449875228T0.18110.04225001.31
FHIT1451470035A0.44220.00750201.31
FHIT1469843007T0.39710.02096001.26
FHIT1474688167C0.29550.04510001.25
PRICKLE214817665101G0.19380.04326000.79
ADAMTS91499847307T0.01670.00732904.73
ADAMTS91506787633G0.01310.01221005.56
MAGI11517612634C0.51810.00538601.32
MAGI11527612636G0.51800.00902001.29
MAGI11537612644C0.51810.01048001.29
FOXP11542597312C0.35650.03169001.25
GBE11572307058T0.31080.01688001.30
GBE11587613144T0.31150.02036001.29
GBE11593772891A0.22710.03985000.79
EPHA616016838196A0.05030.03049000.64
PLCXD216313074817G0.41120.01317000.78
PLCXD21644284954C0.41570.01461000.78
PLCXD216513079085C0.41610.02078000.80
PLCXD21666768713A0.41630.03129000.81
PLCXD216712490166A0.42330.04351000.82
EPHB116839704A0.46380.03439000.81
SPSB41697620622A0.24520.00548501.40
SPSB41706780365C0.17830.00076461.60
SPSB41712086180G0.12710.00183601.66
SERPINI21724955673C0.50990.00960701.30
SERPINI217317246389C0.27150.01865001.31
SERPINI217413062550C0.48420.02257001.25
TNIK1759824475G0.26490.00459000.74
PLD1176187229T0.41710.02455001.25
PLD1177181715T0.40770.03434001.24
NLGN117910936780G0.08310.00150800.60
NLGN118012634066A0.08270.00173800.60
NLGN11819828801T0.06700.01400000.64
LEPREL11829835230A0.22260.00278800.71
LEPREL11831447935T0.18960.00515300.72
LEPREL11846444412T0.28590.00405100.74
LEPREL11851447936C0.20260.01040000.74
LEPREL11867632740C0.30500.03015000.80
LEPREL11871526031C0.20410.04061000.79
UBXD71886774540T0.45090.03242000.81
UBXD71899841810C0.45230.04506000.82
UBXD71909847223T0.45470.04508000.82
SLC2A91911568318C0.23390.04442001.27
SLC2A91924697692T0.21240.04777001.28
SLC2A91933733591A0.16790.04318000.78
LDB2194157631G0.07280.02049000.67
LDB2195284210T0.07040.03399000.69
KIAA123920317575883A0.16500.02368000.75
KIAA123920417575897T0.16990.03411000.77
UBE2K205192779A0.18350.00049610.66
LIMCH12066447080G0.42630.00483501.33
LIMCH12076447081G0.42580.00686701.31
LIMCH12084610372G0.42590.00821801.31
LIMCH12094861118A0.41950.01152001.29
LOC38920721113105520T0.34740.00060470.71
LOC3892072129994547A0.35070.00195000.73
LOC3892072131561147G0.29930.00384200.74
SCD52143897960A0.17910.00689900.72
SCD521517352017G0.13250.03836000.75
HERC32162972021A0.27330.02209001.30
HERC32173017906G0.29770.03969001.26
FAM13A12187657817T0.17780.01875001.37
FAM13A121912507401C0.21750.02005001.34
COL25A12209996734A0.39730.04760001.22
ANK222111942005G0.15550.03802001.34
CAMK2D22211098193T0.28710.04429001.25
NDST32236534079A0.21460.04337000.79
NDST32244576085G0.11080.00173900.64
GPR10322513110738G0.20690.00250701.48
MAML32263796633G0.07760.04626000.71
IL152272139383T0.51320.02749001.24
IL152281389099T0.31940.00568000.75
IL152291389098T0.50480.03150001.23
INPP4B2341497389T0.34710.00575800.76
INPP4B23617715707G0.30260.02514000.79
POU4F22401104532A0.11770.00041480.61
POU4F22411394279G0.11870.00042320.61
DCLK22426535725A0.45420.02349001.25
FSTL52442082669G0.19530.00161501.53
FSTL52456814301T0.32130.02369000.79
TLL124617633393T0.02930.00800402.73
PALLD247924511T0.41990.00874901.30
PALLD24810033898C0.49390.04557001.22
CASP32499685847G0.44260.01087000.78
CASP32502720376C0.44390.01462000.79
PLEKHG4B2516554947G0.31280.00692701.35
PLEKHG4B25217559144T0.45450.02690001.25
AHRR2532721004T0.30750.00047551.48
AHRR2542721012G0.25550.00121001.48
DNAH52606554811G0.40100.01867000.79
DNAH52612401810G0.35320.01868000.79
DNAH526510513155A0.33290.00235501.39
DNAH52667709692C0.20940.00177400.70
DNAH52689885366C0.43900.00022411.45
DNAH52691867679T0.40100.00597501.32
DNAH52706896894C0.39690.00609901.32
DNAH527116902953G0.31780.03727001.25
DNAH52729312854C0.31220.04686001.24
DNAH5273339428T0.52400.00204901.35
DNAH5274339424T0.24460.01355001.34
CDH102757714498A0.18430.04820000.79
CDH102761896890T0.22430.04997000.80
SLC45A227710461928G0.39500.02603000.80
SLC45A227835389G0.04650.01889001.89
SLC1A32791645651A0.36160.01721001.28
SLC1A32803776569G0.47470.00827001.30
EGFLAM2814869580T0.12830.00387301.59
EGFLAM2822589787A0.08370.03686001.50
EGFLAM2832434504A0.45800.01057001.29
EGFLAM2841428263C0.28880.01263001.33
EGFLAM2859292705A0.08970.00155901.86
EGFLAM2862731979C0.16070.01566001.41
ITGA22887719848A0.28380.03858001.26
ELOVL72904700394T0.52400.00827301.30
ELOVL729117332824C0.39610.04975000.82
TNPO12927709640C0.34680.00002691.58
TNPO1293153320T0.18150.00242901.51
TNPO129434653T0.17900.00321201.50
TNPO1295266444C0.17660.00450201.48
TNPO12962548331A0.42700.00016190.69
FCHO2297478575C0.50240.00019571.45
FCHO2298185435G0.17310.01161001.42
FCHO22992277017C0.32440.04170001.25
CMYA53006880680C0.09810.01606001.54
CMYA53013828611G0.07400.01823001.64
CMYA53021991483G0.37500.03849001.24
THBS4303256444C0.18420.02792001.34
THBS43047736549A0.14960.01859001.42
VCAN305178024A0.37890.04230001.23
MEF2C306700592G0.42240.02153001.26
GPR9830716868917G0.05860.03099000.66
GPR983092222244A0.37010.04737001.23
FBXL1731112519388T0.19400.02057001.35
FBXL1731212189428G0.19020.02534001.34
FBXL173167731562C0.18430.01223001.40
FBXL1731810515385C0.18500.02514001.35
FBXL1731911242664G0.17950.03121001.34
PJA23201045706A0.42210.01791001.27
PJA23212963046T0.37410.02958001.25
SNX23224343835C0.39420.00151700.73
SNX23234835894C0.29830.00555000.75
SNX23246872932T0.48190.00093751.39
SNX23253822367G0.47950.00245101.35
SNX232610519715A0.29980.00784000.76
SNX23272407403G0.37080.02282001.27
SNX2432827740T0.48320.00162301.37
SNX243296888023T0.30140.00510100.75
SNX24330246286T0.39250.03007001.25
SNX24331246266C0.39270.03783001.24
SNX243321038078T0.12950.03184001.40
SNX2433330028C0.34620.03942001.24
SNX24334385996G0.35840.04069001.24
ADAMTS1933530651G0.36280.02293001.27
TRPC7336950714G0.11960.00056321.80
TRPC73372649691A0.14460.00674001.51
CTNNA1338906695G0.27180.00035550.68
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CCBE197417065761C0.09790.04330000.73
CCBE197512969965A0.20170.02122001.34
CDH79777228669T0.30650.04278001.25
CDH79782628210G0.21410.00929200.74
CDH79792587427A0.33170.02497000.80
CDH79802587428T0.28110.00639800.75
TXNDC10981309242G0.15060.00007641.84
FERMT19836516104T0.12290.00027561.85
FERMT198416991866C0.11930.00050181.81
PLCB19856055513G0.44350.00607300.76
PLCB49866056653G0.14110.03849000.76
MACROD29876079910C0.10850.00087391.83
MACROD29886043402A0.06270.04749001.56
MACROD2989463020G0.42480.00604400.76
MACROD29906135667T0.33050.04634000.82
KIF16B9916044051T0.18030.00007081.76
KIF16B992720592T0.31380.04419001.24
MAPRE1993410488A0.39590.00217800.74
MAPRE1994242529C0.33530.00063921.44
ZSWIM39961967656A0.46400.00357401.34
ZSWIM39976514065C0.41040.00336301.35
ZSWIM39981045493G0.43150.04713001.22
SNAI19996020157A0.14680.02984000.75
SNAI1100016995010C0.11470.01503000.70
SNAI110016091080G0.17270.00033090.65
SNAI110026020187G0.20640.00178600.70
C21ORF37100512483129C0.45190.00445700.76
C21ORF3710062824301A0.51670.00042031.41
NCAM210079979231G0.26440.00953001.35
PDE9A10112284976A0.38460.00190001.38
ARVCF10122239395G0.03220.02297000.57
ARVCF101312171109A0.19930.04483000.79
SGSM110145760752C0.31820.02996001.26
ASPHD210158140344A0.49510.00381201.33
ASPHD210166005042A0.45500.00417500.75
ASPHD210176519650C0.33730.00033300.70
HPS410185761552T0.45070.00008370.68
ARFGAP310191018448A0.42460.00774500.77
ARFGAP310206002963G0.42720.03021000.81
TTLL110211052160T0.32450.00888501.33
TTLL11022135002C0.47250.00791101.30
EFCAB61023137794A0.10670.04068000.74
EFCAB610245764310C0.08630.03186000.71
RIBC210256007043C0.16830.00046140.65

TABLE 2
CNV Deletions Influencing Schizophrenia Risk
GeneSeq IDNCBI RS#POdds Ratio
CTNNA28119300.0209617.99
CTNNA282101700200.0390206.85
CTNNA28367439800.032919>4.00
CTNNA284134231410.0439112.45
DNER11464368600.032919>4.00
ITPR112037924900.021448<0.17
ROBO115514576590.0316010.14
ROBO115638216030.0316010.14
KCNIP419676945870.0509470.58
STIM219745572500.0333060.58
STIM219845322230.0333060.58
STIM219942748290.0333060.58
STIM220046921280.0136720.43
STIM220176716710.0216960.36
INPP4B23031024390.035939<0.20
INPP4B23119071190.035939<0.20
INPP4B23226366450.021448<0.17
INPP4B2358816110.0301632.98
INPP4B239170161750.0104880.26
FSTL524376903420.0370090.28
DNAH525768766730.032919>4.00
DNAH525837770930.032919>4.00
DNAH525965548080.032919>4.00
DNAH526277158110.008964>6.00
DNAH5263105131530.008964>6.00
DNAH5264100396210.0500443.43
DNAH526768743490.0197945.14
DNAH526898853660.0197945.14
FBXL173132881800.0024200.44
FBXL173142881730.0001720.22
FBXL173172881460.035939<0.20
JARID234840858760.021448<0.17
JARID234922828270.035939<0.20
ELOVL5379109487440.0080600.81
ELOVL538025628980.0090140.81
ELOVL53817358600.0079270.81
ELOVL538220570240.0079270.81
ELOVL538314291460.0062390.80
ELOVL538420730400.0062390.80
ELOVL538594638950.0062390.80
ELOVL538622357230.0070900.81
ELOVL538713466030.0070900.81
ELOVL538894744760.0070900.81
ELOVL538922948670.0070900.81
ELOVL539093496600.0070900.81
ELOVL53919743230.0070900.81
ELOVL539269095920.0062390.80
ELOVL539393675200.0062390.80
ELOVL539493958540.0070900.81
ELOVL53952094850.0070900.81
ELOVL539693958560.0098600.81
ELOVL539777479260.0103710.81
ELOVL539877387880.0103710.81
ELOVL53992095000.0091670.81
ELOVL540093577600.0091670.81
ELOVL540193701960.0058690.80
ELOVL54022095170.0032170.79
ELOVL540393702010.0032170.79
ELOVL540415794540.0032170.79
ELOVL540594745070.0042350.80
ELOVL540692967110.0042350.80
ELOVL540714291430.0053420.80
NXPH144721072800.032919>4.00
NXPH1448100857200.0284601.78
NXPH144944557370.0284601.78
DGKB452171680910.0250561.73
DGKB45369723100.0335011.69
DGKB454126996190.0359390.32
DGKB455104994410.0359390.32
CALN1498117688920.0340940.35
CALN149919143810.0340940.35
MAGI2502126701340.0228480.21
PPP1R9A513102528560.0081061.28
PPP1R9A51464654480.0282951.38
PPP1R9A5158547170.0201371.29
PPP1R9A5168547370.0063790.70
PPP1R9A51769614150.0023040.70
PPP1R9A518173059910.0209611.31
PPP1R9A520117621130.0089140.73
PPP1R9A5238545200.0018731.50
NRCAM5324015730.0394820.70
NRCAM5354220110.0144690.74
NRCAM5364250130.0229801.33
KCND254298861900.0192351.41
SLC13A1547127064940.0289600.78
SLC13A154922225140.0047041.55
SLC13A155024026370.0444340.82
GRM855622995000.0281311.39
GRM8560132404180.0316010.80
GRM856147313300.0103130.70
GRM856222995230.0488650.79
GRM856321881870.0268571.60
GRM856441414150.0404241.38
GRM8565102268890.0491570.72
DGKI57247322550.0150551.27
DGKI57677813270.0463181.27
CNTNAP2580102617660.0164890.79
CNTNAP2581132285260.0237881.57
CNTNAP2588174171540.0138281.49
CNTNAP258916378450.0260911.96
PTPRN25912212470.0452311.91
PTPRN2593117676540.0231131.34
PTPRN2594102312530.0231130.33
PTPRN259577891110.0214482.30
CSMD15973417240.0011310.62
CSMD159970015510.0050541.79
CSMD160178192250.0433940.84
PSD361742985230.0105481.83
PSD361826344350.0254941.62
PSD361969870390.0029961.63
PSD3621101060320.0257910.61
PSD3625117783100.0162101.65
TOX640121150740.0468711.27
TOX641169246230.0175551.29
CSMD366218737460.0428830.80
CSMD3665126768480.0000062.32
CSMD366621234890.0200221.48
CSMD3667105051740.0262421.44
CSMD3669176023930.0227170.70
CSMD3671125457420.0488650.84
CSMD367369993480.0455000.74
CSMD367514029440.0335011.39
SAMD1267646314940.0323471.32
SAMD1267892975870.0025421.52
SAMD12679109558870.0010951.65
SAMD1268125145910.0054921.40
SAMD1268225146020.0444341.54
MTSS168638290370.0096961.29
MTSS168748715170.0474320.81
MTSS16889195440.0149700.79
KCNQ369724696250.0098054.58
KCNQ369824361340.0197945.14
COL22A170278426960.0091670.17
SMARCA2707169371230.0051672.76
FKTN72518587440.0418810.85
FKTN72627682940.0340940.84
FKTN727173098060.0310540.84
FKTN72825181060.0314180.84
FKTN72918587430.0259400.84
FKTN7308859540.0188000.83
FKTN731172511660.0151410.82
ASTN274070320280.00610210.30
CDK5RAP2742107601030.0488652.74
MYO3A770107645970.012993<0.14
JMJD1C772107617390.035939<0.20
JMJD1C773107617410.021448<0.17
ATE1788112001070.032919>4.00
ATE1790118180010.0351064.57
ATE1791107328240.0351064.57
ATE1792105101010.0197945.14
ATE1793107882210.0197945.14
ATE179437508350.0197945.14
ATE1795112002570.0351064.57
ATE1796112002600.0351064.57
ATE1797112002670.0351064.57
USH1C80620722300.0455000.40
USH1C80810763110.0397150.80
USH1C80921904530.0397150.80
USH1C81021904540.0374460.79
USH1C81271139350.0098050.45
USH1C81371063020.0093750.48
USH1C81420735820.0050820.45
DLG282565921420.0376670.66
DLG282619142030.021448<0.17
TSPAN9834108487840.0209617.99
NPAS387280224340.017062>5.00
NPAS3873118516670.0194570.13
PPP2R5E87965735220.0110955.72
RGS6881125869470.0112212.95
RGS688222392680.0112212.95
RGS688521395940.0126320.74
CCDC88C89949000750.0351064.57
A2BP192174044220.0340940.35
WWOX932169470950.00610210.30
CDH1394520616290.0122800.43
CCBE197618643070.035939<0.20
BMP7100321807820.004756>7.00

TABLE 3
CNV Duplications Influencing Schizophrenia Risk
GeneSeq IDNCBI RS#POdds Ratio
CTNNA273101893450.032919>4.00
CTNNA27437959940.017062>5.00
CTNNA27575716580.0209617.99
CTNNA27667415630.0488652.74
FHIT14122053530.0500443.43
CBLB161124974280.0292983.81
CBLB16267959610.0292983.81
NLGN117815531220.017062>5.00
STIM22027259810.0209617.99
LIMCH1210131133140.012993<0.14
INPP4B23326354290.035939<0.20
INPP4B23713910990.0169650.45
INPP4B23893081520.0509470.52
CTNND225568852240.035939<0.20
CTNND225621909890.0390206.85
DNAH526918676790.0488652.74
ITGA1287168762700.0390206.85
PDE4D289352850.021448<0.17
GPR98308100435640.0249122.42
GPR9831018527310.00610210.30
FBXL173152881720.0209617.99
FBXL173172881460.0110955.72
SERPINB634577516760.0426301.17
SFRPINB634613588690.0207221.20
JARID235093965910.032919>4.00
ATXN135122371660.032919>4.00
ATXN13527200060.032919>4.00
ATXN135322371650.032919>4.00
RNF144B3575772870.0034550.37
BTN3A137047129860.0455000.40
PDE7B42793857400.002963<0.10
DGKB45613677800.0209617.99
DGKB45714315380.017062>5.00
ABCA13487119838830.0001250.28
ABCA1348821170890.0008140.33
ABCA1348977780200.032919>4.00
WBSCR17494125381860.0390206.85
WBSCR174956484150.032919>4.00
CALN1496126731090.0235163.43
CALN1497102601830.0231130.33
CALN1500175034000.0002700.06
MAGI250178107780.0110955.72
MAGI2507102557100.032919>4.00
MAGI250977787070.021448<0.17
PPP1R9A5158547170.0058691.48
PPP1R9A51978063040.0244840.65
PPP1R9A520117621130.0474320.74
PPP1R9A52119184820.0197941.49
PPP1R9A5238545200.0019891.75
PPP1R9A5258545370.0136721.82
NRCAM5294097970.0482861.87
NRCAM5304495140.0104881.26
NRCAM5311075890.0263940.74
NRCAM5334042870.0372271.22
NRCAM5343698000.0029311.28
NRCAM5354220110.0027752.38
NRCAM537132367670.0169650.70
NRCAM53822842900.0038781.74
KCND2540121117910.0026561.50
KCND2541102248910.0061701.45
SLC13A155024026370.0199071.37
GRM855122994490.0088641.66
GRM855222377350.0240642.20
GRM855399426810.0240641.21
GRM855410747280.0471511.61
GRM85558861760.0212031.54
GRM8557104874590.0132911.42
GRM855814195080.0000071.78
GRM855920237350.0122801.87
GRM8565102268890.0240641.75
EXOC456611495500.0401861.38
EXOC456777832170.0488652.74
EXOC4568104881640.0054921.40
EXOC457069664030.0353132.10
DGKI57122788290.0029792.09
DGKI57247322550.0140651.32
DGKI57347284150.0029961.69
DGKI57417319130.0301631.28
DGKI57521135780.0080602.08
DGKI5777065610.0184813.21
CNTNAP2579174801330.0316011.43
CNTNAP258215487430.0329190.74
CNTNAP258378027080.000396>11.00
CNTNAP258420222260.0027151.66
CNTNAP258523731330.0096962.11
CNTNAP2586102705510.0000030.59
CNTNAP258769536790.0413891.81
PTPRN25902212420.0040980.72
PTPRN2596100812350.0259400.69
CSMD15973417240.0289600.75
CSMD16007503180.0242031.86
CSMD1602132543440.0061362.62
CSMD16038956960.0073721.65
CSMD1607170662960.0011310.52
PSD3620132597620.0101411.27
PSD36227475550.0120061.55
PSD362370074130.0135181.57
PSD362469934040.0186931.43
PSD3625117783100.0013892.01
PSD362615068940.0098054.58
TOX63878458000.0081511.85
TOX63947387320.0212031.62
CSMD3660105051820.0441710.71
CSMD366469940090.0000102.13
CSMD3665126768480.0488652.74
CSMD366810218760.0477151.39
CSMD36709647640.0002291.94
CSMD3672119956560.0240642.20
CSMD3674126805230.0340940.72
SAMD1267796428410.0000021.86
SAMD12680125419160.0080162.65
SAMD1268125145910.0040533.90
SAMD1268225146020.0045001.57
MTSS168638290370.0335010.73
MTSS1689109561920.0292982.05
MTSS169064702630.0401860.64
KCNQ36969779390.017062>5.00
KCNQ369724696250.002542>8.00
KCNQ369978325890.035939<0.20
KCNQ370013795820.035939<0.20
SMARCA2708109651130.0351064.57
CDK5RAP27419146170.0342941.94
MYO3A769127738560.035939<0.20
ANK377149482540.0112849.14
KCNMA177725693600.035939<0.2
GRK5787107879480.0197945.14
ATE17897534550.0292982.05
USH1C80771040830.0131411.66
USH1C80810763110.0063441.71
USH1C80921904530.0034551.77
USH1C81021904540.0166771.64
USH1C811177146730.0209617.99
DLG282465921410.032919>4.00
TSPAN9835108487890.004756>7.00
TSPAN983679693630.0488652.74
MTIF385137594340.0001816.05
MTIF385237594330.0011944.03
RGS68841496410.021448<0.17
CCDC88C9007471590.0351064.57
CDH139464514340.0112849.14
CA1095193035890.035939<0.20
ATRN98260765240.0008770.22
PTPRT99560166640.008964>6.00
CDH4100448123130.0344950.55
NCAM21008130522860.032919>4.00
NCAM2100928268150.0292983.81
NCAM210102325090.0500443.43

TABLE A
Summary of SNPs (NCBI Human Genome Reference Assembly Build 36.3)
Seq IDGeneChrPositionSeq IDGeneChrPosition
1PIK3CD19,655,8082RP1-21O18.1115,265,882
3AGBL4-C1ORF165149,012,5554AGBL4-C1ORF165149,046,634
5AGBL4-C1ORF165149,107,9176AGBL4-C1ORF165149,124,764
7AGBL4-C1ORF165149,132,4608AGBL4-C1ORF165149,133,207
9AGBL4-C1ORF165149,214,61010SCP2153,261,152
11LRP8153,485,31512LRP8153,504,903
13LRP8153,519,18314PRKACB184,323,437
15PRKACB184,343,59316CGN1149,764,000
17OLFML2B1160,247,12618DPT1166,964,218
19SEC16B1176,175,47520SEC16B1176,178,830
21MR11179,279,59422LAMC11181,352,319
23LAMC11181,374,06924LAMC11181,375,234
25KCNK21213,267,43326KCNK21213,269,771
27KCNK21213,286,96828KCNK21213,304,166
29KCNK21213,312,76530KCNK21213,393,108
31KCNK21213,405,68532KCNK21213,412,561
33KCNK21213,428,83034ESRRG1214,811,868
35ESRRG1214,951,99036ESRRG1214,952,115
37GNG41233,794,43938RYR21235,793,994
39RYR21235,885,63740RYR21236,061,906
41FMN21238,512,71942RGS71239,145,433
43PLD51240,426,89044C2ORF4628,321,006
45C2ORF4628,354,70046C2ORF4628,355,126
47KCNF1210,948,88148KCNF1210,981,799
49KCNF1210,999,21350ASXL2225,956,101
51CRIM1236,467,65852CRIM1236,521,723
53CRIM1236,532,53254CRIM1236,610,853
55CRIM1236,611,60456HAAO242,869,208
57PLEKHH2243,822,98658PRKCE245,919,740
59PRKCE245,927,15660FBXO11247,947,841
61PSME4253,970,30462PSME4254,064,285
63PSME4254,136,33364ACYP2254,201,406
65CCDC85A256,425,86766AAK1269,604,707
67AAK1269,637,78268AAK1269,650,512
69AAK1269,708,59870AAK1269,716,927
71AAK1269,740,26172AAK1269,768,980
73CTNNA2279,724,26374CTNNA2279,726,512
75CTNNA2279,728,81076CTNNA2279,734,051
77CTNNA2279,931,79378CTNNA2279,934,690
79CTNNA2279,942,00180CTNNA2280,337,745
81CTNNA2280,368,18382CTNNA2280,373,325
83CTNNA2280,377,21184CTNNA2280,624,319
85NAP52133,558,45186LRP1B2140,986,740
87LRP1B2142,371,55088LRP1B2142,377,358
89LRP1B2142,395,68290LRP1B2142,419,855
91LRP1B2142,598,63892KYNU2143,405,309
93KYNU2143,455,21194KYNU2143,516,377
95KIF5C2149,600,09196CACNB42152,587,594
97CACNB42152,632,72798FMNL22152,981,465
99FMNL22153,086,705100FMNL22153,096,733
101FMNL22153,097,194102FMNL22153,146,684
103FMNL22153,147,664104FMNL22153,159,182
105PKP42159,240,155106PKP42159,240,805
107SCN7A2166,998,337108CERKL2182,130,703
109CERKL2182,145,339110PDE1A2182,763,240
111PARD3B2205,659,848112NRP22206,441,948
113PIP5K32208,956,492114DNER2229,932,713
115CNTN631,414,974116CNTN432,326,831
117CNTN432,395,095118CNTN432,476,259
119CNTN432,509,772120ITPR134,688,162
121ITPR134,715,592122IRAK2310,234,114
123ATP2B2310,396,240124ATP2B2310,411,869
125SLC6A6314,495,168126SLC6A6314,495,564
127DAZL316,602,593128DAZL316,611,541
129ARPP-21335,817,608130ARPP-21335,819,665
131STAC336,433,107132STAC336,445,311
133ULK4341,455,051134ULK4341,476,741
135ULK4341,482,456136ULK4341,501,971
137ULK4341,507,368138ZNF167344,582,017
139CACNA2D3355,011,390140FLNB358,093,595
141FHIT360,782,868142FHIT361,135,266
143FHIT361,137,444144FHIT361,146,142
145FHIT361,159,361146FHIT361,182,117
147FHIT361,214,250148PRICKLE2364,140,810
149ADAMTS9364,500,753150ADAMTS9364,507,516
151MAGI1365,576,699152MAGI1365,576,717
153MAGI1365,576,735154FOXP1371,021,299
155ROBO1378,866,959156ROBO1378,867,259
157GBE1381,669,129158GBE1381,687,869
159GBE1381,859,450160EPHA6398,268,377
161CBLB3107,007,179162CBLB3107,007,333
163PLCXD23112,949,845164PLCXD23112,950,789
165PLCXD23112,953,907166PLCXD23112,960,464
167PLCXD23112,964,847168EPHB13136,129,897
169SPSB43142,287,637170SPSB43142,294,879
171SPSB43142,328,274172SERPINI23168,658,115
173SERPINI23168,672,301174SERPINI23168,681,607
175TNIK3172,402,113176PLD13172,790,551
177PLD13172,791,538178NLGN13174,870,074
179NLGN13175,493,649180NLGN13175,515,979
181NLGN13175,543,000182LEPREL13191,218,155
183LEPREL13191,244,878184LEPREL13191,245,227
185LEPREL13191,250,258186LEPREL13191,253,292
187LEPREL13191,261,577188UBXD73197,576,308
189UBXD73197,632,452190UBXD73197,636,526
191SLC2A949,480,639192SLC2A949,502,295
193SLC2A949,531,228194LDB2416,363,986
195LDB2416,365,914196KCNIP4420,459,978
197STIM2426,458,937198STIM2426,459,024
199STIM2426,459,062200STIM2426,462,717
201STIM2426,462,750202STIM2426,570,337
203KIAA1239437,005,415204KIAA1239437,007,192
205UBE2K439,464,805206LIMCH1441,213,350
207LIMCH1441,213,408208LIMCH1441,221,506
209LIMCH1441,223,320210LIMCH1441,317,805
211LOC389207442,652,288212LOC389207442,691,897
213LOC389207442,693,025214SCD5483,920,815
215SCD5483,923,596216HERC3489,803,447
217HERC3489,843,208218FAM13A1489,887,882
219FAM13A1489,915,913220COL25A14109,934,307
221ANK24114,340,609222CAMK2D4114,648,856
223NDST34119,186,644224NDST34119,256,090
225GPR1034122,487,863226MAML34140,897,308
227IL154142,764,901228IL154142,911,691
229IL154142,924,868230INPP4B4143,414,201
231INPP4B4143,421,104232INPP4B4143,436,219
233INPP4B4143,463,006234INPP4B4143,524,042
235INPP4B4143,547,226236INPP4B4143,566,886
237INPP4B4143,593,360238INPP4B4143,593,371
239INPP4B4143,610,749240POU4F24147,739,219
241POU4F24147,758,283242DCLK24151,378,402
243FSTL54162,611,763244FSTL54162,953,212
245FSTL54163,224,500246TLL14167,149,564
247PALLD4169,939,539248PALLD4169,971,032
249CASP34185,783,023250CASP34185,791,294
251PLEKHG4B5238,160252PLEKHG4B5241,719
253AHRR5401,598254AHRR5431,413
255CTNND2511,222,945256CTNND2511,637,342
257DNAH5513,780,350258DNAH5513,782,714
259DNAH5513,788,147260DNAH5513,795,858
261DNAH5513,802,952262DNAH5513,822,974
263DNAH5513,823,000264DNAH5513,825,457
265DNAH5513,841,886266DNAH5513,842,420
267DNAH5513,852,381268DNAH5513,854,786
269DNAH5513,875,140270DNAH5513,887,824
271DNAH5513,986,416272DNAH5513,989,500
273DNAH5514,032,397274DNAH5514,034,968
275CDH10524,728,325276CDH10524,738,958
277SLC45A2533,979,974278SLC45A2533,990,637
279SLC1A3536,670,315280SLC1A3536,675,215
281EGFLAM538,269,319282EGFLAM538,296,060
283EGFLAM538,337,535284EGFLAM538,357,424
285EGFLAM538,382,422286EGFLAM538,485,966
287ITGA1552,294,108288ITGA2552,425,212
289PDE4D558,692,313290ELOVL7560,152,959
291ELOVL7560,201,944292TNPO1572,123,236
293TNPO1572,174,208294TNPO1572,182,236
295TNPO1572,217,160296TNPO1572,292,936
297FCHO2572,374,865298FCHO2572,384,028
299FCHO2572,413,771300CMYA5579,058,467
301CMYA5579,070,418302CMYA5579,074,951
303THBS4579,376,918304THBS4579,415,294
305VCAN582,914,275306MEF2C588,138,619
307GPR98589,979,411308GPR98589,986,028
309GPR98590,071,845310GPR98590,428,377
311FBXL175107,223,636312FBXL175107,224,897
313FBXL175107,377,610314FBXL175107,380,193
315FBXL175107,381,014316FBXL175107,400,737
317FBXL175107,420,461318FBXL175107,556,166
319FBXL175107,612,678320PJA25108,742,197
321PJA25108,776,974322SNX25122,116,630
323SNX25122,137,822324SNX25122,173,535
325SNX25122,174,171326SNX25122,194,062
327SNX25122,201,930328SNX245122,232,671
329SNX245122,255,495330SNX245122,273,273
331SNX245122,283,900332SNX245122,309,550
333SNX245122,311,168334SNX245122,383,127
335ADAMTS195129,039,887336TRPC75135,708,380
337TRPC75135,713,994338CTNNA15138,167,176
339CTNNA15138,264,654340CTNNA15138,300,046
341ODZ25167,527,141342ODZ25167,606,948
343ODZ25167,621,874344ODZ25167,634,311
345SERPINB662,876,878346SERPINB662,926,223
347SLC22A2363,395,265348JARID2615,537,710
349JARID2615,545,369350JARID2615,624,264
351ATXN1616,755,137352ATXN1616,755,970
353ATXN1616,762,002354RNF144B618,526,687
355RNF144B618,530,528356RNF144B618,553,561
357RNF144B618,553,773358RNF144B618,561,748
359RNF144B618,566,740360RNF144B618,575,501
361SLC17A4625,876,893362SLC17A4625,892,460
363SLC17A1625,917,888364SLC17A1625,921,129
365SLC17A1625,937,638366SLC17A1625,939,191
367SLC17A1625,950,182368SLC17A3625,978,521
369SLC17A2626,067,106370BTN3A1626,504,182
371BTN3A1626,513,969372BTN3A1626,524,633
373BTN2A3626,532,708374BTN2A3626,534,466
375BTN3A3626,553,839376BTNL2632,463,841
377BTNL2632,482,600378LRFN2640,528,210
379ELOVL5653,213,187380ELOVL5653,221,300
381ELOVL5653,231,077382ELOVL5653,238,040
383ELOVL5653,238,244384ELOVL5653,242,957
385ELOVL5653,246,219386ELOVL5653,254,362
387ELOVL5653,257,221388ELOVL5653,257,463
389ELOVL5653,261,913390ELOVL5653,262,169
391ELOVL5653,267,506392ELOVL5653,271,049
393ELOVL5653,271,883394ELOVL5653,280,718
395ELOVL5653,282,407396ELOVL5653,284,867
397ELOVL5653,292,467398ELOVL5653,294,567
399ELOVL5653,296,096400ELOVL5653,298,093
401ELOVL5653,298,209402ELOVL5653,314,948
403ELOVL5653,318,131404ELOVL5653,341,053
405ELOVL5653,350,763406ELOVL5653,362,070
407ELOVL5653,372,444408RIMS1672,967,122
409KLHL32697,480,306410KLHL32697,589,639
411KLHL32697,595,870412KLHL32697,601,993
413KLHL32697,619,298414KLHL32697,673,659
415SLC22A166110,900,563416SLC22A166110,900,785
417SLC22A166110,903,098418HS3ST56114,502,447
419TRDN6123,982,387420TRDN6123,991,308
421TRDN6124,017,012422NKAIN26124,462,813
423EYA46133,642,955424EYA46133,643,088
425EYA46133,651,991426EYA46133,861,896
427PDE7B6136,206,096428PDE7B6136,218,421
429PDE7B6136,346,863430PLAGL16144,354,821
431PLAGL16144,355,380432UTRN6144,848,384
433SYNE16152,510,881434SYNE16152,511,829
435SYNE16152,553,368436TFB1M6155,655,424
437TFB1M6155,663,514438PARK26161,941,630
439PARK26161,952,077440PARK26162,026,087
441PDE10A6165,674,966442PDE10A6165,679,905
443SDK174,152,228444SDK174,153,102
445SDK174,158,337446SDK174,162,572
447NXPH178,590,239448NXPH178,633,152
449NXPH178,633,615450SCIN712,627,051
451SCIN712,634,312452DGKB714,357,487
453DGKB714,357,894454DGKB714,471,463
455DGKB714,472,219456DGKB714,529,482
457DGKB714,539,481458FERD3L719,167,340
459STK31723,760,554460SKAP2726,770,543
461SKAP2726,795,178462SKAP2726,814,684
463SKAP2726,827,213464SKAP2726,830,698
465SKAP2726,858,965466SKAP2726,880,921
467CREB5728,811,671468CREB5728,906,935
469CREB5728,953,482470CHN2729,215,509
471PDE1C732,037,670472PDE1C732,064,508
473PDE1C732,141,959474BMPER734,112,924
475BMPER734,176,289476BMPER734,184,882
477EEPD1736,280,985478EEPD1736,391,476
479VPS41738,798,875480VPS41738,806,116
481VPS41738,812,386482VPS41738,859,847
483VPS41738,908,142484VPS41738,911,555
485VPS41738,936,691486CDC2L5740,063,896
487ABCA13748,363,317488ABCA13748,380,185
489ABCA13748,427,057490ABCA13748,454,811
491ABCA13748,714,222492GRB10750,823,341
493GRB10750,848,124494WBSCR17770,313,808
495WBSCR17770,765,881496CALN1771,180,137
497CALN1771,235,264498CALN1771,338,388
499CALN1771,339,231500CALN1771,344,745
501MAGI2777,856,639502MAGI2777,950,934
503MAGI2778,091,049504MAGI2778,305,682
505MAGI2778,554,879506MAGI2778,581,862
507MAGI2778,589,166508MAGI2778,760,470
509MAGI2778,817,962510SEMA3E783,011,138
511ABCB4786,897,339512GTPBP10789,357,529
513PPP1R9A794,401,225514PPP1R9A794,411,224
515PPP1R9A794,431,076516PPP1R9A794,479,997
517PPP1R9A794,534,075518PPP1R9A794,589,831
519PPP1R9A794,632,721520PPP1R9A794,677,380
521PPP1R9A794,681,040522PPP1R9A794,717,161
523PPP1R9A794,733,892524PPP1R9A794,747,598
525PPP1R9A794,748,184526DYNC1I1795,556,260
527ZNF3799,480,681528ZNF3799,516,558
529NRCAM7107,585,096530NRCAM7107,598,816
531NRCAM7107,608,956532NRCAM7107,618,181
533NRCAM7107,621,970534NRCAM7107,626,668
535NRCAM7107,627,184536NRCAM7107,628,207
537NRCAM7107,738,458538NRCAM7107,862,002
539KCND27119,925,320540KCND27119,999,690
541KCND27120,001,113542KCND27120,018,452
543CADPS27122,066,038544CADPS27122,074,175
545CADPS27122,146,928546SLC13A17122,533,104
547SLC13A17122,560,268548SLC13A17122,596,470
549SLC13A17122,633,763550SLC13A17122,659,570
551GRM87125,938,463552GRM87125,940,799
553GRM87125,974,975554GRM87126,100,080
555GRM87126,134,129556GRM87126,159,625
557GRM87126,165,491558GRM87126,174,101
559GRM87126,208,986560GRM87126,225,935
561GRM87126,234,800562GRM87126,436,133
563GRM87126,483,848564GRM87126,674,369
565GRM87126,692,493566EXOC47132,728,495
567EXOC47132,754,657568EXOC47132,756,739
569EXOC47132,889,141570EXOC47133,264,961
571DGKI7136,723,471572DGKI7136,749,535
573DGKI7136,769,973574DGKI7136,775,455
575DGKI7136,780,737576DGKI7136,838,221
577DGKI7136,925,970578TBXAS17139,184,991
579CNTNAP27145,414,794580CNTNAP27145,900,444
581CNTNAP27146,180,657582CNTNAP27146,405,829
583CNTNAP27146,414,565584CNTNAP27146,788,354
585CNTNAP27146,792,712586CNTNAP27146,795,212
587CNTNAP27147,069,599588CNTNAP27147,073,223
589CNTNAP27147,710,739590PTPRN27157,017,352
591PTPRN27157,020,289592PTPRN27157,499,807
593PTPRN27157,634,704594PTPRN27157,676,114
595PTPRN27157,714,280596PTPRN27158,015,477
597CSMD182,793,553598CSMD182,864,416
599CSMD182,943,570600CSMD182,954,259
601CSMD183,228,881602CSMD183,230,805
603CSMD183,232,022604CSMD183,232,222
605CSMD183,245,103606CSMD183,250,935
607CSMD183,338,555608MCPH186,414,463
609MCPH186,488,786610SGCZ814,619,388
611SLC7A2817,436,984612SLC7A2817,444,141
613PSD3818,428,754614PSD3818,431,654
615PSD3818,440,935616PSD3818,457,737
617PSD3818,465,235618PSD3818,467,749
619PSD3818,469,732620PSD3818,514,979
621PSD3818,558,380622PSD3818,736,236
623PSD3818,749,712624PSD3818,750,003
625PSD3818,819,182626PSD3818,953,685
627ENTPD4823,357,109628UNC5D835,516,694
629SNTG1851,805,005630SNTG1851,816,608
631LYN857,039,314632LYN857,053,118
633LYN857,054,784634LYN857,108,529
635LYN857,110,114636PLAG1857,246,679
637PLAG1857,263,345638TOX859,966,273
639TOX859,972,497640TOX859,980,027
641TOX860,198,077642NKAIN3863,649,765
643NKAIN3863,900,353644NKAIN3863,935,531
645NKAIN3863,936,341646DEPDC2869,208,963
647DEPDC2869,209,296648CRISPLD1876,073,693
649CRISPLD1876,086,655650CRISPLD1876,127,254
651CRISPLD1876,156,200652CRISPLD1876,158,048
653MMP16889,276,696654BAALC8104,271,601
655ZFPM28106,614,970656ZFPM28106,687,838
657ZFPM28106,688,431658ZFPM28106,847,240
659ZFPM28106,880,874660CSMD38113,337,274
661CSMD38113,443,580662CSMD38113,452,239
663CSMD38113,467,267664CSMD38113,469,659
665CSMD38113,473,493666CSMD38113,510,014
667CSMD38113,554,821668CSMD38114,069,034
669CSMD38114,093,751670CSMD38114,098,597
671CSMD38114,104,594672CSMD38114,105,767
673CSMD38114,160,908674CSMD38114,208,773
675CSMD38114,359,208676SAMD128119,514,190
677SAMD128119,514,541678SAMD128119,518,606
679SAMD128119,531,636680SAMD128119,587,094
681SAMD128119,680,657682SAMD128119,719,731
683FER1L68125,053,616684FER1L68125,122,813
685FER1L68125,123,546686MTSS18125,634,509
687MTSS18125,700,325688MTSS18125,708,636
689MTSS18125,737,780690MTSS18125,802,038
691DDEF18131,286,874692DDEF18131,298,362
693DDEF18131,368,653694DDEF18131,406,218
695DDEF18131,423,273696KCNQ38133,208,937
697KCNQ38133,211,492698KCNQ38133,212,327
699KCNQ38133,346,913700KCNQ38133,351,663
701COL22A18139,744,740702COL22A18139,759,058
703COL22A18139,771,875704COL22A18139,777,590
705COL22A18139,833,578706ZC3H38144,691,326
707SMARCA292,053,356708SMARCA292,170,694
709PIP5K1B970,545,037710PIP5K1B970,687,329
711TRPM3972,616,673712TMC1974,485,413
713TMC1974,492,549714TMC1974,493,473
715TMC1974,507,694716TMC1974,623,740
717PCSK5977,897,682718GNAQ979,856,574
719GNAQ979,934,142720GNAQ979,946,188
721NTRK2986,577,727722DIRAS2992,422,258
723DIRAS2992,476,677724NFIL3993,218,808
725FKTN9107,389,052726FKTN9107,409,195
727FKTN9107,420,176728FKTN9107,435,753
729FKTN9107,445,165730FKTN9107,449,221
731FKTN9107,449,435732PALM29111,506,598
733PALM29111,552,543734PALM29111,554,864
735PALM29111,555,049736PALM29111,556,167
737ZNF6189115,804,104738ZNF6189115,816,110
739ZNF6189115,820,286740ASTN29119,198,404
741CDK5RAP29122,346,776742CDK5RAP29122,377,819
743PTGS19124,225,832744RALGPS19128,769,224
745RALGPS19128,809,594746RALGPS19128,850,765
747RALGPS19128,902,817748RALGPS19128,972,837
749SLC25A259129,899,153750TSC19134,778,093
751TSC19134,786,003752TSC19134,812,111
753VAV29135,708,866754VAV29135,710,406
755VAV29135,710,620756VAV29135,714,835
757PITRM1103,179,115758PRKCQ107,131,891
759PRKCQ107,136,154760PRKCQ107,137,198
761CACNB21018,861,080762ARMC31023,264,868
763ARMC31023,270,471764ARMC31023,271,006
765ARMC31023,343,259766ARMC31023,343,422
767ARMC31023,372,821768ARMC31023,372,952
769MYO3A1026,396,941770MYO3A1026,412,733
771ANK31061,569,339772JMJD1C1064,732,014
773JMJD1C1064,736,192774JMJD1C1064,791,571
775JMJD1C1064,873,814776CDH231072,997,429
777KCNMA11078,258,751778KCNMA11078,320,267
779SORCS310106,525,169780VTI1A10114,448,959
781VTI1A10114,458,127782VTI1A10114,496,282
783VTI1A10114,497,586784VTI1A10114,504,041
785ATRNL110117,429,854786HSPA12A10118,432,901
787GRK510121,055,451788ATE110123,478,029
789ATE110123,484,634790ATE110123,634,335
791ATE110123,644,015792ATE110123,648,119
793ATE110123,648,218794ATE110123,648,608
795ATE110123,666,737796ATE110123,669,674
797ATE110123,679,356798STIM1114,033,624
799STIM1114,047,324800TRIM21114,371,449
801GALNTL41111,222,747802GALNTL41111,228,193
803GALNTL41111,246,740804SPON11113,883,488
805SPON11114,244,704806USH1C1117,475,101
807USH1C1117,487,060808USH1C1117,489,173
809USH1C1117,489,973810USH1C1117,490,211
811USH1C1117,491,427812USH1C1117,519,298
813USH1C1117,520,065814USH1C1117,523,687
815IGSF221118,689,422816IGSF221118,692,523
817IGSF221118,694,857818C11ORF491146,955,088
819C11ORF491147,130,872820C11ORF491147,132,581
821DLG21182,843,293822DLG21182,856,041
823DLG21182,910,180824DLG21183,186,640
825DLG21183,187,421826DLG21183,203,872
827DLG21183,366,230828DLG21184,153,124
829DLG21184,175,263830DLG21184,198,828
831DLG21184,234,326832ELMOD111107,051,899
833OPCML11131,718,194834TSPAN9123,058,775
835TSPAN9123,065,463836TSPAN9123,173,346
837TSPAN9123,331,863838STYK11210,666,462
839STYK11210,697,767840STYK11210,708,924
841STYK11210,711,189842LOC7290251216,250,464
843LRP11255,847,718844LRP11255,878,824
845CNOT21268,831,198846CNOT21269,026,461
847KCNC21273,584,602848NAV31276,913,545
849NAV31276,922,312850GAS2L31299,519,980
851MTIF31326,895,700852MTIF31326,895,999
853SLC46A31328,185,843854SLC46A31328,217,711
855SLC46A31328,267,317856UBL31329,194,621
857N4BP2L21332,021,516858NBEA1335,086,809
859NBEA1335,087,894860NBEA1335,130,015
861SLAIN11377,151,328862GPC51391,268,794
863GPC51391,346,842864GPC51391,372,652
865GPC61393,138,384866GPC61393,183,430
867NALCN13100,517,778868NALCN13100,522,814
869ITGBL113101,013,965870WDR231423,657,479
871WDR231423,671,158872NPAS31432,590,670
873NPAS31432,658,581874GNG21451,414,961
875GNG21451,422,662876SAMD4A1454,319,095
877SAMD4A1454,335,279878SAMD4A1454,335,321
879PPP2R5E1463,040,607880PPP2R5E1463,099,534
881RGS61471,538,177882RGS61471,539,344
883RGS61471,540,089884RGS61471,723,690
885RGS61471,793,717886KCNK101487,792,199
887KCNK131489,783,756888KCNK131489,785,725
889PSMC11489,794,414890PSMC11489,794,847
891PSMC11489,806,078892RPS6KA51490,412,434
893RPS6KA51490,501,524894RPS6KA51490,527,909
895RPS6KA51490,557,351896RPS6KA51490,572,871
897RPS6KA51490,600,927898RPS6KA51490,616,889
899CCDC88C1490,821,027900CCDC88C1490,910,783
901CCDC88C1490,916,433902CCDC88C1490,918,598
903CCDC88C1490,920,049904BCL11B1498,746,376
905BCL11B1498,757,526906BCL11B1498,765,857
907ATP10A1523,493,398908ATP10A1523,513,966
909C15ORF411534,833,829910GLDN1549,457,768
911GLDN1549,457,862912GLDN1549,459,928
913GLDN1549,460,922914CLK31572,707,585
915CLK31572,727,323916TBC1D2B1576,083,890
917TBC1D2B1576,098,398918PCSK61599,842,741
919PCSK61599,858,640920A2BP1167,444,597
921A2BP1167,547,113922A2BP1167,568,164
923TMC51619,365,820924TMC51619,403,812
925TMC51619,413,252926TMC51619,432,372
927GDE11619,435,278928GDE11619,455,004
929HYDIN1669,765,380930HYDIN1669,818,152
931HYDIN1669,856,735932WWOX1676,673,124
933WWOX1676,739,487934WWOX1676,793,572
935WWOX1677,041,675936MPHOSPH61680,728,868
937MPHOSPH61680,759,877938MPHOSPH61680,765,783
939MPHOSPH61680,777,144940MPHOSPH61680,817,367
941MPHOSPH61680,820,057942MPHOSPH61680,831,708
943MPHOSPH61680,833,378944CDH131681,390,450
945CDH131681,430,291946CDH131682,324,245
947USP101683,325,736948DNAH91711,643,618
949DNAH91711,671,648950RAB11FIP41726,746,745
951CA101747,069,220952CA101747,599,744
953HRNBP31774,845,144954ZFP161185,280,198
955ZFP161185,283,943956ZFP161185,284,323
957ZFP161185,398,814958ZFP161185,406,160
959PTPRM187,585,927960PTPRM187,892,147
961PTPRM188,041,285962KIAA0802188,840,062
963KIAA0802188,844,132964OSBPL1A1820,105,278
965CHST91822,787,798966CHST91822,874,298
967CHST91822,874,628968CHST91823,010,213
969CHST91823,012,354970NEDD4L1854,173,333
971NEDD4L1854,202,587972NEDD4L1854,258,677
973NEDD4L1854,259,246974CCBE11855,220,303
975CCBE11855,241,702976CCBE11855,483,138
977CDH71861,594,009978CDH71861,697,973
979CDH71861,739,825980CDH71861,759,477
981TXNDC101864,536,945982ATRN203,400,447
983FERMT1206,037,513984FERMT1206,041,177
985PLCB1208,000,158986PLCB4209,433,807
987MACROD22015,551,153988MACROD22015,559,316
989MACROD22015,586,912990MACROD22016,020,951
991KIF16B2016,445,469992KIF16B2016,454,369
993MAPRE12030,888,730994MAPRE12030,906,484
995PTPRT2040,087,340996ZSWIM32043,921,606
997ZSWIM32043,930,226998ZSWIM32043,939,825
999SNAI12048,025,1651000SNAI12048,036,030
1001SNAI12048,037,2941002SNAI12048,051,852
1003BMP72055,238,5341004CDH42059,359,672
1005C21ORF372117,711,0371006C21ORF372117,738,145
1007NCAM22121,399,1441008NCAM22121,451,606
1009NCAM22121,658,5111010NCAM22121,664,277
1011PDE9A2143,061,1811012ARVCF2218,342,203
1013ARVCF2218,371,9501014SGSM12223,675,537
1015ASPHD22225,130,1991016ASPHD22225,131,287
1017ASPHD22225,166,7801018HPS42225,200,502
1019ARFGAP32241,536,8941020ARFGAP32241,576,090
1021TTLL12241,789,7901022TTLL12241,822,906
1023EFCAB62242,411,0131024EFCAB62242,527,300
1025RIBC22244,217,310