US 201201 OO637A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0100637 A1 Brennan et al. (43) Pub. Date: Apr. 26, 2012

(54) GENETIC MARKERS OF SCHIZOPHRENA (60) Provisional application No. 61/100,176, filed on Sep. ENDOPHENOTYPES 25, 2008. (76) Inventors: Mark David Brennan, Publication Classification Jeffersonville, IN (US); Timothy Lynn Ramsey, Shelbyville, KY (51) Int. C. (US) GOIN 33/53 (2006.01) (52) U.S. Cl...... 436/SO1 (21) Appl. No.: 13/344,123 (57) ABSTRACT (22) Filed: Jan. 5, 2012 This document provides methods and materials related to genetic markers of schizophrenia (SZ), Schizotypal personal Related U.S. Application Data ity disorder (SPD), and/or schizoaffective disorder (SD), (60) Division of application No. 12/612.584, filed on Nov. (collectively referred to herein as "schizophrenia spectrum 4, 2009, now Pat. No. 8,114,600, which is a continua disorders' or SSDs). For example, methods for using such tion of application No. PCT/US2009/058483, filed on genetic markers to identify an SSD (e.g., SZ) endophenotype Sep. 25, 2009. are provided. US 2012/01 OO637 A1 Apr. 26, 2012

GENETIC MARKERS OF SCHIZOPHRENA specific physiological deficits underlying disease. See Braff ENDOPHENOTYPES et al., Schiz. Bull. 33(1):21-32 (2007). SUMMARY CROSS-REFERENCE TO RELATED APPLICATIONS 0006. This disclosure provides methods of determining severity of SZendophenotypes in subjects diagnosed with SZ 0001. This application is a divisional of U.S. patent appli based on genetic variants in genes involved in a number of cation Ser. No. 12/612,584, filed on Nov. 4, 2009, which is a pathways including: glutamate signaling and metabolism, continuation of International Patent Application No. PCT/ cell adhesion, cytoskeletal architecture, vesicle formation, US2009/058483, filed Sep. 25, 2009, which claims priority to and trafficking, G-protein coupled receptors, carrier proteins U.S. Provisional Application Ser. No. 61/100,176, filed on and transporters, cell cycle modulators, neuronal develop Sep. 25, 2008, each of which are hereby incorporated by ment, calcium/calmodulin signaling, neuropeptide signaling, and several additional genes identified by virtue of their inter reference in their entirety. action with genes in high impact pathways and their expres sion in the central nervous system. This disclosure provides FEDERALLY SPONSORED RESEARCHOR methods and claims relating to determining the severity of an DEVELOPMENT SSD endophenotype according to a Subject's underlying genetic architecture. As described herein, methods for deter 0002 This invention was made with government support mining severity of an SSD endophenotype include evaluation under Grant Nos. R43MH078437, NO1 MH900001, and of SNPs for genes relating to endophenotypes in SSDs MH074027, awarded by National Institutes of Health. The including SZ, SPD, and SD. government has certain rights in the invention. 0007. In one aspect, this document features methods for determining a severity of a schizophrenia (SZ) endopheno type in a human Subject. Methods can include determining the TECHNICAL FIELD identity of an allele of at least one single nucleotide polymor phism (SNP) listed in Tables 1-3 in the subject; comparing the 0003. This document provides methods and materials identity of the allele in the subject with a reference allele, related to genetic markers of endophenotypes of Schizophre wherein the reference allele is associated with a severity of a nia (SZ), schizotypal personality disorder (SPD), and/or specific endophenotype; and determining the severity of the schizoaffective disorder (SD), (collectively referred to herein endophenotype in the Subject, based on the comparison of the as "schizophrenia spectrum disorders' or SSDs). For allele in the subject to the reference allele; thereby determin example, this document provides methods for using Such ing the severity of the Schizophrenia endophenotype in the genetic markers to identify an SSD (e.g., SZ) endophenotype Subject. in a Subject. 0008. In another aspect, this document features methods for selecting a treatment for Schizophrenia in a human Sub BACKGROUND ject. Methods can include determining the identity of an allele of at least one polymorphism listed in Tables 1-3 in the 0004. The schizophrenia spectrum disorders include subject; comparing the identity of the allele in the subject with a reference allele, wherein the reference allele is associated schizophrenia (SZ), schizotypal personality disorder (SPD), with a severity of a specific endophenotype; determining the and schizoaffective disorder (SD). Schizophrenia (SZ) is con severity of the endophenotype in the subject, based on the sidered a clinical syndrome, and is probably a constellation of comparison of the allele in the subject to the reference allele; several pathologies. Substantial heterogeneity is seen and selecting a treatment for the Subject based on the deter between cases, which is thought to reflect multiple overlap mined severity of the specific Schizophrenia endophenotype ping etiologic factors, including both genetic and environ for the subject. mental contributions. SD is characterized by the presence of 0009 ASZ endophenotype can be a quantitative trait that affective (depressive or manic) symptoms and Schizophrenic can be measured using one or more of PANSS Total compos symptoms within the same, uninterrupted episode of illness. ite score, PANSS Positive composite score, PANSS Negative SPD is characterized by a pervasive pattern of social and composite score, and PANSS General Psychopathology com interpersonal deficits marked by acute discomfort with, and posite score. A SZ endophenotype can be a quantitative trait reduced capacity for, close relationships as well as by cogni that can be measured using the PANSS Total composite score tive or perceptual distortions and eccentricities of behavior, and the polymorphism can be at position 31 of a sequence beginning by early adulthood and present in a variety of selected from the group consisting of SEQ ID NOs:417. COInteXtS. 1471, 704, 419, 1602, 1401, and 1076. A SZendophenotype 0005 Endophenotypes are quantitative, continuously dis can be a quantitative trait that can be measured using the tributed traits, symptoms or disease dimensions S typically PANSS Positive composite score and the polymorphism can assessed by laboratory-based methods or clinical observa be at position 31 of a sequence selected from the group tion. The use of endophenotypes allows complex psychiatric consisting of SEQID NOs: 1364, 1562, 534, and 1754. A SZ, illnesses like SZ to be divided into more stable, readily defin endophenotype can be a quantitative trait that can be mea able categories that are more amendable to identification of sured using the PANSS Total composite score and the poly clear genetic associations, as they are generally more reflec morphism can be at position 31 of a sequence selected from tive of specific underlying biological processes. Identifying the group consisting of SEQ ID NOs: 1504, 1401, 275, 165, the genetic basis of specific endophenotypes also facilitates and 129. A SZ endophenotype can be a quantitative trait that identification and development of new drugs that target the can be measured using the PANSS Total composite score and US 2012/01 OO637 A1 Apr. 26, 2012 the polymorphism can beat position 31 of a sequence selected or equivalent to those described herein can be used to practice from the group consisting of SEQID NOS:688, 1882, 1751, the invention, suitable methods and materials are described and 1285. below. All publications, patent applications, patents, and 0010. A schizophrenia endophenotype can include one or other references mentioned herein are incorporated by refer more of: a Positive Symptom selected from the group con ence in their entirety. In case of conflict, the present specifi sisting of P1—delusions, P2-conceptual disorganization, cation, including definitions, will control. In addition, the P3—hallucinatory behavior, P4—exitement, P5 grandios materials, methods, and examples are illustrative only and not ity, P6—suspiciousness, P7 hostility; a Negative Symptom intended to be limiting. selected from the group consisting of N1—blunted affect, 0014. The details of one or more embodiments of the N2—emotional withdrawal, N3 poor rapport, N4 pas invention are set forth in the accompanying drawings and the sive/appathetic social withdrawal, N5—difficulty in abstract description below. Other features, objects, and advantages of thinking, N6—lack of spontaneity and flow of conversation, the invention will be apparent from the description and draw N7—stereotyped thinking; or a general psychopathology ings, and from the claims. symptom selected from the group consisting of G1—Somatic concern, G2-anxiety, G3 guilt feelings, G4 tension, DETAILED DESCRIPTION G5—mannerisms and posturing, G6—depression, G7—mo tor retardation, G8 uncooperativeness, G9 unusual 0015 This document provides methods for determining thought content, G10 disorentation, G11—poor attention, severity of an endophenotype in a patient diagnosed with SZ G12—lack of judgment and insight, G13—disturbance of based on evaluation of single nucleotide polymorphisms Volition, G14 poor impulse control, G15 preoccupation, (SNPs) for genes relating to endophenotypes of SSDs includ and G16—active Social avoidance. ing Schizophrenia (SZ), Schizotypal personality disorder 0011 Determining the identity of an allele can include (SPD), and schizoaffective disorder (SD). As described obtaining a sample comprising DNA from the Subject, and herein, bioinformatic and genetic analyses provided evidence determining identity of the nucleotide at the polymorphic site. of association of the disclosed SNP alleles with severity of Determining the identity of the nucleotide can include con intermediate phenotypes, or "endophenotypes, in patients tacting the sample with a probe specific for a selected allele of diagnosed with SZ. the polymorphism, and detecting the formation of complexes between the probe and the selected allele of the polymor DEFINITIONS phism, wherein the formation of complexes between the probe and the test marker indicates the presence of the 0016. As used herein, an “endophenotype' is a quantita selected allele in the sample. Determining the identity of an tive psychiatric trait exhibited by patients diagnosed with SZ. allele can include determining the identity of the nucleotide at One way that Such traits can be measured is by clinical assess position 31 of one of SEQID NOs: 1-1894. A reference allele ment made by administering the Positive and Negative Syn can represent an allele in a subject or subjects who have a drome Scale (PANSS) (Kay et al., Schizophr. Bull. 13:261 known severity of the endophenotype. 276 (1987); Kay et al., Br. J. Psychiatry Suppl 59-67 (1989); 0012 A Subject can be a patient, i.e., a human patient, Leucht et al., Schizophr. Res. 79:231-238 (2005)). having or Suspected of having SZ. A subject can have one or 0017. As used herein, an “allele is one of a pair or series more risk factors associated with SZ. Risk factors associated of genetic variants of a polymorphism at a specific genomic with SZ can include one or more of: a relative afflicted with a location. An "endophenotypicallele' is an allele that is sta Schizophrenia spectrum disorder (SSD); and a genetically tistically associated with severity of a specific endopheno based phenotypic trait associated with risk for a SSD. Meth type. ods can further include selecting or excluding a subject for 0018. A “haplotype' is one or a set of signature genetic enrollment in a clinical trial based on the identity of the allele. changes (polymorphisms) that are normally grouped closely Methods can further include stratifying a Subject population together on the DNA strand, and are usually inherited as a for analysis of a clinical trial based on the identity of the allele group; the polymorphisms are also referred to herein as in the subjects. Methods can further include confirming a “markers.” A “haplotype' as used herein is information severity of a SZ endophenotype using psychometric instru regarding the presence or absence of one or more genetic ments. Methods can further include administering the markers in a given chromosomal region in a subject. A hap selected treatment to the subject. A selected treatment can be lotype can consist of a variety of genetic markers, including an anti-psychotic drug, an anti-depressant drug, anti-anxiety indels (insertions or deletions of the DNA at particular loca drug, mood stabilizer, selective serotonin reuptake inhibitor tions on the chromosome); single nucleotide polymorphisms (SSRI), psychotherapy, or a stimulant. A treatment can be a (SNPs) in which a particular nucleotide is changed; micro combination of an anti-psychotic drug, plus one or more of an satellites; and minisatellites. anti-depressant drug, anti-anxiety drug, mood stabilizer, 0019 Microsatellites (sometimes referred to as a variable selective serotonin reuptake inhibitor (SSRI), psychotherapy, number of tandem repeats or VNTRs) are short segments of or a stimulant. A treatment can be psychotherapy. Methods DNA that have a repeated sequence, usually about 2 to 5 can further include recording the identity of the allele in a nucleotides long (e.g., CACACA), that tend to occur in non tangible medium. A tangible medium can include a computer coding DNA. Changes in the microsatellites sometimes occur readable disk, a Solid state memory device, or an optical during the genetic recombination of sexual reproduction, storage device. increasing or decreasing the number of repeats found at an 0013. Unless otherwise defined, all technical and scien allele, changing the length of the allele. Microsatellite mark tific terms used herein have the same meaning as commonly ers are stable, polymorphic, easily analyzed and occur regu understood by one of ordinary skill in the art to which this larly throughout the genome, making them especially Suit invention pertains. Although methods and materials similar able for genetic analysis. US 2012/01 OO637 A1 Apr. 26, 2012

0020 “Copy number variation” (CNV), as used herein, used. Targets for hybridization can be derived from speci refers to variation from the normal diploid condition for a mens which include, but are not limited to, chromosomes or gene or polymorphism. Individual segments of human chro regions of chromosomes in normal, diseased or malignant mosomes can be deleted or duplicated such that the subject's human cells, either interphase or at any state of meiosis or two chromosome carry fewer than two copies of the gene or mitosis, and either extracted or derived from living or post polymorphism (a deletion or deficiency) or two or more cop mortem tissues, organs or fluids; germinal cells including ies (a duplication). sperm and egg cells, or cells from Zygotes, fetuses, or 0021 “Linkage disequilibrium” refers to when the embryos, or chorionic or amniotic cells, or cells from any observed frequencies of haplotypes in a population does not other germinating body; cells grown in vitro, from either agree with haplotype frequencies predicted by multiplying long-term or short-term culture, and either normal, immor together the frequency of individual genetic markers in each talized or transformed; inter- or intraspecific hybrids of dif haplotype. ferent types of cells or differentiation states of these cells; 0022. The term "chromosome” as used herein refers to a individual chromosomes or portions of chromosomes, or gene carrier of a cell that is derived from chromatin and translocated, deleted or other damaged chromosomes, iso comprises DNA and protein components (e.g., histones). The lated by any of a number of means known to those with skill conventional internationally recognized individual human in the art, including libraries of Such chromosomes cloned genome chromosome numbering identification system is and propagated in prokaryotic or other cloning vectors, or employed herein. The size of an individual chromosome can amplified in vitro by means well known to those with skill; or vary from one type to another with a given multi-chromo any forensic material, including but not limited to blood, or Somal genome and from one genome to another. In the case of other samples. the human genome, the entire DNA mass of a given chromo (0028. The term “hybrid” refers to the product of a hybrid some is usually greater than about 100,000,000 base pairs. ization procedure between a probe and a target. For example, the size of the entire human genome is about 0029. The term “hybridizing conditions' has general ref 3x10 base pairs. erence to the combinations of conditions that are employable 0023 The term “gene’ refers to a DNA sequence in a in a given hybridization procedure to produce hybrids. Such chromosome that codes for a product (either RNA or its conditions typically involving controlled temperature, liquid translation product, a polypeptide). A gene contains a coding phase, and contact between a probe (or probe composition) region and includes regions preceding and following the cod and a target. Conveniently and preferably, at least one dena ing region (termed respectively “leader” and “trailer). The turation step precedes a step wherein a probe or probe com coding region is comprised of a plurality of coding segments position is contacted with a target. Guidance for performing (“exons') and intervening sequences (“introns') between hybridization reactions can be found in Ausubel et al., Cur individual coding segments. rent Protocols in Molecular Biology, John Wiley & Sons, 0024. The term “probe' refers to an oligonucleotide. A N.Y. (2003), 6.3.1-6.3.6. Aqueous and nonaqueous methods probe can be single stranded at the time of hybridization to a are described in that reference and either can be used. Hybrid target. As used herein, probes include primers, i.e., oligo ization conditions referred to herein are a 50% formamide, nucleotides that can be used to prime a reaction, e.g., a PCR 2xSSC wash for 10 minutes at 45° C. followed by a 2xSSC reaction. wash for 10 minutes at 37° C. 0025. The term “label” or “label containing moiety” refers 0030 Calculations of “identity” between two sequences in a moiety capable of detection, such as a radioactive isotope can be performed as follows. The sequences are aligned for or group containing same, and nonisotopic labels, such as optimal comparison purposes (e.g., gaps can be introduced in enzymes, biotin, avidin, Streptavidin, digoxygenin, lumines one or both of a first and a second nucleic acid sequence for cent agents, dyes, haptens, and the like. Luminescent agents, optimal alignment and non-identical sequences can be disre depending upon the Source of exciting energy, can be classi garded for comparison purposes). The length of a sequence fied as radioluminescent, chemiluminescent, bioluminescent, aligned for comparison purposes is at least 30% (e.g., at least and photoluminescent (including fluorescent and phospho 40%, 50%, 60%, 70%, 80%, 90% or 100%) of the length of rescent). A probe described herein can be bound, e.g., chemi the reference sequence. The nucleotides at corresponding cally bound to label-containing moieties or can be suitable to nucleotide positions are then compared. When a position in be so bound. The probe can be directly or indirectly labeled. the first sequence is occupied by the same nucleotide as the 0026. The term “direct label probe' (or “directly labeled corresponding position in the second sequence, then the mol probe') refers to a nucleic acid probe whose label after hybrid ecules are identical at that position. The percent identity formation with a target is detectable without further reactive between the two sequences is a function of the number of processing of hybrid. The term “indirect label probe' (or identical positions shared by the sequences, taking into “indirectly labeled probe') refers to a nucleic acid probe account the number of gaps, and the length of each gap, which whose label after hybrid formation with a target is further need to be introduced for optimal alignment of the two reacted in Subsequent processing with one or more reagents to Sequences. associate therewith one or more moieties that finally result in 0031. The comparison of sequences and determination of a detectable entity. percent identity between two sequences can be accomplished 0027. The terms “target,” “DNA target,” or “DNA target using a mathematical algorithm. In some embodiments, the region” refers to a nucleotide sequence that occurs at a spe percent identity between two nucleotide sequences is deter cific chromosomal location. Each Such sequence orportion is mined using the GAP program in the GCG Software package, preferably at least partially, single stranded (e.g., denatured) using a Blossum 62 scoring matrix with a gap penalty of 12, at the time of hybridization. When the target nucleotide a gap extend penalty of 4, and a frameshift gap penalty of 5. sequences are located only in a single region or fraction of a 0032. As used herein, the term “substantially identical' is given chromosome, the term “target region' is sometimes used to refer to a first nucleotide sequence that contains a US 2012/01 OO637 A1 Apr. 26, 2012

sufficient number of identical nucleotides to a second nucle can include steps that occur at more than one site. For otide sequence Such that the first and second nucleotide example, a sample can be obtained from a Subject at a first sequences have similar activities. Nucleotide sequences that site. Such as at a health care provider, or at the Subject's home are substantially identical are at least 80% (e.g., 85%, 90%, in the case of a self-testing kit. The sample can be analyzed at 95%, 97% or more) identical. the same or a second site, e.g., at a laboratory or other testing 0033. The term “nonspecific binding DNA” refers to DNA facility. which is complementary to DNA segments of a probe, which 0037 Determining the identity of an allele can also DNA occurs in at least one other positionina genome, outside include or consist of reviewing a Subject's medical history, of a selected chromosomal target region within that genome. where the medical history includes information regarding the An example of nonspecific binding DNA comprises a class of identity, presence or absence of one or more response alleles DNA repeated segments whose members commonly occur in in the Subject, e.g., results of a genetic test. more than one chromosome or chromosome region. Such 0038. In some embodiments, to determine the identity of common repetitive segments tend to hybridize to a greater an allele described herein, a biological sample that includes extent than other DNA segments that are present in probe nucleated cells (such as blood, a cheek Swab or mouthwash) composition. is prepared and analyzed for the presence or absence of pre selected markers. Such diagnoses may be performed by diag Methods of Determining the Degree of Specific Endopheno nostic laboratories, or, alternatively, diagnostic kits can be types manufactured and sold to health care providers or to private 0034 Quantitative traits, by definition, are measured by individuals for self-diagnosis. Diagnostic or prognostic tests degree rather than simply presence or absence, like blood can be performed as described herein or using well known glucose or cholesterol. The genetically-based methods techniques, such as described in U.S. Pat. No. 5,800.998. described herein can give a biological indication of the degree 0039 Results of these tests, and optionally interpretive (or severity) of a phenotype a patient might show, and not be information, can be returned to the subject, the health care dependent upon the results of a particular psychiatric test provider or to a third party payor. The results can be used in a done on one particular day. This is similar to testing for LDL number of ways. The information can be, e.g., communicated receptor variants to understand why a person might have high to the tested Subject, e.g., with a prognosis and optionally cholesterol and how it would be best to treat the patient, rather interpretive materials that help the subject understand the test than simply looking at cholesterol levels. In the SZ context, results and prognosis. The information can be used, e.g., by a this is particularly important since a subject's presentation of health care provider, to determine whether to administer a disease may vary from day to day. For example, a Subject with specific drug, or whether a subject should be assigned to a SZ may display more mania one day than the next; if a specific category, e.g., a category associated with a specific medical professional evaluates them on a day when they are disease endophenotype, or with drug response or non-re displaying fewer symptoms of mania, an inappropriate treat sponse. The information can be used, e.g., by a third party ment plan might be prepared. payor Such as a healthcare payer (e.g., insurance company or 0035. Described herein are a variety of methods for iden HMO) or other agency, to determine whether or not to reim tifying, predicting, or determining severity or degree of a burse a health care provider for services to the subject, or subject's SSD (e.g., SZ) endophenotype. “Severity” includes whether to approve the provision of services to the subject. the whole spectrum of expression of the endophenotype, For example, the healthcare payer may decide to reimburse a including both positive and negative scores on the PANSS health care provider for treatments for an SSD if the subject test, e.g., extremely severe expression to mild or Substantially has a particular response allele. As another example, a drug or no expression of the endophenotype. As used herein, deter treatment may be indicated for individuals with a certain mining severity or degree of an SSD endophenotype is based allele, and the insurance company would only reimburse the on the presence or absence of one or more alleles associated health care provider (or the insured individual) for prescrip with severity of the endophenotypes in patients diagnosed tion or purchase of the drug if the insured individual has that with SZ as described herein. Ascertaining whether the subject response allele. The presence or absence of the response has such an allele is included in the concept of determining allele in a patient may be ascertained by using any of the SSD (e.g., SZ) endophenotypes as used herein. The presence methods described herein. an allele associated with a particular severity indicates a spe 0040 Alleles Associated with Severity of SSD Endophe cific genetic (biological) contribution to the particular notypes endophenotype. Such contributions can be positive (tending 0041. This document provides methods for determining to increase the degree of the endophenotype) or negative the degree of an SSD (e.g., SZ) endophenotype based on (tending to decrease the degree of the endophenotype) evaluation of single nucleotide polymorphisms (SNPs) for depending on the specific allele of the polymorphism. genes relating to endophenotypes of SZ-spectrum disorders 0036. As used herein, “determining the identity of an including Schizophrenia (SZ), Schizotypal personality disor allele includes obtaining information regarding the identity, der (SPD), and schizoaffective disorder (SD). The alleles presence or absence of one or more specificalleles in a Sub described herein can be used both to determine patients who ject. Determining the identity of an allele can, but need not, are likely to display higher or lower values for specific include obtaining a sample comprising DNA from a subject, endophenotypes and to determine the contribution of genetic and/or assessing the identity, presence or absence of one or makeup and specific biological/cellular pathways to specific more genetic markers in the sample. The individual or orga endophenotypes and severity thereof. Tables 1-3 and Table A nization who determines the identity of the allele need not list specific SNPs, variation of which is associated with varia actually carry out the physical analysis of a sample from a tions in severity of specific endophenotypes. One of skill in Subject; the methods can include using information obtained the art will appreciate that other variants can be identified via by analysis of the sample by a third party. Thus the methods TDT using families with multiple affected individuals or by US 2012/01 OO637 A1 Apr. 26, 2012

Case/Control comparisons using the SNP markers presented in nucleotide sequence is identified at a particular site that herein. Using SNP markers that are identical to or in linkage determines that a polymorphism exists at that site. In most disequilibrium with the exemplary SNPs, one can determine instances, particularly in the case of SNPs, only two polymor other alleles, including haplotypes and single SNP alleles in phic variants will exist at any location. However, in the case of these genes relating response to an endophenotype of an SSD SNPs, up to four variants may exist since there are four (e.g., of SZ). The allelic variants thus identified can be used naturally occurring nucleotides in DNA. Other polymor equivalently to the exemplary SNPs, e.g., to determine a phisms, such as insertions and deletions, may have more than diagnosis of a specific endophenotype in a patient. four alleles. 0042 Markers in Linkage Disequilibrium (LD) 0048. The methods described herein can also include 0043 Linkage disequilibrium (LD) is a measure of the determining the presence or absence of other markers known degree of association between alleles in a population. One of or suspected to be associated with an SSD (e.g., SZ) endophe skill in the art will appreciate that alleles involving markers in notype, e.g., markers outside of a region identified herein, see, LD with the polymorphisms described herein can also be e.g., Harrison and Owen, Lancet, 361 (9355):417-419 (2003). used in a similar manner to those described herein. Methods In some embodiments, the methods include determining the of calculating LD are known in the art (see, e.g., Morton et al., presence or absence of one or more other markers that are or Proc. Natl. Acad. Sci. USA 98(9):5217-21 (2001); Tapper et may be associated with an SSD (e.g., SZ) endophenotype, al., Proc. Natl. Acad. Sci. USA 102(33): 11835-11839 (2005): e.g., in one or more genes, e.g., e.g., as described in WO Maniatis et al., Proc. Natl. Acad. Sci. USA 99:2228-2233 2009/092032, WO 2009/089120, WO 2009/082743, (2002)). Thus, in some cases, the methods can include analy US2006/0177851, and US2009/0012371 incorporated herein sis of polymorphisms that are in LD with a polymorphism in their entirety. See also, e.g., OMIM entry no. 181500 described herein. Methods are known in the art for identifying (SCZD). Such polymorphisms; for example, the International HapMap 0049 Methods of Determining the Identity of an Allele Project provides a public database that can be used, see hap 0050. The methods described herein include determining map.org, as well as The International HapMap Consortium, the identity, presence or absence of alleles associated with a Nature 426:789-796 (2003), and The International HapMap severity of specific SSD (e.g., SZ) endophenotype. In some Consortium, Nature 437: 1299-1320 (2005). Generally, it will cases, an association with severity of an SSD (e.g., SZ) be desirable to use a HapMap constructed using data from endophenotype is determined by the presence of the same individuals who share ethnicity with the subject. For allele in both the subject and an affected reference individual, example, a HapMap for African Americans would ideally be e.g., in an unrelated reference subject or a first or second used to identify markers in LD with an exemplary marker degree relation of the subject, and the absence of the allele in described herein for use in genotyping a Subject of African an unaffected reference individual. Thus the methods can American descent. include obtaining and analyzing a sample from a suitable 0044 Alternatively, methods described herein can include reference individual. Samples that are suitable for use in the analysis of polymorphisms that show a correlation coefficient methods described herein contain genetic material, e.g., (r) of value20.5 with the markers described herein. Results genomic DNA (gDNA). Genomic DNA is typically extracted can be obtained from on line public resources such as Hap from biological samples such as blood or mucosal scrapings Map.org on the World WideWeb. The correlation coefficient of the lining of the mouth, but can be extracted from other is a measure of LD, and reflects the degree to which alleles at biological samples including urine or expectorant. The two loci (for example, two SNPs) occur together, such that an sample itself will typically include nucleated cells (e.g., blood allele at one SNP position can predict the correlated allele at or buccal cells) or tissue removed from the subject. The sub a second SNP position, in the case where r is >0.5. ject can be an adult, child, fetus, or embryo. In some embodi 0045 Identifying Additional Genetic Markers ments, the sample is obtained prenatally, either from a fetus or 0046. In general, genetic markers can be identified using embryo or from the mother (e.g., from fetal or embryonic any of a number of methods well known in the art. For cells in the maternal circulation). Methods and reagents are example, numerous polymorphisms in the regions described known in the art for obtaining, processing, and analyzing herein are known to exist and are available in public data samples. In some embodiments, the sample is obtained with bases, which can be searched using methods and algorithms the assistance of a health care provider, e.g., to draw blood. In known in the art. Alternately, polymorphisms can be identi Some embodiments, the sample is obtained without the assis fied by sequencing either genomic DNA or cDNA in the tance of a health care provider, e.g., where the sample is region in which it is desired to find a polymorphism. Accord obtained non-invasively, such as a sample comprising buccal ing to one approach, primers are designed to amplify such a cells that is obtained using a buccal Swab or brush, or a region, and DNA from a subject is obtained and amplified. mouthwash sample. The DNA is sequenced, and the sequence (referred to as a 0051. In some cases, a biological sample may be pro “Subject sequence' or “test sequence') is compared with a cessed for DNA isolation. For example, DNA in a cell or reference sequence, which can represent the “normal” or tissue sample can be separated from other components of the “wild type' sequence, or the “affected’ sequence. In some sample. Cells can be harvested from a biological sample embodiments, a reference sequence can be from, for example, using standard techniques known in the art. For example, the human draft genome sequence, publicly available in Vari cells can be harvested by centrifuging a cell sample and ous databases, or a sequence deposited in a database such as resuspending the pelleted cells. The cells can be resuspended GenBank. In some embodiments, the reference sequence is a in a buffered solution such as phosphate-buffered saline composite of ethnically diverse individuals. (PBS). After centrifuging the cell suspension to obtain a cell 0047. In general, if sequencing reveals a difference pellet, the cells can be lysed to extract DNA, e.g., gDNA. See, between the sequenced region and the reference sequence, a e.g., Ausubel et al., 2003, Supra. The sample can be concen polymorphism has been identified. The fact that a difference trated and/or purified to isolate DNA. All samples obtained US 2012/01 OO637 A1 Apr. 26, 2012 from a subject, including those subjected to any sort of further DNA sequencing is yet another approach to detection of processing, are considered to be obtained from the Subject. polymorphisms and polymorphic variants (Alderborn et al., Routine methods can be used to extract genomic DNA from a Genome Research 10(8): 1249-1258 (2000)). Additional biological sample, including, for example, phenol extraction. methods include, for example, PCR amplification in combi Alternatively, genomic DNA can be extracted with kits such nation with denaturing high performance liquid chromatog as the QIAamp(R) Tissue Kit (Qiagen, Chatsworth, Calif.) and raphy (dHPLC) (Underhill et al., Genome Research 7(10): the Wizard R. Genomic DNA purification kit (Promega). Non 996-1005 (1997)). limiting examples of sources of samples include urine, blood, 0055. In order to detect polymorphisms and/or polymor and tissue. phic variants, it will frequently be desirable to amplify a 0052. The absence or presence of an allele associated with severity of an SSD (e.g., SZ) endophenotype as described portion of genomic DNA (gDNA) encompassing the poly herein can be determined using methods known in the art. For morphic site. Such regions can be amplified and isolated by example, gel electrophoresis, capillary electrophoresis, size PCR using oligonucleotide primers designed based on exclusion chromatography, sequencing, and/or arrays can be genomic and/or cDNA sequences that flank the site. PCR used to detect the presence or absence of the allele. Amplifi refers to procedures in which target nucleic acid (e.g., cation of nucleic acids, where desirable, can be accomplished genomic DNA) is amplified in a manner similar to that using methods known in the art, e.g., PCR. In one example, a described in U.S. Pat. No. 4,683,195, and subsequent modi sample (e.g., a sample comprising genomic DNA), is fications of the procedure described therein. Generally, obtained from a subject. The DNA in the sample is then sequence information from the ends of the region of interest examined to determine the identity of an allele as described or beyond are used to design oligonucleotide primers that are herein. The identity of the allele can be determined by any identical or similar in sequence to opposite Strands of a poten method described herein, e.g., by sequencing or by hybrid tial template to be amplified. See e.g., PCR Primer: A Labo ization of the gene in the genomic DNA, RNA, or cDNA to a ratory Manual, Dieffenbach and Dveksler, (Eds.); McPher nucleic acid probe, e.g., a DNA probe (which includes cloNA son et al., PCR Basics. From Background to Bench (Springer and oligonucleotide probes) or an RNA probe. The nucleic Verlag, 2000); Mattila et al., Nucleic Acids Res., 19:4967 acid probe can be designed to specifically or preferentially (1991); Eckert et al., PCR Methods and Applications, 1:17 hybridize with a particular polymorphic variant. (1991): PCR (eds. McPherson et al., IRL Press, Oxford); and 0053 Other methods of nucleic acid analysis can include U.S. Pat. No. 4,683.202. Other amplification methods that direct manual sequencing (Church and Gilbert, Proc. Natl. may be employed include the ligase chain reaction (LCR) Acad. Sci. USA 81:1991-1995 (1988); Sanger et al., Proc. (Wu and Wallace, Genomics 4:560 (1989), Landegren et al., Natl. Acad. Sci. USA 74:5463-5467 (1977); Beavis et al., U.S. Science 241:1077 (1988), transcription amplification (Kwoh Pat. No. 5.288,644); automated fluorescent sequencing: et al., Proc. Natl. Acad. Sci. USA 86: 1173 (1989)), self single-stranded conformation polymorphism assays (SSCP) Sustained sequence replication (Guatelli et al., Proc. Nat. (Schafer et al., Nat. Biotechnol. 15:33-39 (1995)); clamped Acad. Sci. USA 87: 1874 (1990)), and nucleic acid based denaturing gel electrophoresis (CDGE); two-dimensional gel sequence amplification (NASBA). Guidelines for selecting electrophoresis (2DGE or TDGE); conformational sensitive primers for PCR amplification are well known in the art. See, gel electrophoresis (CSGE); denaturing gradient gel electro e.g., McPherson et al., PCR Basics. From Background to phoresis (DGGE) (Sheffield et al., Proc. Natl. Acad. Sci. USA Bench, Springer-Verlag, 2000. A variety of computer pro 86:232-236 (1989); denaturing high performance liquid grams for designing primers are available, e.g., Oligo (Na chromatography (DHPLC. Underhill et al., Genome Res. tional Biosciences, Inc, Plymouth Minn.), MacVector 7:996-1005 (1997)); infrared matrix-assisted laser desorp (Kodak/IBI), and the GCG suite of sequence analysis pro tion/ionization (IR-MALDI) mass spectrometry (WO grams (Genetics Computer Group, Madison, Wis. 53711). 99/57318); mobility shift analysis (Orita et al., Proc. Natl. 0056. In some cases, PCR conditions and primers can be Acad. Sci. USA 86:2766-2770 (1989)); restriction enzyme developed that amplify a product only when the variant allele analysis (Flavellet al., Cell 15:25 (1978); Geever et al., Proc. is present or only when the wild type allele is present Natl. Acad. Sci. USA 78:5081 (1981)); quantitative real-time (MSPCR or allele-specific PCR). For example, patient DNA PCR (Raca et al., Genet Test 8(4):387-94 (2004)); heterodu and a control can be amplified separately using either a wild plex analysis; chemical mismatch cleavage (CMC) (Cotton et type primer or a primer specific for the variant allele. Each set al., Proc. Natl. Acad. Sci. USA 85.4397–4401 (1985)); RNase of reactions is then examined for the presence of amplifica protection assays (Myers et al., Science 230:1242 (1985)); tion products using standard methods to visualize the DNA. use of polypeptides that recognize nucleotide mismatches, For example, the reactions can be electrophoresed through an e.g., E. colimutS protein; allele-specific PCR, and combina agarose geland the DNA visualized by staining with ethidium tions of such methods. See, e.g., Gerber et al., U.S. Patent bromide or other DNA intercalating dye. In DNA samples Publication No. 2004/0014095 which is incorporated herein from heterozygous patients, reaction products would be by reference in its entirety. detected in each reaction. 0054 Sequence analysis can also be used to detect specific 0057 Real-time quantitative PCR can also be used to polymorphic variants. For example, polymorphic variants determine copy number. Quantitative PCR permits both can be detected by sequencing exons, introns, 5' untranslated detection and quantification of specific DNA sequence in a sequences, or 3' untranslated sequences. A sample compris sample as an absolute number of copies or as a relative ing DNA or RNA is obtained from the subject. PCR or other amount when normalized to DNA input or other normalizing appropriate methods can be used to amplify a portion encom genes. A key feature of quantitative PCR is that the amplified passing the polymorphic site, if desired. The sequence is then DNA product is quantified in real-time as it accumulates in ascertained, using any standard method, and the presence of a the reaction after each amplification cycle. Methods of quan polymorphic variant is determined. Real-time pyrophosphate tification can include the use of fluorescent dyes that interca US 2012/01 OO637 A1 Apr. 26, 2012

late with double-stranded DNA, and modified DNA oligo acid can be amplified using the mutagenic primer and a wild nucleotide probes that fluoresce when hybridized with a type primer, followed by digest with the appropriate restric complementary DNA. tion endonuclease. 0058. In some embodiments, a peptide nucleic acid (PNA) 0061. In some embodiments, fluorescence polarization probe can be used instead of a nucleic acid probe in the template-directed dye-terminator incorporation (FP-TDI) is hybridization methods described above. PNA is a DNA used to determine which of multiple polymorphic variants of mimetic with a peptide-like, inorganic backbone, e.g., N-(2- a polymorphism is present in a subject (Chen et al., Genome Research 9(5):492-498 (1999)). Rather than involving use of aminoethyl)glycine units, with an organic base (A, G, C, T or allele-specific probes or primers, this method employs prim U) attached to the glycine nitrogen via a methylene carbonyl ers that terminate adjacent to a polymorphic site, so that linker (see, e.g., Nielsen et al., Bioconjugate Chemistry, The extension of the primer by a single nucleotide results in incor American Chemical Society, 5:1 (1994)). The PNA probe can poration of a nucleotide complementary to the polymorphic be designed to specifically hybridize to a nucleic acid com variant at the polymorphic site. prising a polymorphic variant indicative of an SSD (e.g., SZ) 0062. In some cases, DNA containing an amplified portion endophenotype. may be dot-blotted, using standard methods (see Ausubel et 0059. In some cases, allele-specific oligonucleotides can al., Current Protocols in Molecular Biology, Supra), and the also be used to detect the presence of a polymorphic variant. blot contacted with the oligonucleotide probe. The presence For example, polymorphic variants can be detected by per of specific hybridization of the probe to the DNA is then forming allele-specific hybridization or allele-specific detected. Specific hybridization of an allele-specific oligo restriction digests. Allele specific hybridization is an example nucleotide probe to DNA from the subject can be indicative of of a method that can be used to detect sequence variants, the presence of an allele associated with an SSD (e.g., SZ) including complete haplotypes of a Subject (e.g., a mammal endophenotype. Such as a human). See Stoneking et al., Am. J. Hum. Genet. 0063. The methods can include determining the genotype 48:370-382 (1991); and Prince et al., Genome Res. 11:152 of a subject with respect to both copies of the polymorphic 162 (2001). An “allele-specific oligonucleotide' (also site present in the genome. For example, the complete geno referred to herein as an “allele-specific oligonucleotide type may be characterized as -/-, as -/+, or as +/-, where a probe') is an oligonucleotide that is specific for particular a minus sign indicates the presence of the reference or wildtype polymorphism can be prepared using standard methods (see sequence at the polymorphic site, and the plus sign indicates the presence of a polymorphic variant other than the reference Ausubel et al., Current Protocols in Molecular Biology, sequence. If multiple polymorphic variants exist at a site, this Supra). Allele-specific oligonucleotide probes typically can can be appropriately indicated by specifying which ones are be approximately 10-50 base pairs, preferably approximately present in the subject. Any of the detection means described 15-30 base pairs, that specifically hybridizes to a nucleic acid herein can be used to determine the genotype of a Subject with region that contains a polymorphism. Hybridization condi respect to one or both copies of the polymorphism present in tions are selected Such that a nucleic acid probe can specifi the Subject's genome. cally bind to the sequence of interest, e.g., the variant nucleic 0064 Methods of nucleic acid analysis to detect polymor acid sequence. Such hybridizations typically are performed phisms and/or polymorphic variants can include, e.g., under high Stringency as some sequence variants include only microarray analysis. Hybridization methods, such as South a single nucleotide difference. In some cases, dot-blot hybrid ern analysis, Northern analysis, or in situ hybridizations, can ization of amplified oligonucleotides with allele-specific oli also be used (see Ausubel et al., Current Protocols in Molecu gonucleotide (ASO) probes can be performed. See, for lar Biology, eds., John Wiley & Sons (2003)). To detect example, Saiki et al., Nature (London) 324:163–166 (1986). microdeletions, fluorescence in situ hybridization (FISH) 0060. In some embodiments, allele-specific restriction using DNA probes that are directed to a putatively deleted digest analysis can be used to detect the existence of a poly region in a chromosome can be used. For example, probes that morphic variant of a polymorphism, if alternate polymorphic detect all or a part of a microsatellite marker can be used to variants of the polymorphism result in the creation or elimi detect microdeletions in the region that contains that marker. nation of a restriction site. Allele-specific restriction digests 0065. In some embodiments, it is desirable to employ can be performed in the following manner. A sample contain methods that can detect the presence of multiple polymor ing genomic DNA is obtained from the individual and phisms (e.g., polymorphic variants at a plurality of polymor genomic DNA is isolated for analysis. For nucleotide phic sites) in parallel or Substantially simultaneously. Oligo sequence variants that introduce a restriction site, restriction nucleotide arrays represent one Suitable means for doing so. digest with the particular restriction enzyme can differentiate Other methods, including methods in which reactions (e.g., the alleles. In some cases, polymerase chain reaction (PCR) amplification, hybridization) are performed in individual ves can be used to amplify a region comprising the polymorphic sels, e.g., within individual wells of a multi-well plate or other site, and restriction fragment length polymorphism analysis vessel may also be performed so as to detect the presence of is conducted (see Ausubel et al., Current Protocols in multiple polymorphic variants (e.g., polymorphic variants at Molecular Biology, Supra). The digestion pattern of the rel a plurality of polymorphic sites) in parallel or Substantially evant DNA fragment indicates the presence or absence of a simultaneously according to the methods provided herein. particular polymorphic variant of the polymorphism and is 0.066 Nucleic acid probes can be used to detect and/or therefore indicative of severity of an SSD endophenotype. quantify the presence of a particular target nucleic acid For sequence variants that do not alter a common restriction sequence within a sample of nucleic acid sequences, e.g., as site, mutagenic primers can be designed that introduce a hybridization probes, or to amplify a particular target restriction site when the variant allele is present or when the sequence within a sample, e.g., as a primer. Probes have a wild type allele is present. For example, a portion of a nucleic complimentary nucleic acid sequence that selectively hybrid US 2012/01 OO637 A1 Apr. 26, 2012 izes to the target nucleic acid sequence. In order for a probe to (FITC), 7-diethylaminocoumarin-3-carboxylic acid, tetram hybridize to a target sequence, the hybridization probe must ethylrhodamine-5-(and-6)-isothiocyanate, 5-(and-6)-car have Sufficient identity with the target sequence, i.e., at least boxytetramethylrhodamine, 7-hydroxycoumarin-3-carboxy 70% (e.g., 80%, 90%, 95%, 98% or more) identity to the lic acid, 6-fluorescein 5-(and-6)-carboxamidohexanoic target sequence. The probe sequence must also be sufficiently acid, N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a diaza-3-in long so that the probe exhibits selectivity for the target dacenepropionic acid, eosin-5-isothiocyanate, erythrosin-5- sequence over non-target sequences. For example, the probe isothiocyanate, and CASCADETM blue acetylazide (Molecu will beat least 20 (e.g., 25.30,35,50, 100,200,300,400, 500, lar Probes, Inc., Eugene, Oreg.). Fluorescently labeled probes 600, 700, 800, 900 or more) nucleotides in length. In some can be viewed with a fluorescence microscope and an appro embodiments, the probes are not more than 30, 50, 100, 200, priate filter for each fluorophore, or by using dual or triple 300, 500, 750, or 1000 nucleotides in length. Probes are band-pass filter sets to observe multiple fluorophores. See, for typically about 20 to about 1x10° nucleotides in length. example, U.S. Pat. No. 5,776,688. Alternatively, techniques Probes include primers, which generally refers to a single such as flow cytometry can be used to examine the hybrid Stranded oligonucleotide probe that can act as a point of ization pattern of the probes. Fluorescence-based arrays are initiation of template-directed DNA synthesis using methods also known in the art. Such as PCR (polymerase chain reaction), LCR (ligase chain 0071. In other embodiments, the probes can be indirectly reaction), etc., for amplification of a target sequence. labeled with, e.g., biotin or digoxygenin, or labeled with 0067. The probe can be a test probe such as a probe that radioactive isotopes such as P and H. For example, a probe can be used to detect polymorphisms in a region described indirectly labeled with biotin can be detected by avidin con herein (e.g., polymorphisms as described herein). In some jugated to a detectable marker. For example, avidin can be embodiments, the probe can bind to another marker sequence conjugated to an enzymatic marker Such as alkaline phos associated with SZ, SPD, or SD as described herein. phatase or horseradish peroxidase. Enzymatic markers can be 0068 Control probes can also be used. For example, a detected in standard colorimetric reactions using a substrate probe that binds a less variable sequence, e.g., repetitive DNA and/or a catalyst for the enzyme. Catalysts for alkaline phos associated with a centromere of a chromosome, can be used phatase include 5-bromo-4-chloro-3-indolylphosphate and as a control. Probes that hybridize with various centromeric nitro blue tetrazolium. Diaminobenzoate can be used as a DNA and locus-specific DNA are available commercially, for catalyst for horseradish peroxidase. example, from Vysis, Inc. (Downers Grove, Ill.), Molecular 0072. In another aspect, this document features arrays that Probes, Inc. (Eugene, Oreg.), or from Cytocell (Oxfordshire, include a substrate having a plurality of addressable areas, UK). Probe sets are available commercially such from and methods of using them. At least one area of the plurality Applied Biosystems, e.g., the Assays-on-Demand SNP kits includes a nucleic acid probe that binds specifically to a Alternatively, probes can be synthesized, e.g., chemically or sequence comprising a polymorphism listed in any of Tables in vitro, or made from chromosomal or genomic DNA 1-3, and can be used to detect the absence or presence of said through standard techniques. For example, Sources of DNA polymorphism, e.g., one or more SNPs, microsatellites, mini that can be used include genomic DNA, cloned DNA satellites, or indels, as described herein, to determine the sequences. Somatic cell hybrids that contain one, or a part of identity of an allele. For example, the array can include one or one, human chromosome along with the normal chromosome more nucleic acid probes that can be used to detect a poly complement of the host, and chromosomes purified by flow morphism listed in any of Tables 1-3. In some embodiments, cytometry or microdissection. The region of interest can be the array further includes at least one area that includes a isolated through cloning, or by site-specific amplification via nucleic acid probe that can be used to specifically detect the polymerase chain reaction (PCR). See, for example, Nath another marker associated with severity of an SSD (e.g., SZ), and Johnson, Biotechnic. Histochem. 73(1):6-22 (1998); as described herein. In some embodiments, the probes are Wheeless et al., Cytometry 17:319-326 (1994); and U.S. Pat. nucleic acid capture probes. No. 5,491,224. 0073 Generally, microarray hybridization is performed 0069. In some embodiments, the probes are labeled, e.g., by hybridizing a nucleic acid of interest (e.g., a nucleic acid by direct labeling, with a fluorophore, an organic molecule encompassing a polymorphic site) with the array and detect that fluoresces after absorbing light of lower wavelength/ ing hybridization using nucleic acid probes. In some cases, higher energy. A directly labeled fluorophore allows the probe the nucleic acid of interest is amplified prior to hybridization. to be visualized without a secondary detection molecule. Hybridization and detecting are generally carried out accord After covalently attaching a fluorophore to a nucleotide, the ing to standard methods. See, e.g., Published PCT Applica nucleotide can be directly incorporated into the probe with tion Nos. WO92/10092 and WO95/11995, and U.S. Pat. No. standard techniques such as nick translation, random prim 5,424,186. For example, the array can be scanned to deter ing, and PCR labeling. Alternatively, deoxycytidine nucle mine the position on the array to which the nucleic acid otides within the probe can be transaminated with a linker. hybridizes. The hybridization data obtained from the scan is The fluorophore then is covalently attached to the transami typically in the form of fluorescence intensities as a function nated deoxycytidine nucleotides. See, e.g., U.S. Pat. No. of location on the array. 5,491,224. 0074 Arrays can be formed on substrates fabricated with 0070 Fluorophores of different colors can be chosen such materials such as paper, glass, plastic (e.g., polypropylene, that each probe in a set can be distinctly visualized. For nylon, or polystyrene), polyacrylamide, nitrocellulose, sili example, a combination of the following fluorophores can be con, optical fiber, or any other suitable solid or semisolid used: 7-amino-4-methylcoumarin-3-acetic acid (AMCA), Support, and can be configured in a planar (e.g., glass plates, TEXAS REDTM (Molecular Probes, Inc., Eugene, Oreg.), silicon chips) or three dimensional (e.g., pins, fibers, beads, 5-(and-6)-carboxy-X-rhodamine, lissamine rhodamine B. particles, microtiter wells, capillaries) configuration. Meth 5-(and-6)-carboxyfluorescein, fluorescein-5-isothiocyanate ods for generating arrays are known in the art and include, US 2012/01 OO637 A1 Apr. 26, 2012 e.g., photolithographic methods (see, e.g., U.S. Pat. Nos. SSD, severity of an SZ endophenotype, or a predicted 5,143,854: 5,510,270; and 5,527,681), mechanical methods response to a method of treating SZ, SD, or SPD, prior to or (e.g., directed-flow methods as described in U.S. Pat. No. during contact with the array. 5,384.261), pin-based methods (e.g., as described in U.S. Pat. 0078. In some aspects, the methods described herein can include using an array that can ascertain differential expres No. 5,288,514), and bead-based techniques (e.g., as sion patterns or copy numbers of one or more genes in described in PCT US/93/04145). The array typically includes samples from normal and affected individuals (see, e.g., oligonucleotide hybridization probes capable of specifically Redon et al., Nature 444(7118):444-54 (2006)). For example, hybridizing to different polymorphic variants. Oligonucle arrays of probes to a marker described herein can be used to otide probes that exhibit differential or selective binding to measure polymorphisms between DNA from a subject having polymorphic sites may readily be designed by one of ordinary a known severity of an SSD (e.g., SZ) endophenotype, and skill in the art. For example, an oligonucleotide that is per control DNA, e.g., DNA obtained from an individual that fectly complementary to a sequence that encompasses a poly does not have an SSD (e.g., SZ) endophenotype, or has a morphic site (i.e., a sequence that includes the polymorphic different severity of the SSD (e.g., SZ) endophenotype. Since the clones on the array contain sequence tags, their positions site, within it or at one end) will generally hybridize prefer on the array are accurately known relative to the genomic entially to a nucleic acid comprising that sequence, as sequence. Different hybridization patterns between DNA opposed to a nucleic acid comprising an alternate polymor from an individual afflicted with a severe SSD (e.g., SZ) phic variant. endophenotype and DNA from a normal individual (or an 0075 Oligonucleotide probes forming an array may be individual with SZ not displaying the endophenotype, or dis attached to a substrate by any number of techniques, includ playing a more or less severe degree of the endophenotype) at ing, without limitation, (i) in situ synthesis (e.g., high-density areas in the array corresponding to markers as described oligonucleotide arrays) using photolithographic techniques; herein, indicate the severity of the endophenotype. Methods (ii) Spotting/printing at medium to low density on glass, nylon for array production, hybridization, and analysis are or nitrocellulose; (iii) by masking, and (iv) by dot-blotting on described, e.g., in Snijders et al., Nat. Genetics 29:263-264 a nylon or nitrocellulose hybridization membrane. Oligo (2001): Kleinet al., Proc. Natl. Acad. Sci. USA 96:4494-4499 (1999); Albertson et al., Breast Cancer Research and Treat nucleotides can be immobilized via a linker, including by ment 78:289-298 (2003); and Snijders et al., “BAC microar covalent, ionic, or physical linkage. Linkers for immobilizing ray based comparative genomic hybridization, in: Zhao et al. nucleic acids and polypeptides, including reversible or cleav (eds), Bacterial Artificial Chromosomes. Methods and Pro able linkers, are known in the art. See, for example, U.S. Pat. tocols, Methods in Molecular Biology, Humana Press, 2002. No. 5,451,683 and WO98/20019. Alternatively, oligonucle 0079. In another aspect, this document provides methods otides can be non-covalently immobilized on a substrate by of determining the absence or presence of one or more alleles hybridization to anchors, by means of magnetic beads, or in a associated with severity of an SSD (e.g., SZ) endophenotype fluid phase Such as in microtiter wells or capillaries. Immo as described herein, using an array described above. The bilized oligonucleotide probes are typically about 20 nucle methods can include providing a two dimensional array hav otides in length, but can vary from about 10 nucleotides to ing a plurality of addresses, each address of the plurality about 1000 nucleotides in length. being positionally distinguishable from each other address of 0076 Arrays can include multiple detection blocks (i.e., the plurality having a unique nucleic acid capture probe, multiple groups of probes designed for detection of particular contacting the array with a first sample from a test Subject, and polymorphisms). Such arrays can be used to analyze multiple comparing the binding of the first sample with one or more references, e.g., binding of a sample from a subject who has a different polymorphisms. Detection blocks may be grouped known severity of an SSD (e.g., SZ) endophenotype, and/or within a single array or in multiple, separate arrays so that binding of a sample from a subject who has a different known varying conditions (e.g., conditions optimized for particular severity of the endophenotype, e.g., is unaffected, e.g., a polymorphisms) may be used during the hybridization. For control sample from a subject who has SZ but displays the example, it may be desirable to provide for the detection of endophenotype to a more or less severe degree. In some those polymorphisms that fall within G-C rich stretches of a embodiments, the methods can include contacting the array genomic sequence, separately from those falling in A-T rich with a second sample from a Subject who has a known sever segments. General descriptions of using oligonucleotide ity of an SSD (e.g., SZ) endophenotype; and comparing the arrays for detection of polymorphisms can be found, for binding of the first sample with the binding of the second example, in U.S. Pat. Nos. 5,858,659 and 5,837,832. In addi sample. In some embodiments, the methods can include con tion to oligonucleotide arrays, cDNA arrays may be used tacting the array with a third sample from a cell or Subject that similarly in certain embodiments. does not display an SSD (e.g., SZ) endophenotype (e.g., a low 0077. The methods described herein can include provid score); and comparing the binding of the first sample with the ing an array as described herein; contacting the array with a binding of the third sample. In some embodiments, the sec sample (e.g., all or a portion of genomic DNA that includes at ond and third samples are from first or second-degree rela least a portion of a human chromosome comprising a tives of the test subject. In the case of a nucleic acid hybrid response allele) and/or optionally, a different portion of ization, binding with a capture probe at an address of the genomic DNA (e.g., a portion that includes a different portion plurality, can be detected by any method known in the art, of one or more human chromosomes), and detecting binding e.g., by detection of a signal generated from a label attached of a nucleic acid from the sample to the array. Optionally, the to the nucleic acid. method includes amplifying nucleic acid from the sample, e.g., genomic DNA that includes a portion of a human chro Schizophrenia Spectrum Disorders mosome described herein, and, optionally, a region that 0080. The methods described herein can be used to deter includes another region associated with a diagnosis of an mine severity of an endophenotype of a schizophrenia spec US 2012/01 OO637 A1 Apr. 26, 2012

trum disorder (SSD) in an individual diagnosed with the SSD. rating points. These seven points represent increasing levels The SSDs include schizophrenia (SZ), schizotypal personal of psychopathology, as follows: ity disorder (SPD), and schizoaffective disorder (SD). Meth 0087 1-absent ods for diagnosing SSDs are known in the art, see, e.g., the 0088. 2 minimal Diagnostic and Statistical Manual of Mental Disorders— 0089) 3 mild Fourth Edition (“DSM-IV). See, e.g., WO 2009/092032, 0090 4 moderate incorporated herein by reference. 0091 5 moderate severe Psychiatric Endophenotypes 0092 6-severe 0093 7 extreme 0081. A number of endophenotypes, i.e., intermediate The individual PANSS Individual subcales are described phenotypes, that may more closely reflect biological mecha below. nisms behind SZ, have been suggested. Such as prepulse inhibition, structural abnormalities evident in MRI scans, 0094 P1. DELUSIONS Beliefs which are unfounded, specific domains of cognition (e.g., executive function), fine unrealistic and idiosyncratic. motor performance, and working memory, interalia. 0.095 P2. CONCEPTUAL DISORGANIZATION Dis 0082 Endophenotypes also can include clinical manifes organized process of thinking characterized by disruption of tations such as hallucinations, paranoia, mania, depression, goal-directed sequencing, e.g. circumstantiality, loose asso obsessive-compulsive symptoms, etc., as well as response or ciations, tangentiality, gross illogicality or thought block. lack of response to drugs and comorbidity for Substance and 0.096 P3. HALLUCINATORY BEHAVIOR Verbal alcohol abuse. See, e.g., Kendler et al., Am J Psychiatry report or behavior indicating perceptions which are not gen 152(5):749-54 (1995); Gottesman and Gould, Am J Psychia erated by external stimuli. These may occur in the auditory, try 160(4):636-45 (2003); Cadenhead, Psychiatric Clinics of visual, olfactory or Somatic realms. North America 25(4):837-53 (2002); Heinrichs, Neuro (0097 P4. EXCITEMENT Hyperactivity as reflected in science & Biobehavioral Reviews 28(4):379-94 (2004); and accelerated motor behavior, heightened responsivity to Zobel and Maier, Nervenarzt. 75(3):205-14 (2004). There is stimuli, hypervigilance or excessive mood lability. now evidence that Some candidate genes that were identified (0098 P5. GRANDIOSITY Exaggerated self-opinion using DSM-IV type categorical definitions for “affected and unrealistic convictions of Superiority, including delusions individuals may influence specific endophenotypes, see, e.g., of extraordinary abilities, wealth, knowledge, fame, power Baker et al., Biol Psychiatry 58(1):23-31 (2005); Cannon et and moral righteousness. al., Arch Gen Psychiatry 62(11):1205-13 (2005); Gothelf et 0099 P6. SUSPICIOUSNESS/PERSECUTION Unre al., Nat Neurosci8(11): 1500-2 (2005); Hallmayeret al., Am J alistic or exaggerated ideas of persecution, as reflected in Hum Genet. 77(3):468-76 (2005); Callicott et al., Proc Natl guardedness, ad distrustful attitude, Suspicious hypervigi Acad Sci USA 102(24):8627-32 (2005); Gornick et al., J lance or frank delusions that others mean harm. Autism Dev Disord 1-8 (2005). Thus, the methods described 0100 P7. HOSTILITY Verbal and nonverbal expres herein can be used to associate alleles with specific psychiat sions of anger and resentment, including sarcasm, passive ric endophenotypes. aggressive behavior, Verbal abuse and assualtiveness. I0083 Positive and Negative Syndrome Scale (PANSS) 01.01 N1. BLUNTED AFFECT Diminished emotional I0084. The Positive and Negative Syndrome Scale responsiveness as characterized by a reduction in facial (PANSS) is a comprehensive psychometric scale used to clas Sify psychopathology for severe neuropsychiatric diseases, expression, modulation of feelings and communicative ges including SZ. It measures a number of psychiatric endophe tures. notypes or dimensions using quantitative scales based on the 0102) N2, EMOTIONAL WITHDRAWAL. Lack of scoring of patients by clinicians. It is widely used to classify interest in, involvement with, and affective commitment to patients into specific Subtypes, and is commonly used for life's events. measuring the improvement of symptoms in response to clini (0103) N3. POOR RAPPORT Lack of interpersonal cal interventions (Kay et al., Schizophr. Bull. 13:261-276 empathy, openness in conversation and sense of closeness, (1987); Kay et al., Br. J. Psychiatry Suppl 59-67 (1989); interest or involvement with the interviewer. This is evi Leuchtet al., Schizophr. Res. 79:231-238 (2005)). denced by interpersonal distancing and reduced verbal and I0085 PANSS comprises 30 individual subscales. Seven nonverbal communication. constitute a Positive Symptom Scale, seven make up a Nega 01.04 N4. PASSIVE/APATHETIC SOCIAL WITH tive Symptom Scale, and the remaining 16 items make up a DRAWAL. Diminished interest and initiative in social inter General Psychopathology Scale. The scores for these scales actions due to passivity, apathy, anergy or avolition. This are arrived at by Summation of ratings across component leads to reduced interpersonal involvements and neglect of items. Therefore, the potential ranges are 7 to 49 for the activities of daily living. Positive and Negative Scales, and 16 to 112 for the General 0105 N5. DIFFICULTY IN ABSTRACT THINKING Psychopathology Scale (Source: The PANSS Institute). Impairment in the use of the abstract-symbolic mode of think Detailed information on PANSS and Scoring Criteria can be ing, as evidenced by difficulty in classification, forming gen found at www.panss.org or in the book Positive and Negative eralizations and proceeding beyond concrete or egocentric Syndromes in Schizophrenia, Stanley R. Kay, 1991, ISBN: thinking in problem-solving tasks. 978-0-87630-608-6, Routledge, which is incorporated herein 01.06 N6. LACK OF SPONTANEITY AND FLOW OF in its entirety by reference. Based on these sources, the meth CONVERSATION Reduction in the normal flow of com odology is summarized briefly below. munication associated with apathy, avolition, defensiveness I0086 Each of the 30 items is accompanied by a specific or cognitive deficit. This is manifested by diminished fluidity definition as well as detailed anchoring criteria for all seven and productivity of the verbal interactional process. US 2012/01 OO637 A1 Apr. 26, 2012

01.07 N7. STEREOTYPED THINKING Decreased (0123 G16. ACTIVE SOCIAL AVOIDANCE Dimin fluidity, spontaneity and flexibility of thinking, as evidenced ished social involvement associated with unwarranted fear, in rigid, repetitious or barren thought content. hostility, or distrust. 0108 G1. SOMATIC CONCERN Physical complaints or beliefs about bodily illness or malfunctions. This may Differential Diagnosis and Optimizing Treatment range from a vague sense of ill being to clear-cut delusions of 0.124. Each patient's disease manifestation and process is catastrophic physical disease. unique. PANSS provides a structured, objective way of 0109 G2. ANXIETY Subjective experience of nervous describing the various aspects of psychopathology of a given ness, worry, apprehension or restlessness, ranging from patient. However, proper implementation of the PANSS requires highly trained personnel to conduct the assessment excessive concern about the present or future to feelings of and to interpret the results, and there is potential for site to site panic. variability, especially outside the research setting. Addition 0110 G3. GUILT FEELINGS Sense of remorse or self ally, PANSS does not allow one to determine genetic (or blame for real or imagined misdeeds in the past. biological) vs. environmental contributions to psychopathol 0111 G4. TENSION Overt physical manifestations of ogy, or which of the many possible genetic contributions are fear, anxiety, and agitation, such as stiffness, tremor, profuse relevant to a particular patient. Sweating and restlessness. 0.125 Each of the PANSS composite scales and subscales can be considered a clinical endophenotype. The ability to 0112 G5. MANNERISMS AND POSTURING Un link genetic profiles to these clinical endophenotypes, as natural movements or posture as characterized be an awk described herein, will enable clinicians to refine a patient's ward, stilted, disorganized, or bizarre appearance. diagnosis and develop a personalized therapeutic strategy for 0113 G6. DEPRESSION Feelings of sadness, discour each patient. For example, the Callele of rs3096489, located agement, helplessness and pessimism. in the COL25A1 gene, is associated with increased in the 0114 G7. MOTOR RETARDATION Reduction in Negative Symptom of Increased Difficulty with Abstract motor activity as reflected in slowing or lessening or move Thinking as shown in the regression analysis in Table 2. By ments and speech, diminished responsiveness of stimuli, and identifying these genetic contributions to specific endophe reduced body tone. notypes, the physician can create a personalized diagnosis 0115 G8. UNCOOPERATIVENESS Active refusal to and treatment regime for the patient. 0.126 Results of the methods described herein (e.g., iden comply with the will of significant others, including the inter tifying a specific allele in a Subject), and optionally interpre viewer, hospital staff or family, which may be associated with tive information, can be returned to the subject, the health distrust, defensiveness, stubbornness, negativism, rejection care provider or to a third party payor. The results can be of authority, hostility or belligerence. provided, e.g., in the form of a report; thus, the methods can 0116 G9. UNUSUAL THOUGHT CONTENT Think include preparing a report comprising the results of a method ing characterized by Strange, fantastic or bizarre ideas, rang described herein, and identifying information regarding the ing from those which are remote oratypical to those which are Subject, and optionally interpretive information (e.g., infor distorted, illogical and patently absurd. mation regarding the association of the allele present in the 0117 G10. DISORIENTATION Lack of awareness of Subject with a particular endophenotype). one's relationship to the milieu, including persons, place and I0127. The results can be used in a number of ways. The information can be, e.g., communicated to the tested Subject, time, which may be due to confusion or withdrawal. e.g., with a diagnosis/prognosis and optionally interpretive 0118 G11. POOR ATTENTION Failure in focused materials that help the subject understand the test results and alertness manifested by poor concentration, distractibility diagnosis/prognosis. The information can be used, e.g., by a from internal and external stimuli, and difficulty in harness healthcare provider, to determine whether a subject should be ing, Sustaining or shifting focus to new stimuli. assigned to a specific category (e.g., a category associated 0119 G12. LACK OF JUDGMENT AND INSIGHT with a specific disease endophenotype). The information can Impaired awareness or understanding of one's own psychiat be used, e.g., by a third party payor Such as a healthcare payer ric condition and life situation. This is evidenced by failure to (e.g., insurance company or HMO) or other agency, to deter recognize past or present psychiatric illness or symptoms, mine whether or not to reimburse a health care provider for denial of need for psychiatric hospitalization or treatment, services to the subject, or whether to approve the provision of decisions characterized by poor anticipation or conse services to the Subject. For example, the healthcare payer may quences, and unrealistic short-term and long-range planning. decide to reimburse a health care provider for treatments for SZ, SD, or SPD if the subject has an allele associated with a 0120 G13. DISTURBANCE OF VOLITION Distur particular severity of an SSD endophenotype. In some bance in the willful initiation, Sustenance and control of one's embodiments, the results are used by a healthcare provider to thoughts, behavior, movements and speech. select, change, or optimize treatment for the Subject. 0121 G14. POOR IMPULSE CONTROL Disordered I0128. The addition of a genotypefallele profile which regulation and control of action on inner urges, resulting in details a patient's individual predicted increased or decreased Sudden, unmodulated, arbitrary or misdirected discharge of symptom burden for endophenotypes can provide the treating tension and emotions without concern about consequences. physician with valuable information required to create an 0122 G15. PREOCCUPATION Absorption with inter enhanced, personalized treatment regimen for the patient. nally generated thoughts and feelings and with autistic expe Thus, the methods described herein can be used to select an riences to the detriment of reality orientation and adaptive antipsychotic medication for the Subject, according to treat behavior. ment and clinical methods known in the art. For example, the US 2012/01 OO637 A1 Apr. 26, 2012 methods can include selecting clozapine for positive symp increased symptom burden of mania would suggest that the tom endophenotypes; quetiapine for Subjects with hostility physician add a mood stabilizer to the patient's drug regimen. and aggression endophenotypes: olanzapine, clozapine, or An allele associated with disorientation, inattention, lack of amilsupride for negative symptom endophenotypes; and judgment or insight, preoccupation, or poor impulse control glutamate receptor modulators (several are presently in Phase would indicate administration of a drug for ADHD, e.g., a III clinical trials) for cognitive endophenotypes. non-stimulant (such as Atomoxetine (Strattera) or modafinil) 0129. Standard treatment regimens for the majority of or a stimulant, e.g., amphetamine methylphenidate (Ritalin, patients diagnosed as having SZ typically include polyphar Metadate, Concerta), dextroamphetamine (Dexedrine), macy. See Pickar et al., PLoS ONE 3(9):e3150 (2008). Phy mixed amphetamine salts (Adderall), dextromethamphet sicians often add antidepressants, mood stabilizers, and anti amine (Desoxyn) or lisdexamfetamine (Vyvanse). Additional anxiety medications to the customary treatment with exemplary choices of drugs to be used in addition to an antipsychotics. Additionally, non-medication based therapies antipsychotic for treating a subject identified as having a Such as electroconvulsive shock and cognitive behavioral specific endophenotype are shown below in Table 4. Changes therapy augment the drug treatment. Thus, in addition, the in a patient's PANSS score and clinical endophenotype can be identification of endophenotypes by a method described evaluated following the addition or subtraction of medica herein can be used as an objective criterion to optimize selec tions or non-medication based therapies with the goal of tion of a second drug for administration to the Subject. For optimizing treatment for that patient. See, e.g., Chung et al., example, if a patient's allele equates to a reference allele that World J Biol Psychiatry 10(2):156-62 (2009); Hori et al., indicates alikely increased burden for depression, the treating World J Biol Psychiatry August 25 E-Pub:1-5 (2009); Lipk physician might choose to augment antipsychotic therapy ovich et al., BMC Psychiatry 9:44 (2009); Hwang et al., Int with antidepressants. Similarly, an allele that indicates Clin Psychopharmacol 24(4): 189-98 (2009).

TABLE 4 Example Treatments for Specific Endophenotypes, e.g., in Combination with Anti-Psychotics Example Drug PANSSItem Treatment/Drug Class Trade name Generic name P1-delusions Cognitive Behavioral Therapy (CBT) P2—conceptual disorganization CBT P3—hallucinatory behavior CBT P4—exitement Mood stabilizer ithium, valproate, amotrigine P5—grandiosity Mood stabilizer ithium, valproate, amotrigine P6—Suspiciousness Anti-anxiety benzodiazepines P7—hostility Anti-anxiety benzodiazepines N1–blunted affect SSRI Prozac Fluoxetine NMDA-R glycine, d agonists cycloserine, an -serine N2—emotional withdrawal SSRI Prozac Fluoxetine NMDA-R glycine, d agonists cycloserine, an -serine N3—poor rapport SSRI Prozac Fluoxetine NMDA-R glycine, d agonists cycloserine, an -serine N4 passive appathetic SSRI Prozac Fluoxetine Social withdrawal NMDA-R glycine, d agonists cycloserine, an -serine N5—difficulty in abstract thinking NMDA-R glycine, d agonists cycloserine, an -serine N6—lack of spontaneity and NMDA-R glycine, d flow of conversation agonists cycloserine, an -serine N7—stereotyped thinking NMDA-R glycine, d agonists cycloserine, an -serine G1—Somatic concern SNRI Cymbalta uloxetine G2—anxiety Anti-anxiety benzodiazepines G3—guilt feelings SSRI Prozac fluoxetine G4 tension Mood stabilizer lithium, valproate, lamotrigine US 2012/01 OO637 A1 Apr. 26, 2012 13

TABLE 4-continued Example Treatments for Specific Endophenotypes, e.g., in Combination with Anti-Psychotics Example Drug PANSSItem Treatment Drug Class Trade name Generic name G5—mannerisms and posturing Mood stabilizer lithium, valproate, lamotrigine G6—depression SSRI Prozac Fluoxetine G7—motor retardation Dopaminergics G8—uncooperativeness Levomepromazine G9—unusual thought content CBT G10—disorentation ADHD Stratera, atomoxetine, treatinent Ritalin methylphenidate G11—poor attention ADHD Stratera, atomoxetine, treatment; Ritalin methylphenidate cholinesterase inhibitors G12—lack of judgment and insight ADHD Stratera, atomoxetine, treatment; Ritalin methylphenidate cholinesterase inhibitors G13—disturbance of volition cholinesterase inhibitors G14 poor impulse control ADHD Stratera, atomoxetine, treatment; Ritalin methylphenidate beta-blockers lithium, valproate, mood stabilizers, lamotrigine G15 preoccupation ADHD Stratera, atomoxetine, treatment; Ritalin methylphenidate cholinesterase inhibitors G16—active social avoidance. CBT: cholinesterase inhibitors SSRI = selective serotonin reuptake inhibitors SNRI = serotonin-norepinephrine reuptake inhibitor ADHD = attention deficit hyperactivity disorder

0130. In some cases, a medical or research professional professional can enroll a patient in a clinical trial for, by way can assess whether a Subject has an allele contributing to a of example, detecting correlations between an allele as clinical endophenotype according to the methods provided described herein and any measurable or quantifiable param herein. Medical professionals can be, for example, doctors, eter relating to an endophenotype as described above. nurses, medical laboratory technologists, and pharmacists. Research professionals can be, for example, principle inves I0133. A medical professional can communicate informa tigators, research technicians, postdoctoral trainees, and tion regarding severity of an SSD (e.g., SZ) endophenotype to graduate students. A professional can be assisted by (1) deter a patient or a patient's family. In some cases, a medical mining whether specific polymorphic variants are presentina professional can provide a patient and/or a patient's family biological sample from a subject, and (2) communicating with information regarding SSDs and severity of endopheno information about polymorphic variants to that professional. type information, including treatment options, prognosis, and 0131) Using information about specific polymorphic vari referrals to specialists. In some cases, a medical professional ants obtained using a method described herein, a medical can provide a copy of a patient's medical records to a special professional can take one or more actions that can affect ist. patient care. For example, a medical professional can record I0134. A research professional can apply information information in the patient's medical record regarding the regarding the presence of alleles associated with a severity of presence or absence of an SSD (e.g., SZ) endophenotype. In an SSD (e.g., SZ) endophenotype in a subject to advance Some cases, a medical professional can record information Scientific research. For example, a researcher can compile regarding an SSD (e.g., SZ) endophenotype, or otherwise data on specific polymorphic variants. In some cases, a transform the patient's medical record, to reflect the patient’s research professional can obtain information regarding the current medical condition. In some cases, a medical profes identity of an allele associated with a specific endophenotype sional can review and evaluate a patient's entire medical in a subject as described herein to evaluate a subject's enroll record and assess multiple treatment strategies for clinical ment, or continued participation, in a research study or clini intervention of a patient's condition. cal trial. In some cases, a research professional can commu 0132. In some cases, a medical professional can initiate or nicate information regarding a subject's alleles associated modify treatment after receiving genetic information regard with severity of an SSD (e.g., SZ) endophenotype to a medi ing endophenotype. In some cases, a medical professional cal professional. In some cases, a research professional can can recommenda change in therapy. In some cases, a medical refer a Subject to a medical professional. US 2012/01 OO637 A1 Apr. 26, 2012

0135 Any appropriate method can be used to communi test requisition form, and instructions on how to use the kit in cate information to another person (e.g., a professional). For a method described herein. Methods for using such kits are example, information can be given directly or indirectly to a also included herein. One or more of the forms (e.g., the test professional. For example, a laboratory technician can input a requisition form) and the container holding the sample can be patient's polymorphic variant alleles as described herein into coded, for example, with a barcode for identifying the subject a computer-based record. In some cases, information is com who provided the sample. municated by making a physical alteration to medical or research records. For example, a medical professional can Databases and Reports make a permanent notation or flag a medical record for com municating the risk assessment to other medical professionals 0.139. Also provided herein are databases that includealist reviewing the record. In addition, any type of communication of polymorphisms as described herein, and wherein the list is can be used to communicate allelic, genotypic, severity of largely or entirely limited to polymorphisms identified as endophenotype, and/or treatment information. For example, useful for determining severity of an SSD (e.g., SZ) endophe mail, e-mail, telephone, and face-to-face interactions can be notype as described herein. The list is stored, e.g., on a flat file used. The information also can be communicated to a profes sional by making that information electronically available to or computer-readable medium. The databases can further the professional. For example, the information can be com include information regarding one or more Subjects, e.g., municated to a professional by placing the information on a whether a subject is affected or unaffected, clinical informa computer database Such that the professional can access the tion Such as endophenotype, age of onset of symptoms, any information. In addition, the information can be communi treatments administered and outcomes (e.g., data relevant to cated to a hospital, clinic, or research facility serving as an pharmacogenomics, diagnostics or theranostics), and other agent for the professional. details, e.g., about the disorder in the Subject, or environmen tal or other genetic factors. The databases can be used to Articles of Manufacture detect correlations between a particular severity of an SSD (e.g., SZ) endophenotype and the information regarding the 0136. Also provided herein are articles of manufacture Subject. comprising a probe that hybridizes with a region of human 0140. The methods described herein can also include the chromosome as described herein and can be used to detect a generation of reports, e.g., for use by a patient, care giver, polymorphism described herein. For example, any of the payor, or researcher, that include information regarding a probes for detecting polymorphisms described herein can be subject's response allele(s), and optionally further informa combined with packaging material to generate articles of tion Such as treatments administered, treatment history, medi manufacture or kits. The kit can include one or more other cal history, predicted response, and actual response. The elements including: instructions for use; and other reagents reports can be recorded in a tangible medium, e.g., a com Such as a label or an agent useful for attaching a label to the puter-readable disk, a Solid State memory device, oran optical probe. Instructions for use can include instructions for diag storage device. nostic applications of the probe for assessing the severity of an SSD (e.g., SZ) endophenotype in a method described 0141 Engineered Cells and Methods of Screening herein. Other instructions can include instructions for attach 0142. Also provided herein are engineered cells that har ing a label to the probe, instructions for performing in situ bor one or more polymorphism described herein, e.g., one or analysis with the probe, and/or instructions for obtaining a more polymorphisms associated with severity of one or more sample to be analyzed from a Subject. In some cases, the kit SSD (e.g., SZ) endophenotypes. Such cells are useful for can include a labeled probe that hybridizes to a region of studying the effect of a polymorphism on physiological func human chromosome as described herein. tion, and for identifying and/or evaluating potential therapeu 0137 The kit can also include one or more additional tic agents such as anti-psychotics for the treatment of specific reference or control probes that hybridize to the same chro SSD endophenotypes. Methods of using such cells to identify mosome or another chromosome or portion thereof that can candidate therapeutics for the treatment of SZ are known in have an abnormality associated with a particular endopheno the art, e.g., contacting the cells with a test compound and type. A kit that includes additional probes can further include assaying for an effect of the test compound on the cell. The labels, e.g., one or more of the same or different labels for the methods can also include detecting an effect of a polymor probes. In other embodiments, the additional probe or probes phism described herein on the activity or levels of a gene or provided with the kit can be a labeled probe or probes. When protein associated with that polymorphism, to identify a tar the kit further includes one or more additional probe or get for therapeutics. probes, the kit can further provide instructions for the use of 0143. As one example, included herein are cells in which the additional probe or probes. Kits for use in self-testing can one of the various alleles of the genes described herein has be also be provided. Such test kits can include devices and re-created that is associated with a particular severity of an instructions that a Subject can use to obtain a biological SSD (e.g., SZ) endophenotype. Methods are known in the art sample (e.g., buccal cells, blood) without the aid of a health for generating cells, e.g., by homologous recombination care provider. For example, buccal cells can be obtained using between the endogenous gene and an exogenous DNA mol a buccal Swab or brush, or using mouthwash. ecule introduced into a cell, e.g., a cell of an animal. In some 0138 Kits as provided herein can also include a mailer cases, the cells can be used to generate transgenic animals (e.g., a postage paid envelope or mailing pack) that can be using methods known in the art. used to return the sample for analysis, e.g., to a laboratory. 0144. The cells are preferably mammalian cells (e.g., neu The kit can include one or more containers for the sample, or ronal type cells) in which an endogenous gene has been the sample can be in a standard blood collection vial. The kit altered to include a polymorphism as described herein. Tech can also include one or more of an informed consent form, a niques such as targeted homologous recombinations, can be US 2012/01 OO637 A1 Apr. 26, 2012

used to insert the heterologous DNA as described in, e.g., ated with the minor allele. For quantitative values. PLINK Chappel, U.S. Pat. No. 5,272,071; WO 91/06667, published performs a linear regression using an additive model for the in May 16, 1991. minor allele. 0153. Tables 1-3 report results for specific SNP alleles that EXAMPLES affect quantitative endophenotypes for SZ, along with Beta values and P values for the particular alleles of SNPs listed 0145 The invention is further described in the following therein. The Beta, beta weight from the regression, measures examples, which do not limit the scope of the invention the impact of the SNP allele on the particular scale. A positive described in the claims. Beta means that the allele for the test SNP increases the score for that measure of psychopathology by the stated Beta value, Example 1 while a negative Beta means that the allele for the test SNP decreases the score that for that measure of psychopathology Novel Markers Associated with Overal Psychiatric by the stated Beta value. Endophenotypes in SZ 0154) Table 1 shows selected examples for PANSS Total score, and Table 2 shows selected examples for Positive 0146 The Clinical Antipsychotic Trials of Intervention Symptoms subscale, Negative Symptoms Subscale, and the Effectiveness (CATIE), a large federally funded clinical trial General Psychopathology Subscale, analyzed as quantitative designed to assess the efficacy of antipsychotics in a real traits in PLINK using linear regression. world setting, is a valuable resource for determining the role 0155 Table 3 shows selected examples for the individual of genes in drug response (Stroup et al., Schizophr. Bull. PANSS components. The component evaluated in each row is 29:15-31 (2003); Lieberman et al., N. Engl. J. Med. 353: identified by one of the following abbreviations: Positive 1209-1223 (2005)). As part of the CATIE trial, SNP genotyp Symptoms: P1—delusions, P2-conceptual disorganization, ing was performed for roughly half of the trial participants P3—hallucinatory behavior, P4—exitement, P5 grandios (Sullivan et al., Mol. Psychiatry. 13:570-584 (2008)). When ity, P6—suspiciousness, P7 hostility; Negative Symptoms: combined with disease status, PANSS scores, and clinical N1—blunted affect, N2—emotional withdrawal, N3—poor drug response data, the genotyping data allows the identifi rapport, N4 passive/appathetic social withdrawal, N5—dif cation of genetic variants (e.g., SNPs) that are statistically ficulty in abstract thinking, N6—lack of spontaneity and flow associated with specific endophenotypes. of conversation, N7—steryotyped thinking; General Psycho 0147 The design of the CATIE study has been described pathology Symptoms: G1—somatic concern, G2 anxiety, in detail by others (see, e.g., Stroup et al., Schizophr. Bull. G3 guilt feelings, G4 tension, G5—mannerisms and pos 29:15-31 (2003); Lieberman et al., N. Engl. J. Med. 353: turing, G6—depression, G7 motor retardation, G8—unco 1209-1223 (2005)). Briefly, 1460 subjects were randomly operativeness, G9 unusual thought content, G10 disoren assigned one of several antipsychotics and those who did not tation, G11—poor attention, G12—lack of judgment and respond or chose to quit their current medication were re insight, G13 disturbance of volition, G14 poor impulse randomized to another drug. Details regarding SNP genotyp control, G15-preoccupation, G16—active social avoidance. ing and quality control have been recently published (Sullivan 0156 Table A lists the chromosome and position for each et al., Mol. Psychiatry. 13:570-584 (2008)). SNP by SEQ ID NO.; the genomic position is relative to 0148 Genotype and phenotype data for the CATIE trial NCBI Human Genome Reference Assembly Build 36.3. were made available to qualified researchers through the NIMH Center for Collaborative Genetic Studies on Mental Other Embodiments Disorders. Data for 417 patients with schizophrenia and 419 0157. It is to be understood that while the invention has unaffected controls self reported as having exclusively Euro been described in conjunction with the detailed description pean ancestry were evaluated. This same patient population thereof, the foregoing description is intended to illustrate and was described in a recent study by Sullivan and coworkers, not limit the scope of the invention, which is defined by the which confirmed that there is no hidden stratification in the Scope of the appended claims. Other aspects, advantages, and sample (Sullivan et al., Mol. Psychiatry. 13:570-584 (2008)). modifications are within the scope of the following claims. 0149 For the CATIE study, individual cases were diag nosed as having SZ based on DSM-III/IV criteria. TABLE 1 0150 Confirmation of SNP Effects on Psychiatric Endophenotypes Alleles Influencing Total PANSS 0151. Genotype and PANSS phonotype data were evalu Sequence NCBI ated for 417 SZ patients enrolled in the CATIE trial. Follow Gene ID RS # Allele Beta P ing a period of drug wash-out, the CATIE study investigators KIF1B 3 1555849 G 2.66 0.0467 rated each participant at baseline for psychopathology using CGN 16 1547832 A. -395 O.0421 the PANSS. RALGPS2 32 12O76230 G -3.O2 O.O169 USH2A 42 7548730 C 2.92 O.O239 0152 Each of the individual and composite scores is a RYR2 66 27794OO A. -2.62 O.O3SS quantitative trait that can be assessed using quantitative sta CHRM3 69 16838637 G 2.40 O.O397 tistical genetics methods. Genetic analysis to determine the FMN2 86 10926257 T S.23 O.O181 influence of haplotypes on quantitative PANSS values was AGBL4-C1 ORF16S 91 319965 A. 2.78 O.O262 performed using the PLINK 1.03 whole genome analysis SCP2 98 3766762 C -6.05 O.O383 ELTD1 1OO 17102632 T 3.37 0.042S toolset developed by Purcell and coworkers (Purcell et al., HPCAL1 105 16856O20 T 4.SS O.O1 O2 Am. J. Hum. Genet. 81:559-575 (2007). For dichotomous NTSR2 108 46697.67 C -299 OO158 values. PLINK calculates P values for the allele-specific chi RAB3GAP1 112 16831315 C 4.04 0.0490 squared test and the odds ratio (OR; or relative risk) associ

US 2012/01 OO637 A1 Apr. 26, 2012 21

TABLE 2-continued Alleles Influencing PANSS Scales Gene Name Sequence ID NCBI RS # Allele PANSS Scale Beta P SLC7A14 371 1861938 T General -151 O.O2914 SLC7A14 372 6788S96 G General -146 (O.O3211 SLC7A14 372 6788S96 G. Positive -O.89 O.O3413 PLD1 377 7633,686 G General -190 O.04844 PLD1 378 67676OO T Positive -132 O.O2O48 PLD1 379 2178532 A Positive -131 O.O2693 NLGN1 380 4894645 T Positive S8 O.OO617 NLGN1 381 1263618O T Positive O.95 0.041.99 HTR3D 385 93.9334 G Negative 14 O.O1755 HTR3D 386 6779545 A Negative 29 O.OOS82 HTR3D 386 6779545 A Genera 34 0.04623 IL1RAP 394 679.1374 C Negative -2.58 O.OO275 CENTB2 396 2050810 A Negative 13 O.O4537 CENTB2 397 9859822 G Negative -1.11 O.O3605 UBXD7 398 3973 T Genera -138 0.04893 RARB 400 7525900 C Negative -1.88 O.O1234 CNTN4 40S 1420O20 G Genera 2.22 O.O4942 CLASP2 410 9853831 T Genera -1.28 O.O4451 CLASP2 411 764102O G Genera -144 O.O2355 STAC 413 7186340 T Genera 2.69 O.O1598 ULK4 415 1495698 C Genera 87 0.00579 ULK4 416 1691964 T Genera 2.35 O.OOO19 ULK4 417 1691966 G Negative 34 O.OO244 ULK4 418 1691998 G Negative 22 O.OO598 ULK4 419 3069172 G Negative 18 O.OO788 ULK4 419 3069172 G Genera 2.34 O.OOO19 SEMA3F 424 2518796 G. Positive O.84 O.O4723 SEMA3F 425 2632110 A Negative -0.95 O.O4788 CACNA2D2 426 743757 C Positive -1.10 O.O4985 CACNA2D3 427 1130396 T Positive -1.07 O.O1458 ERC2 433 1993539 T Negative 17 O.O4242 ERC2 435 7647.972 C Negative -O.98 O.O4457 ERC2 438 7619653 C Negative -1.01 O.O.3263 ERC2 440 782S4O9 C Negative -1.29 O.OO721 ERC2 442 49742OO G Negative -1.26 O.OO942 ERC2 443 49742O6 G Negative -1.10 O.O216O ERC2 444 3064S25 C Negative -109 O.O262O ERC2 445 1546060 C Negative -151 O.OO117 ERC2 446 68.05882 C Negative -144 O.OO174 ERC2 447 885211 A Negative -1.25 O.OO744 ERC2 450 98.73381 A Negative -1.16 O.O1153 ERC2 453 762.7759 C Negative -1.06 O.O2O17 FHIT 454 639244 G Negative 46 (O.OO222 FHIT 454 639244 G General 86 O.OO613 FHIT 455 22S3211 C Negative 24 O.OOSO6 FHIT 455 22S3211 C General 31 O.O3719 FHIT 456 2121865 T General 45 0.02600 FHIT 457 1332O646 A Negative O.93 0.04266 FHIT 458 7631246 T Negative O.91 O.O4386 PTPRG 459 624755 G. Positive O.86 O.O3164 CADPS 467 1355551 T Negative 6O O.OO679 CADPS 469 9311842 T Negative 24 O.O1790 CADPS 471 13313979 A General -1.53 0.02767 CADPS 471 13313979 A Negative -113 O.O2112 CADPS 473 186236 C Negative -119 O.O1263 CADPS 474 1728.0557 A General -1.61 O.O.3648 CADPS 474 1728.0557 A Negative -148 O.OO616 CADPS 475 1728.0571 T Negative -146 (O.OO361 CADPS 476 17357618 C General -1.6O O.O2389 CADPS 476 17357618 C Negative -130 O.OO899 CADPS 477 1192S708 A General -1.65 O.OO918 PRICKLE2 479 161661 A Negative 10 O.O1731 MAGI1 482 2371948 A General 4.96 O.O1513 MAGI1 483 9845819 C General -1.65 O.O1521 MAGI1 484 7612636 C Positive O.80 O.O4761 FAM19A1 485 11707519 G Negative -1.62 O.O1054 FOXP1 487 2196356 C Positive O.94 O.O2442 GBE1 490 7622741 G Negative O6 0.02757 GBE1 490 7622741 G General 7S O.O1095 GBE1 491 6769230 A Negative OO O.O3881 GBE1 491 6769230 A General 7S O.O1152 GBE1 492 2307058 T General 63 (0.01934 US 2012/01 OO637 A1 Apr. 26, 2012 22

TABLE 2-continued Alleles Influencing PANSS Scales Gene Name Sequence ID NCBI RS # Allele PANSS Scale Beta P GBE 494 76.13144 T General S9 O.O2.238 GBE 495 17O19088 T Positive -O.99 O.O45O2 GBE 498 268O245 A General -1.43 0.02444 GBE 498 268O245 A Negative -O.98 O.O2995 GBE 499 3860595 C Negative O.96 O.O3451 HTR1F 500 1027689 T Positive 46 0.02814 HTR1F 500 1027689 T General 2.38 O.O2649 DKK2 505 379333 T Positive -149 0.03572 COL25A1 SO8 794-149 G Negative O.97 O.O3330 COL25A1 509 3096483 C Negative O.94 O.O4193 COL25A1 510 3096489 C Negative O.91 O.O4566 ANK2 512 13134375 C Negative -1.38 O.OO232 ANK2 513 13107082 G Negative 37 O.OO2S2 ANK2 S1.4 413019 C Negative 34 O.OO3O6 ANK2 517 29306 G Negative 14 O.O2465 ANK2 S18 29311 A Negative 37 O.OO716 ANK2 S18 29311 A General 80 O.O1303 NDST3 521 23895O1 A Positive -1.24 O.O4798 MAML3 525 6819304 A General -1.91 O.O4975 L15 527 17.007695 C Positive S1 O.O3432 NPP4B 528 2667101 G Negative O.96 O.O3672 NPP4B 529 2667108 C General 4.31 O.O.3599 NPP4B 531 13536O3 A Negative 3.06 O.OO875 NPP4B 532 336329 G Negative 2.97 O.O3997 NPP4B 532 336329 G General 4.31 O.O.3599 NPP4B 533 1701SS44 T Positive 1.63 O.OO671 NPP4B 534 2276942 A Positive 2.11 O.OO222 NPP4B 535 3775655 C Positive 1.84 O.OO689 NPP4B 536 2627828 G. Positive 1.91 O.O3133 POU4F2 538 1979903 C Negative -2.17 O.O1897 FSTL5 543 682SO91 A General 1.85 O.O1004 FSTL5 544 7442468 C General 1.79 0.01173 FSTL5 545 1431490 G General 2.68 O.O1648 FSTL5 S46 12499128 A General 2.60 OO1918 FSTL5 547 17459658 C General 2.01 O.O3261 LDB2 552 157631 G General 3.03 O.O1049 LDB2 553 284210 T General 2.SO 0.04007 LDB2 556 13110882 G Negative -130 O.OO288 TLL1 557 11.9426SO G. Positive -1.88 O.O4937 PALLD 559 17OS4309 A Negative -1.21 O.O4563 PALLD S64 3.1092O6 T Negative -1.2O O.OO7SS PALLD 565 11930576 C Negative -1.15 O.O1329 PALLD 566 442S335 G Negative -145 O.OOS/2 PALLD 567 42807OO T Negative -146 (O.O2O35 PALLD 568 1251.1925 T Negative -131 O.O4313 ODZ3 570 2726792 G. Positive O1 O.O1596 ODZ3 571 2675534 T Negative .77 O.OOO84 ODZ3 572 2675532 C Positive O.90 O.O3O89 ODZ3 572 2675532 C Negative 38 O.OO338 ODZ3 572 2675532 C General S1 O.02450 ENPP6 574 683O766 G General -1.36 0.03770 ENPP6 575 44.31268 A General -1.SS O.O2259 ENPP6 576 4241786 C General -153 O.O2423 ENPP6 577 4340829 A General -146 (O.O273O ENPP6 578 68151.45 A General -147 O.O3O43 ENPP6 579 17584O49 C General -1.85 O.OO475 ENPP6 579 17584O49 C Positive -1.02 O.O1215 KIAA1239 589 4585313 C General 3.06 O.O1647 KIAA1239 590 17575883 A Positive -1.10 O.04116 KIAA1239 592 2973226 C Positive -O.95 O.O1429 KIAA1239 593 1382979 A Positive -104 O.O2140 UBE2K 595 2054718 T Positive 27 O.O.1985 UBE2K 596 192779 A Positive 28 0.01435 LIMCH1. 598 4343753 T General 2.02 O.OO656 NPFFR2 611 765.4531 T Negative O4 O.O3353 NPFFR2 612 6824703 C Negative O4 O.O3375 NPFFR2 614 17775309 G General -1.64 OO153O SCD5 62O 76798.57 A Positive -1.24 O.O2O71 SCD5 621 7684732 C General -1.83 O.O2561 SCD5 622 17006038 C Positive -1.24 O.O22O2 SCD5 622 17006038 C Negative -1.20 O.04882 SCD5 623 6848.340 T General -2.27 O.O.3066 US 2012/01 OO637 A1 Apr. 26, 2012 23

TABLE 2-continued Alleles Influencing PANSS Scales Gene Name Sequence ID NCBI RS # Allele PANSS Scale Beta P FAM13A1 626 454.4678 C General 49 O.O1797 FAM13A1 627 769 1186 G General 48 0.01929 PDLIMS 632 68.12098 C General 68 0.04393 SLC2A9 637 13111638 T Negative -140 O.O1145 SLC2A9 641 12509955 T Negative -134 O.O1153 SLC2A9 643 7671266 T Negative -145 O.OO682 FBXL17 646 11242664 G Negative .33 O.O2S1.4 FBXL17 646 11242664 G General 86 0.02767 PA2 653 11957188 T Positive -2.79 0.00495 KCNN2 654 14.57762 A General 34 0.03426 HSD17B4 662 24.6968 A General -1.6O O.OO943 SNX2 669 12109789 G. Positive O.79 0.04779 SNX2 670 10519715 A Negative O.97 O.O4493 SNX2 670 10519715 A General 42 (0.03964 SNX2 671 24O7403 G Negative -1.14 O.O1761 SNX24 672 6888023 T General 42 (0.03843 SNX24 673 246286 T Negative -O.97 O.O3999 SNX24 674 246.266 C Negative -O.96 O.O446O SNX24 674 246.266 C Positive -O.86 O.O4O92 SNX24 675 68664OO A Negative O.96 O.O4S15 WDAC1 677 4958172 A Genera -1.98 O.O3716 TRPC7 68O 377.7150 A Negative 1.13 O.O1239 TRPC7 682 96.3590 C Positive -O.91 O.O3266 DNAHS 686 105.13155 A Genera 1.39 O.O3933 DNAHS 688 47.01997 T Genera 2.38 O.OOO27 DNAHS 691 1315445S G Genera 2.22 O.OOO79 GRLA1 694 773.5696 C Negative O.98 0.02728 GRLA1 695 17518831 C Negative O.90 O.O4258 GRLA1 696 778822 C Positive -1.18 O.OO987 GRLA1 701 7708391 A Genera -147 O.O3123 ODZ2 704 2337017 C Genera -3.31 O.OOO22 ODZ2 704 2337017 C Negative -145 0.02177 MYO10 705 428.263 A Positive O.92 O.O2306 MYO10 706 388887 T Positive O.87 O.O3O24 ODZ2 707 7714651 A Genera -2.07 O.O33OO ODZ2 707 7714651 A Positive -1.38 O.O2204 ODZ2 708 1421989 G Genera -2.67 O.OO145 ODZ2 708 1421989 G. Positive -153 O.OO32O ODZ2 711 6868169 G. Positive 19 O.OO429 ODZ2 711 6868169 G Genera SS O.O.2104 ODZ2 712 11748886 G. Positive .72 0.04326 MYO10 713 11750538 G. Positive -O.88 O.O3391 MYO10 714 11133860 G. Positive -1.16 OO1532 PLEKHG4B 716 93.12845 T Negative 69 O.OO876 PLEKHG4B 717 93.128SO G Negative S6 O.O1509 PLEKHG4B 718 6888.246 T Negative SS O.O1701 PLEKHG4B 719 3853.521 A Negative 57 0.01763 PLEKHG4B 720 688S136 C General 37 O.O2941 CDH10 722 3822429 T General -148 O.O2O17 CDH10 722 3822429 T Negative -1.07 O.O1629 CDH10 722 3822429 T Positive -1.02 O.OO950 SLC45A2 723 3S388 T Negative -1.OO O.O2O24 SLC45A2 724 22780O8 C Negative -O.98 O.04719 C1OTNF3 725 17583.316 C Negative -1.27 O.OO913 C1OTNF3 728 9292S23 C Negative -1.11 O.O1589 EGFLAM 730 486958O T Negative 66 O.O1214 AHRR 734 4956936 C Negative O1 O.O388O AHRR 735 2672734 C Negative -1.12 O.O1572 EXOC3 736 2561667 T Negative -1.05 O.O2605 ITGA1 739 10474-81 G General -135 0.04787 ITGA2 740 32.12576 G Negative 17 O.O4568 CMYA5 753 11.960229 C General 2.O2 O.O1984 CMYA5 754 688068O C General 2.80 O.OO792 CMYA5 755 3828611 G Negative 86 0.02235 CMYA5 755 3828611 G General 2.7O O.O1945 SEMASA 768 98.5723 A Negative 48 002151 SEMASA 769 2S7094 C Negative 3O 0.04861 SEMASA 770 111343S4 A General -2.05 O.OO944 SEMASA 771 47O2625 G General -1.88 O.O1741 SEMASA 772 2684.81 C General -2.13 O.O2437 SEMASA 773 268529 G General -134 O.O4990 SLC22A16 775 9398237 T Negative -1.24 O.O1156

US 2012/01 OO637 A1 Apr. 26, 2012 27

TABLE 2-continued Alleles Influencing PANSS Scales Gene Name Sequence ID NCBI RS # Allele PANSS Scale Beta C DEPDC2 219 699O381 T Negative O.94 O.O3520 KCNB2 227 132S1896 G Negative -1.10 O.O1395 KCNB2 227 132S1896 G. Positive -O.82 O.O3948 KCNB2 230 2196904 C Negative -1.11 O.O1975 KCNB2 231 866,740 A Negative -O.93 0.04845 KCNB2 232 13277104 G Negative -1.02 O.O2351 KCNB2 232 13277104 G. Positive -O.89 O.O2549 MMP16 236 6994.019 T Genera -1.78 O.O1335 MMP16 236 6994.019 T Negative -1.07 O.O.3595 MMP16 237 8792O3 C Negative -1.10 O.O3726 MMP16 238 384-4198 A Genera -1.7O O.O2O28 MMP16 241 4548227 A Negative -140 O.OO384 GABBR2 242 435253 T Genera -1.91 O.O1876 GABBR2 243 10985765 C Genera -1.86 O.O1922 GABBR2 244 2778.913 T Genera -2.14 O.O3218 GABBR2 245 93O139 G Negative -1.24 O.O182O STOM 260 17086 G. Positive -O.79 0.04711 FREQ 269 120O3792 A Positive O.88 O.O4157 ABL1. 273 10901294 T Genera -3.10 O.O1311 TSC1 275 11243940 G. Positive -1.03 O.O2O27 TSC1 276 70353O8 A Positive -O.90 O.O4546 OLFM1 278 665748 A Positive 49 0.038OO OLFM1 278 665748 A Genera 3.SO O.OO246 OLFM1 279 S42172 A Genera 3.19 O.OOS/3 NPP5E 28O 38.12591 C Negative 28 0.01173 KIAA1797 285 12338810 T Genera -2.6S O.OO175 KIAA1797 285 12338810 T Positive -117 O.O2646 KIAA1797 286 12336110 A Genera -2.65 O.OO2O4 KIAA1797 286 12336110 A Positive -1.12 O.O3654 KIAA1797 289 1051 1687 G Negative S2 O.OOO99 KIAA1797 289 1051 1687 G Genera 2.10 O.OO138 KIAA1797 291 2383.162 G Genera -137 O.O4082 KIAA1797 292 4977823 T Genera -1.54 O.O2497 KIAA1797 294 10511693 G Negative 24 OO1526 KIAA1797 295 45.7961.2 C Genera 2.OS O.OO322 KIAA1797 296 4977848 A Genera -144 O.O.3549 KIAA1797 298 7030990 G Negative 22 O.O2O58 KIAA1797 299 4977881 A Negative 1O O.O2813 KIAA1797 299 4977881 A Genera 93 O.OO666 KIAA1797 3OO 4468O2O T Negative O3 O.O3784 KIAA1797 3OO 4468O2O T Genera 89 O.OO718 TEK 306 10967731 A Positive -1.11 O.OO607 TEK 307 1322051 A Positive -1.89 O.04390 TEK 3O8 2273719 T Genera -2.13 O.O2223 TEK 309 12339867 Genera -2.01 O.O2410 PIPSK1B 312 7023009 T Positive O.81 O.O3S33 PIPSK1B 313 126863SS Positive -O.96 OO1543 PIPSK1B 316 111441.33 T Negative O7 O.O1861 PIPSK1B 317 4745.375 T Negative 24 O.O1342 APBA1 318 104.81751 T Negative 24 O.O1613 APBA1 318 104.81751 T General S2 O.O3800 TRPM3 319 1932.701 C Negative -1.89 O.OO415 TRPM3 322 1337028 T Negative -O.93 0.04526 TRPM3 323 2993010 Negative -1.07 O.O2O22 PCSKS 327 7862766 T General 2.16 O.O2270 PCSKS 329 914367 T General -137 O.O4347 PCSKS 329 914367 T Negative -1.26 O.OO808 NTRK2 335 1187321 A Negative 39 O.O2333 NTRK2 335 1187321 A General 2.22 O.O1051 NTRK2 336 1187328 G Negative 31 O.O3S38 NTRK2 337 1899641 G General 6O 0.02849 DAPK1 338 1927976 G Negative -1.OO O.O2631 SORCS3 341 10884O26 G. Positive -1.01 O.O4628 SORCS3 345 24.96022 A General -1.28 O.O4790 CUGBP2 353 3243 C General 45 0.04284 VTI1A 355 108853S2 T Positive -O.91 O.O3S09 VTI1A 357 7907012 G Negative O7 O.O2739 VTI1A 360 41.45776 G Negative O.99 O.O4223 ATE 363 7086.628 C Positive -109 OOO447 ATE 364 1219505 T Positive -1.29 O.OOO67 ATE 364 1219505 T General -1.21 O.O4798 ATE 365 1693.682 A General -1.29 O.O451O US 2012/01 OO637 A1 Apr. 26, 2012 28

TABLE 2-continued Alleles Influencing PANSS Scales Gene Name Sequence ID NCBI RS # Allele PANSS Scale Beta P ATE1 366 10732824 A General -2.18 O.O4567 ATE1 367 2420970 T Positive 23 O.OO122 ATE1 368 1120O2S1 T Positive O.89 O.O313S ATE1 369 1120O260 T General .82 0.04378 CTBP2 370 496.2718 C Positive -O.96 O.O2804 ARMC3 371 17440393 A Positive 18 O.O1570 ARMC3 372 11013210 T Positive 11 O.O2O29 PITRM1 383 3740607 A Positive -O.82 O.O.3317 PITRM1 384 424,2746 T Positive -O.85 O.O4967 SLC16A9 386 6481469 A General 2.59 O.O3613 SLC16A9 387 3763747 C Negative -148 O.OO519 SLC16A9 388 22422O6 T Negative -130 O.OO719 SLC16A9 389 1171648 A Negative -134 O.OO846 SLC16A9 390 1171643 G Negative -1.33 O.O1007 PRKCQ 392 9423765 A Negative O.96 O.O3963 KCNMA1 4O1 7897566 C Positive O4 O.O1086 KCNMA1 4O1 7897566 C General 6O O.O1494 KCNMA1 4O1 7897566 C Negative 64 O.OOO34 NRG3 4.08 11193681 T Positive -1.24 O.O2809 NRG3 410 474496 G General 42 (0.03465 NRG3 411 S12O64 A General 25 0.04994 GALNTL4 421 71228O1 T General -1.49 O.O.3276 MICAL2 422 10765929 T Positive -1.21 O.OO386 MICAL2 423 2010463 A Positive -O.80 O.04857 MICAL2 424 11822285 T Positive -O.84 O.O3138 OPCML 428 10894536 A Negative 68 O.O3902 ARNTL 430 7107711 C General -1.86 O.O1999 ARNTL 431 7112233 T General -1.7O O.O3204 OPCML 432 7107264 C General -1.89 O.04851 SPON 435 15075.27 C General 48 0.03603 SPON 436 2O49723 C General S9 O.O2683 SPON 437 1528668 C Negative O3 O.O2759 SPON 440 108321.70 T Negative 2O O.OO721 SPON 440 108321.70 T General 31 O.O4048 SPON 441 1406356 A Negative 2O O.OO803 SPON 441 1406356 A General 40 O.O.3069 SPON 442 7116296 T General -1.33 O.O4002 SPON 442 7116296 T Negative -1.03 O.O2319 SPON 443 11023O88 T Negative -O.98 O.O3476 INSC 445 1792.571 A Negative 62 O.OO168 INSC 445 1792.571 A General .63 0.02657 KCNA4 446 11030913 C Positive 25 O.O1607 KCNA4 447 108356O7 A Positive O8 O.O3341 STIM1 448 7952O83 C Positive -O.85 O.O2340 STIM1 449 10835249 G. Positive -O.80 O.O4205 STIM1 451 2959068 T Positive -O.84 O.O4313 TRIM21 452 1426378 A Positive -1.17 O.O2S72 DLG2 455 11233564 A Positive -2.74 O.OO227 DLG2 456 1123356S C Positive -2.49 O.OOSSO DLG2 457 6S921.13 A Negative -O.99 O.O.3066 DLG2 458 2507850 A Negative -O.97 O.O4316 DLG2 459 7108874 T Negative -1.22 O.O2O33 DLG2 462 251.4147 G Negative S8 O.O3268 DLG2 463 10898.192 G Negative 66 0.02OSO DLG2 465 1945832 T Positive -1.58 O.O2446 DLG2 466 65922O2 C General -135 0.03773 DLG2 466 65922O2 C Positive -104 O.OO98O DLG2 466 65922O2 C Negative -O.94 O.O3982 DLG2 467 44S1754 A General -140 O.O3522 DLG2 467 44S1754 A Positive -1.07 O.OO927 DLG2 468 1943,708 C Positive -O.89 O.O2995 DLG2 469 11234.194 C Positive -O.88 O.O3398 DLG2 470 11234221 A Positive -113 O.OO457 DLG2 471 11234222 A General -1.86 O.OO385 DLG2 471 11234222 A Negative -145 O.OO134 DLG2 472 4943900 C Negative OO 0.02898 DLG2 474 6592211 A General -1.49 O.O2007 DLG2 474 6592211 A Positive -1.14 0.00424 DLG2 475 7101.454 C General -142 O.O2852 DLG2 475 7101.454 C Positive -1.08 O.OO72O DLG2 476 582652 A Negative -134 O.O417O ATXN2 480 1544396 G Negative O9 O.O4327

US 2012/01 OO637 A1 Apr. 26, 2012 31

TABLE 2-continued Alleles Influencing PANSS Scales Gene Name Sequence ID NCBI RS # Allele PANSS Scale Beta P OSBPL1A 758 275857 C General 3.17 O.O4077 OSBPL1A 759 641885 T General -2.46 0.0377S CHST9 760 17703962 G. Positive 38 O.O1471 CHST9 762 99653.71 C Positive 21 O.O273S DLGAP1 763 96.35857 G. Positive O.94 O.O4321 NEDD4L 766 7243662 G. Positive 24 O.O1038 NEDD4L 767 OO8899 A Positive 18 0.01254 NEDD4L 768 494.1364 G. Positive 14 O.O1420 NEDD4L 769 292444 C Positive O.93 O.O2791 NEDD4L 770 5258.39 A Positive O.90 O.O3453 NEDD4L 771 11663936 T Negative -1.18 O.O3859 NEDD4L 772 17064977 C Negative 10 O.O3738 NEDD4L 773 11152O73 A Negative O7 O.O4122 CDHT 781 8092259 G Negative 38 O.OO316 CDHT 781 8092259 G General 41 O.O3486 CDHT 782 7228669 T General 34 0.04448 CDHT 783 942832 A Negative 26 O.OO745 CDHT 784 942831 G General 34 0.04464 CDHT 786 484725 T Negative 24 O.OO820 CDHT 790 S64815 C Negative 2.42 0.02279 DOK6 791 1296.1718 C General S8 O.O2195 DOK6 792 8097743 G. Positive -O.85 0.027S3 DOK6 793 4426448 G. Positive O.94 O.O1905 DOK6 794 12605879 G. Positive O.90 O.O22O1 MBP 796 11660442 A Negative O7 O.O2397 PTPRM 797 495288 G Negative 2.51 O.O2S61 PTPRM 798 8O8969S C Negative 2.27 O.OO638 KIAAO8O2 803 12386117 A General -2.31 O.OO964 KIAAO8O2 803 12386117 A Positive -132 O.O1762 KIAAO8O2 804 7235093 A Negative 2.20 OOO394 LDLR 805 8110695 A General .72 O.O.2348 LDLR 807 1433,099 A Positive -O.88 O.O4421 MACROD2 809 6079395 G. Positive O.84 O.O3441 MACROD2 809 6079395 G Negative O.99 O.O2883 MACROD2 810 607991O C General -2.02 O.O4O25 KIF1.6B 813 6O43875 C General -1.62 O.O1173 KIF1.6B 818 6135739 G General -134 O.O4O77 KIF1.6B 821 6034464 A General -140 O.O2717 KIF1.6B 823 12624938 A General 83 O.O3290 KIF1.6B 826 6O7SO69 T General 2.46 O.OO261 KIF1.6B 827 608O359 C Negative -1.16 O.O272O PTPRT 832 6065432 T Negative -135 O.OO638 PTPRT 833 746413 C Negative -104 O.O2O87 PTPRT 833 746413 C Positive 15 O.OO399 PTPRT 834 6065434 T Negative -1.27 O.OO885 PTPRT 835 6O16688 T Positive O.98 O.O3708 PTPRT 836 6065487 A Positive -1.OO O.O1421 PTPRT 838 2017914 G General 40 0.04442 PTPRT 839 6O72869 G Negative 24 O.O1854 KCNB1 841 1961.192 T Negative -O.95 O.O386O KCNB1 84.4 609.5546 A General -148 0.04378 KCNB1 84.4 609.5546 A Positive -O.93 0.04204 KCNB1 845 4647 T Positive -0.95 O.O3795 CDH4 846 6O281.27 G General -141 0.0428O CDH4 847 481.231.3 G General -142 O.O4339 FERMT1 855 8121939 G General -134 O.04231 PLCB1 856 6055577 A Positive O6 0.04019 PLCB1 857 223.5212 A Positive O.95 0.04340 PLCB4 859 6O77505 C Negative -117 O.O1308 PLCB4 860 6039424 G Negative -O.92 O.O4737 C21 ORF37 861 12483129 C Negative O.97 0.02832 SLC37A1 872 38.1899 A Negative -139 O.OO591 SGSM1 874 576O752 C Negative O.97 O.O4133 ARFGAP3 876 60O2963 G General -1.76 O.OO781 ARFGAP3 877 738536 A General 37 0.02863 PACSIN2 882 4140554 C General -2.0S O.OO13S PACSIN2 883 7291153 C General -1.95 O.OO238 PACSIN2 887 737782 G Negative 16 O.O1019 PACSIN2 887 737782 G General .7O O.OO803 PACSIN2 888 2284.097 C General -1.87 O.OO345 PACSIN2 889 738379 A General -1.71 O.OO737 PACSIN2 889 738379 A Negative -O.96 O.O.338O

US 2012/01 OO637 A1 Apr. 26, 2012 68

TABLE A-continued Summary of SNPs (NCBI Human Genome Reference Assembly Build 36.3 Seq ID Gene Chr Position (BP) Seq ID Gene Chr Position (BP) 171 GFRA2 21,616,512 172 PEBP4. 22,632,507 173 ENTPD4 23,353,499 174 SLC25A37 23,453,211 175 SLC25A37 23,471,600 176 CSMD1 2,849,233 177 CSMD1 2,864,416 178 CSMD1 2,958,438 179 CSMD1 3,206,762 18O CSMD1 3,209,023 181 CSMD1 3,211,642 182 CSMD1 3,216,613 183 CSMD1 3,245,103 184 CSMD1 3,275,090 185 CSMD1 3,292,328 186 UNCSD 35,516,694 187 UNCSD 35,586,829 188 SFRP1 41,244,318 189 SFRP1 41,247,567 190 SFRP1 41,247,867 191 SFRP1 41,262,183 192 SFRP1 41,284.951 193 SNTG1 50,981,354 194 SNTG1 51,028,383 195 SNTG1 51,082,766 196 SNTG1 51,127,991 197 MCPH1 6,266,787 198 MCPH1 6,290,817 199 MCPH1 6,290,919 200 MCPH1 6,297,826 2O1 MCPH1 6,306,930 2O2 MCPH1 6,307,055 2O3 MCPH1 6,307,171 204 MCPH1 6,313,383 205 MCPH1 6,316,969 2O6 NKAIN3 63.450,524 2O7 NKAIN3 63,573,341 208 MCPH1 6,357,338 209 MCPH1 6,362,452 210 NKAIN3 63,670,367 211 NKAIN3 63,897,057 212 NKAIN3 64,008,938 213 NKAIN3 64,056,708 214 NKAIN3 64,084,956 215 MCPH1 6,460,526 216 DEPDC2 69,098.456 217 DEPDC2 69,098,725 218 DEPDC2 69,121,712 219 DEPDC2 69,144,533 220 DEPDC2 69,156,370 221 DEPDC2 69,207,400 222 DEPDC2 69,209,296 223 DEPDC2 69,301,731 224 DEPDC2 69,314,054 225 KCNB2 73,614,029 226 KCNB2 73,618,324 227 KCNB2 73,754,111 228 KCNB2 73,756,664 229 KCNB2 73,762,984 230 KCNB2 73,776,211 231 KCNB2 73,783,806 232 KCNB2 73,813,319 233 MMP16 89,061,627 234 MMP16 89,120,413 235 MMP16 89,148,139 236 MMP16 89,337,659 237 MMP16 89,367,315 238 MMP16 89,392,120 239 MMP16 89,413,738 240 MMP16 89.414,303 241 MMP16 89,421,430 242 GABBR2 O0,094,975 243 GABBR2 O0,095,943 244 GABBR2 O0.419,601 245 GABBR2 O0,469,409 246 RP11-3SN6.1 O2.472,272 247 FER1L6 O3,382,443 248 GRIN3A O3,473,056 249 GRIN3A O3,521,201 250 FKTN 07:409,195 251 FKTN 07:449,221 252 FKTN 07:455,377 253 SVEP1 12,152,393 254 SVEP1 12,166,117 255 SVEP1 12,167,878 256 CDK5RAP2 22,209,539 257 CDK5RAP2 22,337,266 258 CDK5RAP2 22,362,134 259 CDK5RAP2 22,370,634 260 STOM 23,165,341 261 DAB2IP 23,691,611 262 RALGPS1 28,698,499 263 RALGPS1 28,769,224 264 RALGPS1 28,789,061 26S RALGPS1 28,809,594 266 RALGPS1 28,902,817 267 SLC25A2S 29,886,889 268 SLC25A2S 29,899,153 269 FREQ 31,997,035 270 EXOSC2 32.588,852 271 ABL1. 32,715,588 272 ABL1. 32,721,005 273 ABL1. 32,722,573 274 ABL1. 32,723,896 275 TSC1 34,811, 193 276 34,812,111 277 WAV2 35,795,115 278 37,113,249 279 OLFM1 37,127,054 28O 38.461,433 281 NOTCH1 38,555,218 282 40,072,737 283 CACNA1B 40,075,368 284 19,460,804 285 KIAA1797 20,673.404 286 20,678,117 287 KIAA1797 20,732,210 288 20,753,840 289 KIAA1797 20,754,870 290 20,804,142 291 KIAA1797 20,898,513 292 20,921,349 293 KIAA1797 20,935,372 294 20,943,233 295 KIAA1797 20,943,335 296 20,943,750 297 KIAA1797 20,951,906 298 20,977,703 299 KIAA1797 20,978.426 300 20,986,709 301 SMARCA2 2,120,828 3O2 2,120,917 303 SMARCA2 2,121,990 304 2,178,383 305 IFTT 4 26,999,100 306 27,129,817 307 TEK 27,175,101 3O8 27,210,066 309 TEK 27,224,049 310 4,550,348 311 SLC1A1 4,552,472 312 70,507,948 313 PIPSK1B 70,552,216 314 70,672,108 US 2012/01 OO637 A1 Apr. 26, 2012 69

TABLE A-continued Summary of SNPs (NCBI Human Genome Reference Assembly Build 36.3 Seq ID Gene Chr Position (BP) Seq ID Gene Chr Position (BP) 315 PIP5K1B 70,687,329 316 PIPSK1B 70,691,508 317 PIP5K1B 70,703,782 318 APBA1 71,324,196 319 TRPM3 72,346,211 320 TRPM3 72,637,875 321 TRPM3 72,648,924 322 TRPM3 72,649,911 323 TRPM3 72,673,741 324 TMC1 74,397.486 325 TMC1 74.443,712 326 TMC1 74,579,921 327 PCSKS 77,687,086 328 PCSKS 77,896,771 329 PCSKS 77,912,756 330 GNAQ 79,595,252 331 GNAQ 79,703,143 332 GNAQ 79,908,612 333 PTPRD 8,372,966 334 PTPRD 8,390,681 33S NTRK2 86,472,851 336 NTRK2 86,479,077 337 NTRK2 86,599,187 338 DAPK1 89.448,453 339 DAPK1 89.452,483 340 DAPK1 89,511,843 341 SORCS3 106,371,034 342 SORCS3 106,592,352 343 SORCS3 106,614,338 344 SORCS3 106,622,111 345 SORCS3 106,622,468 346 SORCS3 106,625,786 347 SORCS3 106,777,753 348 SORCS3 106,782,237 349 SORCS3 106,897,228 3SO SORCS3 106,906,037 351 SORCS3 106,906,641 352 SORCS3 107,025,958 353 CUGBP2 11,277,934 3S4 VT1A 114.226,855 355 VTI1A 114,228,361 356 WTI1A 114,424,611 357 VTI1A 114,458,106 358 WTI1A 114.458,428 359 VTI1A 114,506,363 360 VT1A 114,508,308 361 HSPA12A 118,432,901 362 HSPA12A 118,469,221 363 ATE1 123,432,831 364 ATE1 123,450,896 365 ATE1 123,453,723 366 ATE1 123,644,015 367 ATE1 123,651,712 368 ATE1 123,663,196 369 ATE1 123,669,674 370 CTBP2 126,677,518 371 ARMC3 23,277,574 372 ARMC3 23,289,115 373 ARMC3 23,314,154 374. ARMC3 23,318,053 37S ARMC3 23,337,258 376 ARMC3 23,364,367 377 ARMC3 23,372,952 378 ARHGAP21 25,046,553 379 MYO3A 26,398,660 380 MYO3A 26,552,050 381 PITRM1 3,166,363 382 PITRM1 3,169,968 383 PITRM1 3,179,380 384 PITRM1 3,192,065 385 PITRM1 3,213,179 386 SLC16A9 61,024,452 387 SLC16A9 61,082,341 388 SLC16A9 61,084,017 389 SLC16A9 61,120,938 390 SLC16A9 61,122,758 391 PRKCQ 6,567,350 392 PRKCQ 7,152,082 393 CDH23 72,997.429 394 CDH23 73,104,912 395 CDH23 73,126,384 396 KCNMA1 78,319,405 397 KCNMA1 78,319,936 398 KCNMA1 78,320,267 399 KCNMA1 78.324,802 400 KCNMA1 78,348,173 401 KCNMA1 78,626,486 402 KCNMA1 78,738,970 403 KCNMA1 78,757,625 404 KCNMA1 78,799,763 40S KCNMA1 78,817,839 406 KCNMA1 78,872.456 407 KCNMA1 79,094,637 408 NRG3 84,068.972 409 NRG3 84,070,208 410 NRG3 84,604,364 411 NRG3 84,613,706 412 NRG3 84,616,939 413 SORBS1 97,061,507 414 SORBS1 97,122,546 415 SORBS1 97,122,783 416 SORBS1 97,126,192 417 SORBS1 97,127,095 418 SORBS1 97.216,419 419 ELMOD1 107,077,060 42O GALNTL4 11,246,740 421 GALNTL4 11,497,136 422 MICAL2 12,139,036 423 MICAL2 12,142,872 424 MICAL2 12,149,199 425 MICAL2 12,155,884 426 MICAL2 12,175,779 427 MICAL2 12,222,118 428 OPCML 131,718,194 429 OPCML 132,078,600 430 ARNTL 13,212,114 431 ARNTL 13,212,547 432 OPCML 132,803,817 433 OPCML 132,884,694 434 OPCML 132,895,944 43S SPON1 13,882,655 436 SPON1 13,922,920 437 SPON1 13,994,054 438 SPON1 14,008,775 439 SPON1 14,014,762 440 SPON1 14,023,125 441 SPON1 14,034,087 442 SPON1 14,070,335 443 SPON1 14,075,677 444 SPON1 14,215,231 445 INSC 15,138,272 446 KCNA4 29,964,590 447 KCNA4 29,984,859 448 STIM1 3,847,536 449 STIM1 3,867,621 450 STIM1 3,927,655 451 STIM1 4,033,624 452 TRIM21 4,371,449 453 C11 ORF49 47,089,300 454 81.99 mb. 81,921,684 4SS DLG2 82,719,582 456 DLG2 82,720,706 457 DLG2 82,743,548 458 DLG2 82,843,293

US 2012/01 OO637 A1 Apr. 26, 2012 73

TABLE A-continued Summary of SNPs (NCBI Human Genome Reference Assembly Build 36.3 Seq ID Gene Chr Position (BP) Seq ID Gene Chr Position (BP) 1891 TTLL1 22 41,822,583 1892 TTLL1 22 41,822,906 1893 EFCAB6 22 42.278,436 1894 EFCAB6 22 42,320,777

SEQUENCE LISTING

<16O is NUMBER OF SEO ID NOS : 1894

<210s, SEQ ID NO 1 &211s LENGTH: 61 &212s. TYPE: DNA <213> ORGANISM: Homo Sapiens <4 OOs, SEQUENCE: 1 gcagtactica cccaaattgc titctgtct cartgataccaa gcact attct ttaattt cot 6 O t 61

<210s, SEQ ID NO 2 &211s LENGTH: 61 &212s. TYPE: DNA <213> ORGANISM: Homo Sapiens <4 OOs, SEQUENCE: 2 gctt acttga actgacagaa gat atctgca yactctggga ggatt coact ggcctgcaac 6 O a. 61

<210s, SEQ ID NO 3 &211s LENGTH: 61 &212s. TYPE: DNA <213> ORGANISM: Homo Sapiens

<4 OOs, SEQUENCE: 3 gcqc ccagcc tdatgagtga ctittaattgc kctatgcttic agt catcto a gctaacacag 6 O

9 61

<210s, SEQ ID NO 4 &211s LENGTH: 61 &212s. TYPE: DNA <213> ORGANISM: Homo Sapiens

<4 OOs, SEQUENCE: 4 ttggcg tatg gttctittagg atgattgaca rtggcagtac Ctggactaac gtgactittag 6 O c 61

<210s, SEQ ID NO 5 &211s LENGTH: 61 &212s. TYPE: DNA <213> ORGANISM: Homo Sapiens

<4 OOs, SEQUENCE: 5 gag.acctgga ctittagaccc tict accc.cca rttagctgtg agaccttgag caaat cattt 6 O c 61

US 2012/01 OO637 A1 Apr. 26, 2012 91

- Continued <213> ORGANISM: Homo Sapiens <4 OOs, SEQUENCE: 113 ttagtic Cagg tagdalaatt accctgaata rgtgttgtagg ctic cct c cct gccaccgagg 6 O

9 61

<210s, SEQ ID NO 114 &211s LENGTH: 61 &212s. TYPE: DNA <213> ORGANISM: Homo Sapiens <4 OOs, SEQUENCE: 114 at acticagoc gagatacc cc catttgtta ygggatggca aaaagatatt taaggctatt 6 O c 61

<210s, SEQ ID NO 115 &211s LENGTH: 61 &212s. TYPE: DNA <213> ORGANISM: Homo Sapiens <4 OOs, SEQUENCE: 115 aactgtttitc aggttgcaac agacaaggca raaaacctitt agcagtgaala Ctgaaaagat 6 O t 61

<210s, SEQ ID NO 116 &211s LENGTH: 61 &212s. TYPE: DNA <213> ORGANISM: Homo Sapiens

<4 OOs, SEQUENCE: 116 ttgatt tatt agaaggattt ggcatcagga rcataaaaat ggittaatggg tectgtaact 6 O t 61

<210s, SEQ ID NO 117 &211s LENGTH: 61 &212s. TYPE: DNA <213> ORGANISM: Homo Sapiens

<4 OOs, SEQUENCE: 117 aaaagttt at t cagttittaa tittctggcta sagcttctitt gctaagaata acaaatactic 6 O a. 61

<210s, SEQ ID NO 118 &211s LENGTH: 61 &212s. TYPE: DNA <213> ORGANISM: Homo Sapiens

<4 OOs, SEQUENCE: 118 t cacacattg cacticagatc tag cct citta ydttittalacc ttagt ct coc cct taaatct 6 O c 61

<210s, SEQ ID NO 119 &211s LENGTH: 61 &212s. TYPE: DNA <213> ORGANISM: Homo Sapiens

<4 OOs, SEQUENCE: 119

US 2012/01 OO637 A1 Apr. 26, 2012 94

- Continued <213> ORGANISM: Homo Sapiens <4 OOs, SEQUENCE: 132 tttittcaacg togg taccaca aatgtggc.ca saaggattitt cataatggga tattgtacat 6 O a. 61

<210s, SEQ ID NO 133 &211s LENGTH: 61 &212s. TYPE: DNA <213> ORGANISM: Homo Sapiens <4 OOs, SEQUENCE: 133 aattacct cit gccatggata cittgcaatag stagcaaact ggit ct coct g gttcaacticc 6 O t 61

<210s, SEQ ID NO 134 &211s LENGTH: 61 &212s. TYPE: DNA <213> ORGANISM: Homo Sapiens <4 OOs, SEQUENCE: 134 tggCataggg act acgttcc aggagc.cagt rtt CCaagag gaccagaaag aagttgtata 6 O a. 61

<210s, SEQ ID NO 135 &211s LENGTH: 61 &212s. TYPE: DNA <213> ORGANISM: Homo Sapiens

<4 OOs, SEQUENCE: 135 caataactta aatacat cag cagagaaaac rittatgaggc ataaggacca totggttctg 6 O

9 61

<210s, SEQ ID NO 136 &211s LENGTH: 61 &212s. TYPE: DNA <213> ORGANISM: Homo Sapiens

<4 OOs, SEQUENCE: 136 aattittagga attagtgaga gttacatctt watccatttt tactittagaa cittattttitt 6 O t 61

<210s, SEQ ID NO 137 &211s LENGTH: 61 &212s. TYPE: DNA <213> ORGANISM: Homo Sapiens

<4 OOs, SEQUENCE: 137 tct cat attt gagatagaat acctatagtic yat cotggag gggaagaaag catgcaaaaa 6 O t 61

<210s, SEQ ID NO 138 &211s LENGTH: 61 &212s. TYPE: DNA <213> ORGANISM: Homo Sapiens

<4 OOs, SEQUENCE: 138