(12) Patent Application Publication (10) Pub. No.: US 2012/0100637 A1 Brennan Et Al
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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),