Genetic markers of schizophrenia endophenotypes

Abstract

This document provides methods and materials related to genetic markers of schizophrenia (SZ), schizotypal personality disorder (SPD), and/or schizoaffective disorder (SD), (collectively referred to herein as “schizophrenia spectrum disorders” or SSDs). For example, methods for using such genetic markers to identify an SSD (e.g., SZ) endophenotype are provided.

1 . A method of determining a likelihood or risk of severity of a schizophrenia (SZ) endophenotype in a human subject, the method comprising:
 determining the identity of an allele at rs7897566 in a sample comprising genomic DNA of a subject having or suspected of having SZ;   wherein the presence of a C allele at rs7897566 indicates that the subject is more likely to have a higher PANSS Total composite score, a higher PANSS Positive composite score, a higher PANSS General Psychopathology composite score, a higher PANSS Negative composite score, a higher N4 score, a higher N6 score, a higher N7 score, a higher G14 score, a higher G15 score, a higher G7 score, a higher G13 score, a higher G16 score, a higher G11 score, or a higher P2 score, as compared to a subject who does not have a C allele at rs7897566.   
     
     
         2 . The method of  claim 1 , further comprising obtaining the sample from the subject. 
     
     
         3 . The method of  claim 1 , wherein determining the identity of an allele at rs7897566 comprises:
 contacting the sample with a probe specific for a selected allele at rs7897566; and   detecting the formation of complexes between the probe and the selected allele,   wherein the formation of complexes between the probe and the selected allele indicates the presence of the selected allele in the sample.   
     
     
         4 . The method of  claim 1 , wherein determining the identity of an allele at rs7897566 comprises determining the identity of the nucleotide at position 31 of SEQ ID NO: 1401. 
     
     
         5 . The method of  claim 1 , further comprising selecting a subject who has or is suspected of having SZ. 
     
     
         6 . The method of  claim 1 , wherein the subject has one or more risk factors associated with SZ. 
     
     
         7 . The method of  claim 6 , wherein the risk factors associated with SZ include one or both of: a relative afflicted with a schizophrenia spectrum disorder (SSD), and a genetically-based phenotypic trait associated with risk for a SSD. 
     
     
         8 . The method of  claim 1 , further comprising selecting or excluding a subject for enrollment in a clinical trial based on the identity of the allele in the subject. 
     
     
         9 . The method of  claim 1 , further comprising stratifying a subject population for analysis of a clinical trial based on the identity of the allele in the subjects. 
     
     
         10 . The method of  claim 1 , further comprising confirming a severity of a SZ endophenotype using a psychometric instrument. 
     
     
         11 . The method of  claim 1 , further comprising recording the identity of the allele in a tangible medium. 
     
     
         12 . The method of  claim 11 , wherein the tangible medium comprises a computer-readable disk, a solid state memory device, or an optical storage device. 
     
     
         13 . A method of determining a likelihood or risk of severity of a schizophrenia (SZ) endophenotype in a human subject, the method comprising:
 determining the identity of an allele at rs7897566 in the potassium large conductance calcium-activated channel, subfamily M, alpha member 1 (KCNMA1) gene in a sample comprising genomic DNA of a subject having or suspected of having SZ; and   determining the identity of one or more allele(s) at rs2288840, rs7067873, rs1907729, rs11002139, rs10824547, and rs2719986 in the KCNMA1 gene in the sample;   wherein the presence of a C allele at rs7897566 indicates that the subject is more likely to have a higher PANSS Total composite score, a higher PANSS Positive composite score, a higher PANSS General Psychopathology composite score, a higher PANSS Negative composite score, a higher N4 score, a higher N6 score, a higher N7 score, a higher G14 score, a higher G15 score, a higher G7 score, a higher G13 score, a higher G16 score, a higher G11 score, or a higher P2 score, as compared to a subject who does not have a C allele at rs7897566;   the presence of a G allele at rs2288840 indicates that the subject is more likely to have a higher P7 score, as compared to a subject who does not have a G allele at rs2288840;   the presence of a C allele at rs7067873 indicates that the subject is more likely to have a higher P4 score, as compared to a subject who does not have a C allele at rs7067873;   the presence of a T allele at rs1907729 indicates that the subject is more likely to have a lower G6 score, as compared to a subject who does not have a T allele at rs1907729;   the presence of an A allele at rs11002139 indicates that the subject is more likely to have a lower G12 score, as compared to a subject who does not have an A allele at rs11002139;   the presence of a T allele at rs10824547 indicates that the subject is more likely to have a higher N3 score, as compared to a subject who does not have a T allele at rs10824547; and   the presence of a T allele at rs2719986 indicates that the subject is more likely to have a lower P6 score, as compared to a subject who does not have a T allele at rs2719986.   
     
     
         14 . The method of  claim 13 , wherein the identity of the alleles at rs7897566, rs2288840, rs7067873, rs1907729, rs11002139, rs10824547, and rs2719986 in the KCNMA1 gene in the sample are determined. 
     
     
         15 . The method of  claim 13 , further comprising obtaining the sample from the subject. 
     
     
         16 . The method of  claim 13 , wherein determining the identity of an allele at rs7897566 or determining the identity of an allele at rs2288840, rs7067873, rs1907729, rs11002139, rs10824547, or rs2719986 comprises:
 contacting the sample with a probe specific for a selected allele at rs7897566, rs2288840, rs7067873, rs1907729, rs11002139, rs10824547, or rs2719986; and   detecting the formation of complexes between the probe and the selected allele,   wherein the formation of complexes between the probe and the selected allele indicates the presence of the selected allele in the sample.   
     
     
         17 . The method of  claim 13 , wherein determining the identity of an allele at rs7897566 comprises determining the identity of the nucleotide at position 31 of SEQ ID NO: 1401; determining the identity of an allele at rs2288840 comprises determining the identity of the nucleotide at position 31 of SEQ ID NO: 1396; determining the identity of an allele at rs7067873 comprises determining the identity of the nucleotide at position 31 of SEQ ID NO: 1399, determining the identity of an allele at rs1907729 comprises determining the identity of the nucleotide at position 31 of SEQ ID NO: 1400, determining the identity of an allele at rs11002139 comprises determining the identity of the nucleotide at position 31 of SEQ ID NO: 1404, determining the identity of an allele at rs10824547 comprises determining the identity of the nucleotide at position 31 of SEQ ID NO: 1406, or determining the identity of an allele at rs2719986 comprises determining the identity of the nucleotide at position 31 of SEQ ID NO: 1407. 
     
     
         18 . The method of  claim 13 , further comprising selecting a subject who has or is suspected of having SZ. 
     
     
         19 . The method of  claim 13 , wherein the subject has one or more risk factors associated with SZ. 
     
     
         20 . The method of  claim 19 , wherein the risk factors associated with SZ include one or both of: a relative afflicted with a schizophrenia spectrum disorder (SSD), and a genetically-based phenotypic trait associated with risk for a SSD. 
     
     
         21 . The method of  claim 13 , further comprising selecting or excluding a subject for enrollment in a clinical trial based on the identity of the allele at rs7897566 and the identity of one or more allele(s) at rs2288840, rs7067873, rs1907729, rs11002139, rs10824547, and rs2719986 in the subject. 
     
     
         22 . The method of  claim 13 , further comprising stratifying a subject population for analysis of a clinical trial based on the identity of the allele at rs7897566 and the identity of one or more allele(s) at rs2288840, rs7067873, rs1907729, rs11002139, rs10824547, and rs2719986 in the subjects. 
     
     
         23 . The method of  claim 13 , further comprising confirming a severity of a SZ endophenotype using a psychometric instrument. 
     
     
         24 . The method of  claim 13 , further comprising recording the identity of the allele at rs7897566, and the identity of one or more allele(s) at rs2288840, rs7067873, rs1907729, rs11002139, rs10824547, and rs2719986 in a tangible medium. 
     
     
         25 . The method of  claim 24 , wherein the tangible medium comprises a computer-readable disk, a solid state memory device, or an optical storage device.