Genetic assessment of additional endophenotypes from the Consortium on the Genetics of Schizophrenia Family Study

SCHIZOPHRENIA RESEARCH

卷:170

Article

Greenwood, Tiffany A.¹  Lazzeroni, Laura C.²  Calkins, Monica E.³  Freedman, Robert⁴  Green, Michael F.^5,6  Gur, Raquel E.³  Gur, Ruben C.³  Light, Gregory A.^1,7  Nuechterlein, Keith H.⁵  Olincy, Ann⁴  Radant, Allen D.^8,9  Seidman, Larry J.^10,11  Siever, Larry J.^12,13  Silverman, Jeremy M.^12,13  Stone, William S.^10,11  Sugar, Catherine A.¹⁴  Swerdlow, Neal R.¹  Tsuang, Debby W.^8,9  Tsuang, Ming T.^1,15,16  Turetsky, Bruce I.³  Braff, David L.^1,7 

[1] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA

[2] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA

[3] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA

[4] Univ Colorado, Hlth Sci Ctr, Dept Psychiat, Denver, CO 80262 USA

[5] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA

[6] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA

[7] VA San Diego Healthcare Syst, VISN Mental Illness Res Educ & Clin Ctr MIRECC 22, San Diego, CA 92161 USA

[8] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA

[9] VA Puget Sound Hlth Care Syst, Seattle, WA USA

[10] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA

[11] Beth Israel Deaconess Med Ctr, Massachusetts Mental Hlth Ctr, Publ Psychiat Div, Boston, MA 02215 USA

[12] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA

[13] James J Peters VA Med Ctr, New York, NY USA

[14] Univ Calif Los Angeles, Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90024 USA

[15] Univ Calif San Diego, Inst Genom Med, Ctr Behav Genom, La Jolla, CA 92093 USA

[16] Harvard Inst Psychiat Epidemiol & Genet, Boston, MA USA

关键词: Endophenotype;    Genetics;    Schizophrenia;    Association;    Linkage;    Heritability;   

DOI  :  10.1016/j.schres.2015.11.008

来源: Elsevier

【 摘 要 】

The Consortium on the Genetics of Schizophrenia Family Study (COGS-1) has previously reported our efforts to characterize the genetic architecture of 12 primary endophenotypes for schizophrenia. We now report the characterization of 13 additional measures derived from the same endophenotype test paradigms in the COGS-1 families. Nine of the measures were found to discriminate between schizophrenia patients and controls, were significantly heritable (31 to 62%), and were sufficiently independent of previously assessed endophenotypes, demonstrating utility as additional endophenotypes. Genotyping via a custom array of 1536 SNPs from 94 candidate genes identified associations for CTNNA2, ERBB4, GRID1, GRID2, GRIK3, GRIK4, GRIN2B, NOS1AP, NRG1, and RELN across multiple endophenotypes. An experiment-wide p value of 0.003 suggested that the associations across all SNPs and endophenotypes collectively exceeded chance. Linkage analyses performed using a genome-wide SNP array further identified significant or suggestive linkage for six of the candidate endophenotypes, with several genes of interest located beneath the linkage peaks (e.g., CSMD1, DISC1, DLGAP2, GRIK2, GRIN3A, and SLC6A3). While the partial convergence of the association and linkage likely reflects differences in density of gene coverage provided by the distinct genotyping platforms, it is also likely an indication of the differential contribution of rare and common variants for some genes and methodological differences in detection ability. Still, many of the genes implicated by COGS through endophenotypes have been identified by independent studies of common, rare, and de novo variation in schizophrenia, all converging on a functional genetic network related to glutamatergic neurotransmission that warrants further investigation. (C) 2015 Elsevier B. V. All rights reserved.

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