Gene expression elucidates functional impact of polygenic risk for schizophrenia

• Published in: Nature neuroscience Vol. 19; no. 11; pp. 1442 - 1453
• Main Authors: Fromer, Menachem, Roussos, Panos, Sieberts, Solveig K, Johnson, Jessica S, Kavanagh, David H, Perumal, Thanneer M, Ruderfer, Douglas M, Oh, Edwin C, Topol, Aaron, Shah, Hardik R, Klei, Lambertus L, Kramer, Robin, Pinto, Dalila, Gümüş, Zeynep H, Cicek, A Ercument, Dang, Kristen K, Browne, Andrew, Lu, Cong, Xie, Lu, Readhead, Ben, Stahl, Eli A, Xiao, Jianqiu, Parvizi, Mahsa, Hamamsy, Tymor, Fullard, John F, Wang, Ying-Chih, Mahajan, Milind C, Derry, Jonathan M J, Dudley, Joel T, Hemby, Scott E, Logsdon, Benjamin A, Talbot, Konrad, Raj, Towfique, Bennett, David A, De Jager, Philip L, Zhu, Jun, Zhang, Bin, Sullivan, Patrick F, Chess, Andrew, Purcell, Shaun M, Shinobu, Leslie A, Mangravite, Lara M, Toyoshiba, Hiroyoshi, Gur, Raquel E, Hahn, Chang-Gyu, Lewis, David A, Haroutunian, Vahram, Peters, Mette A, Lipska, Barbara K, Buxbaum, Joseph D, Schadt, Eric E, Hirai, Keisuke, Roeder, Kathryn, Brennand, Kristen J, Katsanis, Nicholas, Domenici, Enrico, Devlin, Bernie, Sklar, Pamela
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2016; Nature Publishing Group
• Subjects: 13/100; 38/22; 38/39; 45/100; 45/43; 45/91; 631/208/199; 631/208/212; 631/378/2583; 64/116; 692/699/476/1799; 706/648/697/129; Alzheimer's disease; Animal Genetics and Genomics; Behavioral Sciences; Biological Techniques; Biology; Biomedicine; Brain - metabolism; Brain research; Consortia; Danio rerio; Disease; Female; Gene expression; Gene Expression Regulation - genetics; Gene loci; Genetic aspects; Genetic Predisposition to Disease; Genetics; Genome-Wide Association Study; Genomics; Health risk assessment; Humans; Male; Medicine; Mental disorders; Multifactorial Inheritance - genetics; Neurobiology; Neurosciences; Pharmaceutical industry; Physiological aspects; Polymorphism, Single Nucleotide; Psychiatry; Risk; Risk factors; Schizophrenia; Schizophrenia - genetics; United States; Japan; North Carolina; New York; United States > US; Massachusetts; Pittsburgh Pennsylvania; Pennsylvania
• ISSN: 1097-6256; 1546-1726; 1546-1726
• DOI: 10.1038/nn.4399

The CommonMind Consortium sequenced RNA from dorsolateral prefrontal cortex of subjects with schizophrenia ( N = 258) and control subjects ( N = 279), creating a resource of gene expression and its genetic regulation. Using this resource, they found that ∼20% of schizophrenia loci have variants that may contribute to altered gene expression and liability. Over 100 genetic loci harbor schizophrenia-associated variants, yet how these variants confer liability is uncertain. The CommonMind Consortium sequenced RNA from dorsolateral prefrontal cortex of people with schizophrenia ( N = 258) and control subjects ( N = 279), creating a resource of gene expression and its genetic regulation. Using this resource, ∼20% of schizophrenia loci have variants that could contribute to altered gene expression and liability. In five loci, only a single gene was involved: FURIN , TSNARE1 , CNTN4 , CLCN3 or SNAP91 . Altering expression of FURIN , TSNARE1 or CNTN4 changed neurodevelopment in zebrafish; knockdown of FURIN in human neural progenitor cells yielded abnormal migration. Of 693 genes showing significant case-versus-control differential expression, their fold changes were ≤ 1.33, and an independent cohort yielded similar results. Gene co-expression implicates a network relevant for schizophrenia. Our findings show that schizophrenia is polygenic and highlight the utility of this resource for mechanistic interpretations of genetic liability for brain diseases.