Gene expression elucidates functional impact of polygenic risk for schizophrenia.
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.
Fromer, M; Roussos, P; Sieberts, SK; Johnson, JS; Kavanagh, DH; Perumal, TM; Ruderfer, DM; Oh, EC; Topol, A; Shah, HR; Klei, LL; Kramer, R; Pinto, D; Gümüş, ZH; Cicek, AE; Dang, KK; Browne, A; Lu, C; Xie, L; Readhead, B; Stahl, EA; Xiao, J; Parvizi, M; Hamamsy, T; Fullard, JF; Wang, Y-C; Mahajan, MC; Derry, JMJ; Dudley, JT; Hemby, SE; Logsdon, BA; Talbot, K; Raj, T; Bennett, DA; De Jager, PL; Zhu, J; Zhang, B; Sullivan, PF; Chess, A; Purcell, SM; Shinobu, LA; Mangravite, LM; Toyoshiba, H; Gur, RE; Hahn, C-G; Lewis, DA; Haroutunian, V; Peters, MA; Lipska, BK; Buxbaum, JD; Schadt, EE; Hirai, K; Roeder, K; Brennand, KJ; Katsanis, N; Domenici, E; Devlin, B; Sklar, P
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