Gene expression elucidates functional impact of polygenic risk for schizophrenia

Menachem Fromer, Panos Roussos, Solveig K. Sieberts, Jessica S. Johnson, David H. Kavanagh, Thanneer M. Perumal, Douglas M. Ruderfer, Edwin C. Oh, Aaron Topol, Hardik R. Shah, Lambertus L. Klei, Robin Kramer, Dalila Pinto, Zeynep H. Gümüş, A. Ercument Cicek, Kristen K. Dang, Andrew Browne, Cong Lu, Lu Xie, Ben ReadheadEli A. Stahl, Jianqiu Xiao, Mahsa Parvizi, Tymor Hamamsy, John F. Fullard, Ying Chih Wang, Milind C. Mahajan, Jonathan M.J. Derry, Joel T. Dudley, Scott E. Hemby, Benjamin A. Logsdon, Konrad Talbot, Towfique Raj, David A. Bennett, Philip L. De Jager, Jun Zhu, Bin Zhang, Patrick F. Sullivan, Andrew Chess, Shaun M. Purcell, Leslie A. Shinobu, Lara M. Mangravite, Hiroyoshi Toyoshiba, Raquel E. Gur, Chang Gyu Hahn, David A. Lewis, Vahram Haroutunian, Mette A. Peters, Barbara K. Lipska, Joseph D. Buxbaum, Eric E. Schadt, Keisuke Hirai, Kathryn Roeder, Kristen J. Brennand, Elias Nicholas Katsanis, Enrico Domenici, Bernie Devlin, Pamela Sklar*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

699 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1442-1453
Number of pages12
JournalNature neuroscience
Issue number11
StatePublished - Oct 26 2016

ASJC Scopus subject areas

  • General Neuroscience


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