Gene expression elucidates functional impact of polygenic risk for schizophrenia.
Authors | |
Abstract | 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. |
Year of Publication | 2016
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Journal | Nat Neurosci
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Volume | 19
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Issue | 11
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Pages | 1442-1453
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Date Published | 2016 Nov
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ISSN | 1546-1726
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DOI | 10.1038/nn.4399
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PubMed ID | 27668389
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PubMed Central ID | PMC5083142
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Links | |
Grant list | P50 MH094268 / MH / NIMH NIH HHS / United States
P50 MH096891 / MH / NIMH NIH HHS / United States
R01 AG050986 / AG / NIA NIH HHS / United States
R37 MH057881 / MH / NIMH NIH HHS / United States
R01 MH075916 / MH / NIMH NIH HHS / United States
R01 MH074313 / MH / NIMH NIH HHS / United States
T32 MH087004 / MH / NIMH NIH HHS / United States
P50 MH084053 / MH / NIMH NIH HHS / United States
R01 MH101454 / MH / NIMH NIH HHS / United States
I01 BX002395 / BX / BLRD VA / United States
R01 MH097276 / MH / NIMH NIH HHS / United States
R01 MH109706 / MH / NIMH NIH HHS / United States
R01 MH093725 / MH / NIMH NIH HHS / United States
HHSN271201300031C / MH / NIMH NIH HHS / United States
P50 MH066392 / MH / NIMH NIH HHS / United States
R01 AG036836 / AG / NIA NIH HHS / United States
R01 MH085542 / MH / NIMH NIH HHS / United States
U01 MH096296 / MH / NIMH NIH HHS / United States
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