Gene expression elucidates functional impact of polygenic risk for schizophrenia.

Nat Neurosci
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
Journal
Nat Neurosci
Volume
19
Issue
11
Pages
1442-1453
Date Published
2016 Nov
ISSN
1546-1726
DOI
10.1038/nn.4399
PubMed ID
27668389
PubMed Central ID
PMC5083142
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