A role for noncoding variation in schizophrenia.

Cell Rep
Authors
Keywords
Abstract

A large portion of common variant loci associated with genetic risk for schizophrenia reside within noncoding sequence of unknown function. Here, we demonstrate promoter and enhancer enrichment in schizophrenia variants associated with expression quantitative trait loci (eQTL). The enrichment is greater when functional annotations derived from the human brain are used relative to peripheral tissues. Regulatory trait concordance analysis ranked genes within schizophrenia genome-wide significant loci for a potential functional role, based on colocalization of a risk SNP, eQTL, and regulatory element sequence. We identified potential physical interactions of noncontiguous proximal and distal regulatory elements. This was verified in prefrontal cortex and -induced pluripotent stem cell-derived neurons for the L-type calcium channel (CACNA1C) risk locus. Our findings point to a functional link between schizophrenia-associated noncoding SNPs and 3D genome architecture associated with chromosomal loopings and transcriptional regulation in the brain.

Year of Publication
2014
Journal
Cell Rep
Volume
9
Issue
4
Pages
1417-29
Date Published
2014 Nov 20
ISSN
2211-1247
URL
DOI
10.1016/j.celrep.2014.10.015
PubMed ID
25453756
PubMed Central ID
PMC4255904
Links
Grant list
R01 MH095034 / MH / NIMH NIH HHS / United States
R01 NS047229 / NS / NINDS NIH HHS / United States
R01MH095034 / MH / NIMH NIH HHS / United States
R01MH097276 / MH / NIMH NIH HHS / United States
U01 MH103392 / MH / NIMH NIH HHS / United States
R21 NS076958 / NS / NINDS NIH HHS / United States
U01MH103392 / 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
R37 AG017926 / AG / NIA NIH HHS / United States
P50 AG005138 / AG / NIA NIH HHS / United States
P50 MH096890 / MH / NIMH NIH HHS / United States
MANMKBRU-2012-1 / Department of Health / United Kingdom
Wellcome Trust / United Kingdom
T32 MH096678 / MH / NIMH NIH HHS / United States