Cell Reports
Volume 9, Issue 4, 20 November 2014, Pages 1417-1429
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Article
A Role for Noncoding Variation in Schizophrenia

https://doi.org/10.1016/j.celrep.2014.10.015Get rights and content
Under a Creative Commons license
open access

Highlights

  • Schizophrenia SNPs are enriched for eQTLs and cis-regulatory elements

  • The enrichment is greater for enhancers in fetal and adult brain tissue

  • Schizophrenia risk SNPs participate in long-range promoter-enhancer interactions

  • CACNA1C variants are associated with transcriptional regulation in the brain

Summary

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.

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This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).

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Co-senior author