A role for noncoding variation in schizophrenia.

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.

• Authors: Panos Roussos, Amanda C Mitchell, Georgios Voloudakis, John F Fullard, Venu M Pothula, Jonathan Tsang, Eli A Stahl, Anastasios Georgakopoulos, Douglas M Ruderfer, Alexander Charney, Yukinori Okada, Katherine A Siminovitch, Jane Worthington, Leonid Padyukov, Lars Klareskog, Peter K Gregersen, Robert M Plenge, Soumya Raychaudhuri, Menachem Fromer, Shaun M Purcell, Kristen J Brennand, Nikolaos K Robakis, Eric E Schadt, Schahram Akbarian, Pamela Sklar
• Journal: Cell reports (Cell Rep) Vol. 9 Issue 4 Pg. 1417-29 (Nov 20 2014) ISSN: 2211-1247 [Electronic] United States
• PMID: 25453756 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• CACNA1C protein, human
• Calcium Channels, L-Type
• DNA, Intergenic

Topics

• Arthritis, Rheumatoid (genetics)
• Calcium Channels, L-Type (genetics)
• DNA, Intergenic (genetics)
• Databases, Genetic
• Enhancer Elements, Genetic (genetics)
• Gene Expression Regulation
• Genetic Loci
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Humans
• Molecular Sequence Annotation
• Organ Specificity (genetics)
• Polymorphism, Single Nucleotide (genetics)
• Promoter Regions, Genetic
• Protein Binding (genetics)
• Risk Factors
• Schizophrenia (genetics)