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Landscape of Conditional eQTL in Dorsolateral Prefrontal Cortex and Co-localization with Schizophrenia GWAS

Authors :
Amanda Dobbyn
Laura M. Huckins
James Boocock
Laura G. Sloofman
Benjamin S. Glicksberg
Claudia Giambartolomei
Gabriel E. Hoffman
Thanneer M. Perumal
Kiran Girdhar
Yan Jiang
Towfique Raj
Douglas M. Ruderfer
Robin S. Kramer
Dalila Pinto
Schahram Akbarian
Panos Roussos
Enrico Domenici
Bernie Devlin
Pamela Sklar
Eli A. Stahl
Solveig K. Sieberts
Joseph Buxbaum
David Lewis
Raquel Gur
Chang-Gyu Hahn
Keisuke Hirai
Hiroyoshi Toyoshiba
Laurent Essioux
Lara Mangravite
Mette Peters
Thomas Lehner
Barbara Lipska
A. Ercument Cicek
Cong Lu
Kathryn Roeder
Lu Xie
Konrad Talbot
Scott E. Hemby
Andrew Browne
Andrew Chess
Aaron Topol
Alexander Charney
Ben Readhead
Bin Zhang
David A. Bennett
David H. Kavanagh
Eric E. Schadt
Hardik R. Shah
Jun Zhu
Jessica S. Johnson
John F. Fullard
Joel T. Dudley
Kristen J. Brennand
Menachem Fromer
Milind C. Mahajan
Shaun M. Purcell
Tymor Hamamsy
Vahram Haroutunian
Ying-Chih Wang
Zeynep H. Gümüş
Geetha Senthil
Robin Kramer
Benjamin A. Logsdon
Jonathan M.J. Derry
Kristen K. Dang
Roberto Visintainer
Leslie A. Shinobu
Patrick F. Sullivan
Lambertus L. Klei
Source :
American Journal of Human Genetics
Publication Year :
2018
Publisher :
Elsevier BV, 2018.

Abstract

Causal genes and variants within genome-wide association study (GWAS) loci can be identified by integrating GWAS statistics with expression quantitative trait loci (eQTL) and determining which variants underlie both GWAS and eQTL signals. Most analyses, however, consider only the marginal eQTL signal, rather than dissect this signal into multiple conditionally independent signals for each gene. Here we show that analyzing conditional eQTL signatures, which could be important under specific cellular or temporal contexts, leads to improved fine mapping of GWAS associations. Using genotypes and gene expression levels from post-mortem human brain samples (n = 467) reported by the CommonMind Consortium (CMC), we find that conditional eQTL are widespread; 63% of genes with primary eQTL also have conditional eQTL. In addition, genomic features associated with conditional eQTL are consistent with context-specific (e.g., tissue-, cell type-, or developmental time point-specific) regulation of gene expression. Integrating the 2014 Psychiatric Genomics Consortium schizophrenia (SCZ) GWAS and CMC primary and conditional eQTL data reveals 40 loci with strong evidence for co-localization (posterior probability > 0.8), including six loci with co-localization of conditional eQTL. Our co-localization analyses support previously reported genes, identify novel genes associated with schizophrenia risk, and provide specific hypotheses for their functional follow-up.

Details

ISSN :
00029297
Volume :
102
Database :
OpenAIRE
Journal :
The American Journal of Human Genetics
Accession number :
edsair.doi.dedup.....c2195e247d6f51da5e445339e007da95
Full Text :
https://doi.org/10.1016/j.ajhg.2018.04.011