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Meta-Analysis
. 2012;8(6):e1002707.
doi: 10.1371/journal.pgen.1002707. Epub 2012 Jun 7.

Brain expression genome-wide association study (eGWAS) identifies human disease-associated variants

Fanggeng Zou  1 , High Seng Chai, Curtis S Younkin, Mariet Allen, Julia Crook, V Shane Pankratz, Minerva M Carrasquillo, Christopher N Rowley, Asha A Nair, Sumit Middha, Sooraj Maharjan, Thuy Nguyen, Li Ma, Kimberly G Malphrus, Ryan Palusak, Sarah Lincoln, Gina Bisceglio, Constantin Georgescu, Naomi Kouri, Christopher P Kolbert, Jin Jen, Jonathan L Haines, Richard Mayeux, Margaret A Pericak-Vance, Lindsay A Farrer, Gerard D Schellenberg; Alzheimer's Disease Genetics Consortium; Ronald C Petersen, Neill R Graff-Radford, Dennis W Dickson, Steven G Younkin, Nilüfer Ertekin-Taner
Collaborators, Affiliations
Meta-Analysis

Brain expression genome-wide association study (eGWAS) identifies human disease-associated variants

Fanggeng Zou et al. PLoS Genet. 2012.

Abstract

Genetic variants that modify brain gene expression may also influence risk for human diseases. We measured expression levels of 24,526 transcripts in brain samples from the cerebellum and temporal cortex of autopsied subjects with Alzheimer's disease (AD, cerebellar n=197, temporal cortex n=202) and with other brain pathologies (non-AD, cerebellar n=177, temporal cortex n=197). We conducted an expression genome-wide association study (eGWAS) using 213,528 cisSNPs within ± 100 kb of the tested transcripts. We identified 2,980 cerebellar cisSNP/transcript level associations (2,596 unique cisSNPs) significant in both ADs and non-ADs (q<0.05, p=7.70 × 10(-5)-1.67 × 10(-82)). Of these, 2,089 were also significant in the temporal cortex (p=1.85 × 10(-5)-1.70 × 10(-141)). The top cerebellar cisSNPs had 2.4-fold enrichment for human disease-associated variants (p<10(-6)). We identified novel cisSNP/transcript associations for human disease-associated variants, including progressive supranuclear palsy SLCO1A2/rs11568563, Parkinson's disease (PD) MMRN1/rs6532197, Paget's disease OPTN/rs1561570; and we confirmed others, including PD MAPT/rs242557, systemic lupus erythematosus and ulcerative colitis IRF5/rs4728142, and type 1 diabetes mellitus RPS26/rs1701704. In our eGWAS, there was 2.9-3.3 fold enrichment (p<10(-6)) of significant cisSNPs with suggestive AD-risk association (p<10(-3)) in the Alzheimer's Disease Genetics Consortium GWAS. These results demonstrate the significant contributions of genetic factors to human brain gene expression, which are reliably detected across different brain regions and pathologies. The significant enrichment of brain cisSNPs among disease-associated variants advocates gene expression changes as a mechanism for many central nervous system (CNS) and non-CNS diseases. Combined assessment of expression and disease GWAS may provide complementary information in discovery of human disease variants with functional implications. Our findings have implications for the design and interpretation of eGWAS in general and the use of brain expression quantitative trait loci in the study of human disease genetics.

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Conflict of interest statement

NR Graff-Radford has served as a consultant to Codman and received grant support from Elan Pharmaceutical Research, Pfizer Pharmaceuticals, Medivation, and Forrest. RC Petersen has been a consultant to GE Healthcare and Elan Pharmaceuticals, has served on a data safety monitoring committee for Pfizer and Janssen Alzheimer Immunotherapy, and has provided a CME lecture for Novartis. ADGC Authors: T.D.B. received licensing fees from and is on the speaker's bureau of Athena Diagnostics. M.R.F. receives research funding from BristolMyersSquibb Company, Danone Research, Elan Pharmaceuticals, Eli Lilly, Novartis Pharmaceuticals, OctaPharma AG, Pfizer, and Sonexa Therapeutics; receives honoraria as scientific consultant from Accera, Astellas Pharma US Inc., Baxter, Bayer Pharmaceuticals Corporation, BristolMyersSquibb, Eisai Medical Research, GE Healthcare, Medavante, Medivation, Merck, Novartis Pharmaceuticals, Pfizer, Prana Biotechnology, QR Pharma, The sanofi-aventis Group, and Toyama Chemical; and is speaker for Eisai Medical Research, Forest Laboratories, Pfizer, and Novartis Pharmaceuticals. A.M.G. has research funding from AstraZeneca, Pfizer and Genentech, and has received remuneration for giving talks at Pfizer and Genentech. R.C.P. is on the Safety Monitory Committee of Pfizer (Wyeth) and a consultant to the Safety Monitoring Committee at Janssen Alzheimer's Immunotherapy Program (Elan), to Elan Pharmaceuticals, and to GE Healthcare. R.E.T. is a consultant to Eisai, Japan, in the area of Alzheimer's genetics and a shareholder in, and consultant to, Pathway Genomics, San Diego, CA.

Figures

Figure 1
Figure 1. Summary of brain eGWAS and human disease associations.
See this image and copyright information in PMC

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