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PLoS Genet. 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.

Collaborators (150)

Apostolova LG, Arnold SE, Baldwin CT, Barber R, Barmada MM, Beach T, Beecham GW, Beekly D, Bennett DA, Bigio EH, Bird TD, Blacker D, Boeve BF, Bowen JD, Boxer A, Burke JR, Buros J, Buxbaum JD, Cairns NJ, Cantwell LB, Cao C, Carlson CS, Carney RM, Carroll SL, Chui HC, Clark DG, Corneveaux J, Cotman CW, Crane PK, Cruchaga C, Cummings JL, De Jager PL, DeCarli C, DeKosky ST, Demirci FY, Diaz-Arrastia R, Dick M, Dombroski BA, Duara R, Ellis WG, Evans D, Faber KM, Fallon KB, Farlow MR, Ferris S, Foroud TM, Frosch MP, Galasko DR, Gallins PJ, Ganguli M, Gearing M, Geschwind DH, Ghetti B, Gilbert JR, Gilman S, Giordani B, Glass JD, Goate AM, Green RC, Growdon JH, Hakonarson H, Hamilton RL, Hardy J, Harrell LE, Head E, Honig LS, Huentelman MJ, Hulette CM, Hyman BT, Jarvik GP, Jicha GA, Jin LW, Johnson N, Jun G, Kamboh I, Karlawish J, Karydas A, Kauwe JS, Kaye JA, Kim R, Koo EH, Kowall NW, Kramer P, Kukull WA, Lah JJ, Larson EB, Levey AI, Lieberman AP, Lopez OL, Lunetta KL, Mack WJ, Marson DC, Martin ER, Martiniuk F, Mash DC, Masliah E, McCormick WC, McCurry SM, McDavid AN, McKee AC, Mesulam M, Miller BL, Miller CA, Miller JW, Montine TJ, Morris JC, Myers AJ, Naj AC, Nowotny P, Parisi JE, Perl DP, Peskind E, Poon WW, Potter H, Quinn JF, Raj A, Rajbhandary RA, Raskind M, Reiman EM, Reisberg B, Reitz C, Ringman JM, Roberson ED, Rogaeva E, Rosenberg RN, Sano M, Saykin AJ, Schneider JA, Schneider LS, Seeley W, Shelanski ML, Slifer MA, Smith CD, Sonnen JA, Spina S, George-Hyslop PS, Stern RA, Tanzi RE, Trojanowski JQ, Troncoso JC, Tsuang DW, Van Deerlin VM, Vardarajan BN, Vinters HV, Vonsattel JP, Wang LS, Weintraub S, Welsh-Bohmer KA, Williamson J, Woltjer RL.

Author information

1
Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.

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.

PMID:
22685416
PMCID:
PMC3369937
DOI:
10.1371/journal.pgen.1002707
[Indexed for MEDLINE]
Free PMC Article

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.

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