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

TitleBrain expression genome-wide association study (eGWAS) identifies human disease-associated variants.
Publication TypeJournal Article
Year of Publication2012
AuthorsZou F, Chai HSeng, Younkin CS, Allen M, Crook J, V Pankratz S, Carrasquillo MM, Rowley CN, Nair AA, Middha S, Maharjan S, Nguyen T, Ma L, Malphrus KG, Palusak R, Lincoln S, Bisceglio G, Georgescu C, Kouri N, Kolbert CP, Jen J, Haines JL, Mayeux R, Pericak-Vance MA, Farrer LA, Gerard D Schellenberg, Petersen RC, Graff-Radford NR, Dickson DW, Younkin SG, Ertekin-Taner N
Corporate AuthorsAlzheimer's Disease Genetics Consortium
JournalPLoS Genet
Volume8
Issue6
Paginatione1002707
Date Published2012
ISSN1553-7404
KeywordsAlzheimer Disease, Autopsy, Gene Expression Regulation, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Polymorphism, Single Nucleotide, RNA, Temporal Lobe
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.

DOI10.1371/journal.pgen.1002707
Alternate JournalPLoS Genet.
PubMed ID22685416
PubMed Central IDPMC3369937
Grant ListAG003949 / AG / NIA NIH HHS / United States
AG010491 / AG / NIA NIH HHS / United States
AG017216 / AG / NIA NIH HHS / United States
AG019757 / AG / NIA NIH HHS / United States
AG021547 / AG / NIA NIH HHS / United States
AG025688 / AG / NIA NIH HHS / United States
AG025711 / AG / NIA NIH HHS / United States
AG027944 / AG / NIA NIH HHS / United States
AG030653 / AG / NIA NIH HHS / United States
AG17586 / AG / NIA NIH HHS / United States
K01 AG030514 / AG / NIA NIH HHS / United States
K24 AG027841 / AG / NIA NIH HHS / United States
KL2 RR024151 / RR / NCRR NIH HHS / United States
MO1RR00096 / RR / NCRR NIH HHS / United States
P01 AG002219 / AG / NIA NIH HHS / United States
P01 AG019724 / AG / NIA NIH HHS / United States
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P30 AG008017 / AG / NIA NIH HHS / United States
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P50 AG005131 / AG / NIA NIH HHS / United States
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P50 AG005146 / AG / NIA NIH HHS / United States
P50 AG005681 / AG / NIA NIH HHS / United States
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R01 032990 / / PHS HHS / United States
R01 AG009029 / AG / NIA NIH HHS / United States
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R01 AG017173 / AG / NIA NIH HHS / United States
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U24 AG026390 / AG / NIA NIH HHS / United States
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UL1 RR029893 / RR / NCRR NIH HHS / United States
UL1 RR029893 / RR / NCRR NIH HHS / United States
UL1RR02777 / RR / NCRR NIH HHS / United States
UO1 AG06781 / AG / NIA NIH HHS / United States
UO1 HG004610 / HG / NHGRI NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada
/ / Howard Hughes Medical Institute / United States
/ / Wellcome Trust / United Kingdom