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

Fanggeng Zou, High Seng Chai, Curtis S. Younkin, Mariet Allen, Juliana 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. KolbertJin Jen, Jonathan L. Haines, Richard Mayeux, Margaret A. Pericak-Vance, Lindsay A. Farrer, Gerard D. Schellenberg, Ronald Carl Petersen, Neill R Graff Radford, Dennis W Dickson, Steven G Younkin, Nilufer Taner

Research output: Contribution to journalArticle

130 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1002707
JournalPLoS Genetics
Volume8
Issue number6
DOIs
StatePublished - Jun 2012

Fingerprint

Genome-Wide Association Study
human diseases
brain
genome
Brain
Temporal Lobe
cortex
gene expression
Parkinson disease
Alzheimer disease
pathology
nervous system
Gene Expression
Parkinson Disease
lupus erythematosus
Pathology
fold
nervous system diseases
Progressive Supranuclear Palsy
insulin-dependent diabetes mellitus

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Brain expression genome-wide association study (eGWAS) identifies human disease-associated variants. / Zou, Fanggeng; Chai, High Seng; Younkin, Curtis S.; Allen, Mariet; Crook, Juliana; Pankratz, V. Shane; Carrasquillo, Minerva M; Rowley, Christopher N.; Nair, Asha A.; Middha, Sumit; Maharjan, Sooraj; Nguyen, Thuy; Ma, Li; Malphrus, Kimberly G.; Palusak, Ryan; Lincoln, Sarah; Bisceglio, Gina; Georgescu, Constantin; Kouri, Naomi; Kolbert, Christopher P.; Jen, Jin; Haines, Jonathan L.; Mayeux, Richard; Pericak-Vance, Margaret A.; Farrer, Lindsay A.; Schellenberg, Gerard D.; Petersen, Ronald Carl; Graff Radford, Neill R; Dickson, Dennis W; Younkin, Steven G; Taner, Nilufer.

In: PLoS Genetics, Vol. 8, No. 6, e1002707, 06.2012.

Research output: Contribution to journalArticle

Zou, F, Chai, HS, Younkin, CS, Allen, M, Crook, J, Pankratz, VS, 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, Schellenberg, GD, Petersen, RC, Graff Radford, NR, Dickson, DW, Younkin, SG & Taner, N 2012, 'Brain expression genome-wide association study (eGWAS) identifies human disease-associated variants', PLoS Genetics, vol. 8, no. 6, e1002707. https://doi.org/10.1371/journal.pgen.1002707
Zou, Fanggeng ; Chai, High Seng ; Younkin, Curtis S. ; Allen, Mariet ; Crook, Juliana ; Pankratz, V. Shane ; Carrasquillo, Minerva M ; Rowley, Christopher N. ; Nair, Asha A. ; Middha, Sumit ; Maharjan, Sooraj ; Nguyen, Thuy ; Ma, Li ; Malphrus, Kimberly G. ; Palusak, Ryan ; Lincoln, Sarah ; Bisceglio, Gina ; Georgescu, Constantin ; Kouri, Naomi ; Kolbert, Christopher P. ; Jen, Jin ; Haines, Jonathan L. ; Mayeux, Richard ; Pericak-Vance, Margaret A. ; Farrer, Lindsay A. ; Schellenberg, Gerard D. ; Petersen, Ronald Carl ; Graff Radford, Neill R ; Dickson, Dennis W ; Younkin, Steven G ; Taner, Nilufer. / Brain expression genome-wide association study (eGWAS) identifies human disease-associated variants. In: PLoS Genetics. 2012 ; Vol. 8, No. 6.
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AU - Zou, Fanggeng

AU - Chai, High Seng

AU - Younkin, Curtis S.

AU - Allen, Mariet

AU - Crook, Juliana

AU - Pankratz, V. Shane

AU - Carrasquillo, Minerva M

AU - Rowley, Christopher N.

AU - Nair, Asha A.

AU - Middha, Sumit

AU - Maharjan, Sooraj

AU - Nguyen, Thuy

AU - Ma, Li

AU - Malphrus, Kimberly G.

AU - Palusak, Ryan

AU - Lincoln, Sarah

AU - Bisceglio, Gina

AU - Georgescu, Constantin

AU - Kouri, Naomi

AU - Kolbert, Christopher P.

AU - Jen, Jin

AU - Haines, Jonathan L.

AU - Mayeux, Richard

AU - Pericak-Vance, Margaret A.

AU - Farrer, Lindsay A.

AU - Schellenberg, Gerard D.

AU - Petersen, Ronald Carl

AU - Graff Radford, Neill R

AU - Dickson, Dennis W

AU - Younkin, Steven G

AU - Taner, Nilufer

PY - 2012/6

Y1 - 2012/6

N2 - 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.

AB - 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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