Genome-wide gene-environment study identifies glutamate receptor gene grin2a as a parkinson's disease modifier gene via interaction with coffee

Taye H. Hamza, Honglei Chen, Erin M. Hill-Burns, Shannon L. Rhodes, Jennifer Montimurro, Denise M. Kay, Albert Tenesa, Victoria I. Kusel, Patricia Sheehan, Muthukrishnan Eaaswarkhanth, Dora Yearout, Ali Samii, John W. Roberts, Pinky Agarwal, Yvette Bordelon, Yikyung Park, Liyong Wang, Jianjun Gao, Jeffery M. Vance, Kenneth S. KendlerSilviu Alin Bacanu, William K. Scott, Beate Ritz, John Nutt, Stewart A. Factor, Cyrus P. Zabetian, Haydeh Payami

Research output: Contribution to journalArticle

128 Citations (Scopus)

Abstract

Our aim was to identify genes that influence the inverse association of coffee with the risk of developing Parkinson's disease (PD). We used genome-wide genotype data and lifetime caffeinated-coffee-consumption data on 1,458 persons with PD and 931 without PD from the NeuroGenetics Research Consortium (NGRC), and we performed a genome-wide association and interaction study (GWAIS), testing each SNP's main-effect plus its interaction with coffee, adjusting for sex, age, and two principal components. We then stratified subjects as heavy or light coffee-drinkers and performed genome-wide association study (GWAS) in each group. We replicated the most significant SNP. Finally, we imputed the NGRC dataset, increasing genomic coverage to examine the region of interest in detail. The primary analyses (GWAIS, GWAS, Replication) were performed using genotyped data. In GWAIS, the most significant signal came from rs4998386 and the neighboring SNPs in GRIN2A. GRIN2A encodes an NMDA-glutamate-receptor subunit and regulates excitatory neurotransmission in the brain. Achieving P2df = 10-6, GRIN2A surpassed all known PD susceptibility genes in significance in the GWAIS. In stratified GWAS, the GRIN2A signal was present in heavy coffee-drinkers (OR = 0.43; P = 6×10-7) but not in light coffee-drinkers. The a priori Replication hypothesis that "Among heavy coffee-drinkers, rs4998386_T carriers have lower PD risk than rs4998386_CC carriers" was confirmed: ORReplication = 0.59, PReplication = 10-3; ORPooled = 0.51, PPooled = 7×10-8. Compared to light coffee-drinkers with rs4998386_CC genotype, heavy coffee-drinkers with rs4998386_CC genotype had 18% lower risk (P = 3×10-3), whereas heavy coffee-drinkers with rs4998386_TC genotype had 59% lower risk (P = 6×10-13). Imputation revealed a block of SNPs that achieved P2df-8 in GWAIS, and OR = 0.41, P = 3×10-8 in heavy coffee-drinkers. This study is proof of concept that inclusion of environmental factors can help identify genes that are missed in GWAS. Both adenosine antagonists (caffeine-like) and glutamate antagonists (GRIN2A-related) are being tested in clinical trials for treatment of PD. GRIN2A may be a useful pharmacogenetic marker for subdividing individuals in clinical trials to determine which medications might work best for which patients.

Original languageEnglish (US)
Article numbere1002237
JournalPLoS Genetics
Volume7
Issue number8
DOIs
StatePublished - Aug 2011

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Modifier Genes
modifiers (genes)
gene interaction
Parkinson disease
Coffee
Glutamate Receptors
coffee
Genome-Wide Association Study
Parkinson Disease
genome
Genome
gene
Genes
genes
genotype
Single Nucleotide Polymorphism
antagonists
clinical trials
Genotype
pharmacogenomics

ASJC Scopus subject areas

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

Cite this

Genome-wide gene-environment study identifies glutamate receptor gene grin2a as a parkinson's disease modifier gene via interaction with coffee. / Hamza, Taye H.; Chen, Honglei; Hill-Burns, Erin M.; Rhodes, Shannon L.; Montimurro, Jennifer; Kay, Denise M.; Tenesa, Albert; Kusel, Victoria I.; Sheehan, Patricia; Eaaswarkhanth, Muthukrishnan; Yearout, Dora; Samii, Ali; Roberts, John W.; Agarwal, Pinky; Bordelon, Yvette; Park, Yikyung; Wang, Liyong; Gao, Jianjun; Vance, Jeffery M.; Kendler, Kenneth S.; Bacanu, Silviu Alin; Scott, William K.; Ritz, Beate; Nutt, John; Factor, Stewart A.; Zabetian, Cyrus P.; Payami, Haydeh.

In: PLoS Genetics, Vol. 7, No. 8, e1002237, 08.2011.

Research output: Contribution to journalArticle

Hamza, TH, Chen, H, Hill-Burns, EM, Rhodes, SL, Montimurro, J, Kay, DM, Tenesa, A, Kusel, VI, Sheehan, P, Eaaswarkhanth, M, Yearout, D, Samii, A, Roberts, JW, Agarwal, P, Bordelon, Y, Park, Y, Wang, L, Gao, J, Vance, JM, Kendler, KS, Bacanu, SA, Scott, WK, Ritz, B, Nutt, J, Factor, SA, Zabetian, CP & Payami, H 2011, 'Genome-wide gene-environment study identifies glutamate receptor gene grin2a as a parkinson's disease modifier gene via interaction with coffee', PLoS Genetics, vol. 7, no. 8, e1002237. https://doi.org/10.1371/journal.pgen.1002237
Hamza, Taye H. ; Chen, Honglei ; Hill-Burns, Erin M. ; Rhodes, Shannon L. ; Montimurro, Jennifer ; Kay, Denise M. ; Tenesa, Albert ; Kusel, Victoria I. ; Sheehan, Patricia ; Eaaswarkhanth, Muthukrishnan ; Yearout, Dora ; Samii, Ali ; Roberts, John W. ; Agarwal, Pinky ; Bordelon, Yvette ; Park, Yikyung ; Wang, Liyong ; Gao, Jianjun ; Vance, Jeffery M. ; Kendler, Kenneth S. ; Bacanu, Silviu Alin ; Scott, William K. ; Ritz, Beate ; Nutt, John ; Factor, Stewart A. ; Zabetian, Cyrus P. ; Payami, Haydeh. / Genome-wide gene-environment study identifies glutamate receptor gene grin2a as a parkinson's disease modifier gene via interaction with coffee. In: PLoS Genetics. 2011 ; Vol. 7, No. 8.
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abstract = "Our aim was to identify genes that influence the inverse association of coffee with the risk of developing Parkinson's disease (PD). We used genome-wide genotype data and lifetime caffeinated-coffee-consumption data on 1,458 persons with PD and 931 without PD from the NeuroGenetics Research Consortium (NGRC), and we performed a genome-wide association and interaction study (GWAIS), testing each SNP's main-effect plus its interaction with coffee, adjusting for sex, age, and two principal components. We then stratified subjects as heavy or light coffee-drinkers and performed genome-wide association study (GWAS) in each group. We replicated the most significant SNP. Finally, we imputed the NGRC dataset, increasing genomic coverage to examine the region of interest in detail. The primary analyses (GWAIS, GWAS, Replication) were performed using genotyped data. In GWAIS, the most significant signal came from rs4998386 and the neighboring SNPs in GRIN2A. GRIN2A encodes an NMDA-glutamate-receptor subunit and regulates excitatory neurotransmission in the brain. Achieving P2df = 10-6, GRIN2A surpassed all known PD susceptibility genes in significance in the GWAIS. In stratified GWAS, the GRIN2A signal was present in heavy coffee-drinkers (OR = 0.43; P = 6×10-7) but not in light coffee-drinkers. The a priori Replication hypothesis that {"}Among heavy coffee-drinkers, rs4998386_T carriers have lower PD risk than rs4998386_CC carriers{"} was confirmed: ORReplication = 0.59, PReplication = 10-3; ORPooled = 0.51, PPooled = 7×10-8. Compared to light coffee-drinkers with rs4998386_CC genotype, heavy coffee-drinkers with rs4998386_CC genotype had 18{\%} lower risk (P = 3×10-3), whereas heavy coffee-drinkers with rs4998386_TC genotype had 59{\%} lower risk (P = 6×10-13). Imputation revealed a block of SNPs that achieved P2df-8 in GWAIS, and OR = 0.41, P = 3×10-8 in heavy coffee-drinkers. This study is proof of concept that inclusion of environmental factors can help identify genes that are missed in GWAS. Both adenosine antagonists (caffeine-like) and glutamate antagonists (GRIN2A-related) are being tested in clinical trials for treatment of PD. GRIN2A may be a useful pharmacogenetic marker for subdividing individuals in clinical trials to determine which medications might work best for which patients.",
author = "Hamza, {Taye H.} and Honglei Chen and Hill-Burns, {Erin M.} and Rhodes, {Shannon L.} and Jennifer Montimurro and Kay, {Denise M.} and Albert Tenesa and Kusel, {Victoria I.} and Patricia Sheehan and Muthukrishnan Eaaswarkhanth and Dora Yearout and Ali Samii and Roberts, {John W.} and Pinky Agarwal and Yvette Bordelon and Yikyung Park and Liyong Wang and Jianjun Gao and Vance, {Jeffery M.} and Kendler, {Kenneth S.} and Bacanu, {Silviu Alin} and Scott, {William K.} and Beate Ritz and John Nutt and Factor, {Stewart A.} and Zabetian, {Cyrus P.} and Haydeh Payami",
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T1 - Genome-wide gene-environment study identifies glutamate receptor gene grin2a as a parkinson's disease modifier gene via interaction with coffee

AU - Hamza, Taye H.

AU - Chen, Honglei

AU - Hill-Burns, Erin M.

AU - Rhodes, Shannon L.

AU - Montimurro, Jennifer

AU - Kay, Denise M.

AU - Tenesa, Albert

AU - Kusel, Victoria I.

AU - Sheehan, Patricia

AU - Eaaswarkhanth, Muthukrishnan

AU - Yearout, Dora

AU - Samii, Ali

AU - Roberts, John W.

AU - Agarwal, Pinky

AU - Bordelon, Yvette

AU - Park, Yikyung

AU - Wang, Liyong

AU - Gao, Jianjun

AU - Vance, Jeffery M.

AU - Kendler, Kenneth S.

AU - Bacanu, Silviu Alin

AU - Scott, William K.

AU - Ritz, Beate

AU - Nutt, John

AU - Factor, Stewart A.

AU - Zabetian, Cyrus P.

AU - Payami, Haydeh

PY - 2011/8

Y1 - 2011/8

N2 - Our aim was to identify genes that influence the inverse association of coffee with the risk of developing Parkinson's disease (PD). We used genome-wide genotype data and lifetime caffeinated-coffee-consumption data on 1,458 persons with PD and 931 without PD from the NeuroGenetics Research Consortium (NGRC), and we performed a genome-wide association and interaction study (GWAIS), testing each SNP's main-effect plus its interaction with coffee, adjusting for sex, age, and two principal components. We then stratified subjects as heavy or light coffee-drinkers and performed genome-wide association study (GWAS) in each group. We replicated the most significant SNP. Finally, we imputed the NGRC dataset, increasing genomic coverage to examine the region of interest in detail. The primary analyses (GWAIS, GWAS, Replication) were performed using genotyped data. In GWAIS, the most significant signal came from rs4998386 and the neighboring SNPs in GRIN2A. GRIN2A encodes an NMDA-glutamate-receptor subunit and regulates excitatory neurotransmission in the brain. Achieving P2df = 10-6, GRIN2A surpassed all known PD susceptibility genes in significance in the GWAIS. In stratified GWAS, the GRIN2A signal was present in heavy coffee-drinkers (OR = 0.43; P = 6×10-7) but not in light coffee-drinkers. The a priori Replication hypothesis that "Among heavy coffee-drinkers, rs4998386_T carriers have lower PD risk than rs4998386_CC carriers" was confirmed: ORReplication = 0.59, PReplication = 10-3; ORPooled = 0.51, PPooled = 7×10-8. Compared to light coffee-drinkers with rs4998386_CC genotype, heavy coffee-drinkers with rs4998386_CC genotype had 18% lower risk (P = 3×10-3), whereas heavy coffee-drinkers with rs4998386_TC genotype had 59% lower risk (P = 6×10-13). Imputation revealed a block of SNPs that achieved P2df-8 in GWAIS, and OR = 0.41, P = 3×10-8 in heavy coffee-drinkers. This study is proof of concept that inclusion of environmental factors can help identify genes that are missed in GWAS. Both adenosine antagonists (caffeine-like) and glutamate antagonists (GRIN2A-related) are being tested in clinical trials for treatment of PD. GRIN2A may be a useful pharmacogenetic marker for subdividing individuals in clinical trials to determine which medications might work best for which patients.

AB - Our aim was to identify genes that influence the inverse association of coffee with the risk of developing Parkinson's disease (PD). We used genome-wide genotype data and lifetime caffeinated-coffee-consumption data on 1,458 persons with PD and 931 without PD from the NeuroGenetics Research Consortium (NGRC), and we performed a genome-wide association and interaction study (GWAIS), testing each SNP's main-effect plus its interaction with coffee, adjusting for sex, age, and two principal components. We then stratified subjects as heavy or light coffee-drinkers and performed genome-wide association study (GWAS) in each group. We replicated the most significant SNP. Finally, we imputed the NGRC dataset, increasing genomic coverage to examine the region of interest in detail. The primary analyses (GWAIS, GWAS, Replication) were performed using genotyped data. In GWAIS, the most significant signal came from rs4998386 and the neighboring SNPs in GRIN2A. GRIN2A encodes an NMDA-glutamate-receptor subunit and regulates excitatory neurotransmission in the brain. Achieving P2df = 10-6, GRIN2A surpassed all known PD susceptibility genes in significance in the GWAIS. In stratified GWAS, the GRIN2A signal was present in heavy coffee-drinkers (OR = 0.43; P = 6×10-7) but not in light coffee-drinkers. The a priori Replication hypothesis that "Among heavy coffee-drinkers, rs4998386_T carriers have lower PD risk than rs4998386_CC carriers" was confirmed: ORReplication = 0.59, PReplication = 10-3; ORPooled = 0.51, PPooled = 7×10-8. Compared to light coffee-drinkers with rs4998386_CC genotype, heavy coffee-drinkers with rs4998386_CC genotype had 18% lower risk (P = 3×10-3), whereas heavy coffee-drinkers with rs4998386_TC genotype had 59% lower risk (P = 6×10-13). Imputation revealed a block of SNPs that achieved P2df-8 in GWAIS, and OR = 0.41, P = 3×10-8 in heavy coffee-drinkers. This study is proof of concept that inclusion of environmental factors can help identify genes that are missed in GWAS. Both adenosine antagonists (caffeine-like) and glutamate antagonists (GRIN2A-related) are being tested in clinical trials for treatment of PD. GRIN2A may be a useful pharmacogenetic marker for subdividing individuals in clinical trials to determine which medications might work best for which patients.

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