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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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 P(2df) = 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 = 6x10(-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: OR(Replication) = 0.59, P(Replication) = 10(-3); OR(Pooled) = 0.51, P(Pooled) = 7x10(-8). Compared to light coffee-drinkers with rs4998386_CC genotype, heavy coffee-drinkers with rs4998386_CC genotype had 18% lower risk (P = 3x10(-3)), whereas heavy coffee-drinkers with rs4998386_TC genotype had 59% lower risk (P = 6x10(-13)). Imputation revealed a block of SNPs that achieved P(2df)
Original languageEnglish
Article numbere1002237
Pages (from-to)e1002237
JournalPLoS Genetics
Issue number8
Publication statusPublished - Aug 2011


  • Case-Control Studies
  • Coffee
  • Female
  • Gene-Environment Interaction
  • Genetic Predisposition to Disease
  • Genome, Human
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Male
  • Parkinson Disease
  • Polymorphism, Single Nucleotide
  • Receptors, N-Methyl-D-Aspartate
  • Risk Factors


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