Genome-Wide Gene-Environment Study Identifies Glutamate Receptor Gene GRIN2A as a Parkinson's Disease Modifier Gene via Interaction with Coffee

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 weperformed a genome-wideassociation 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 asheavyor 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 NMDAglutamate-receptor subunit and regulates excitatory neurotransmission in the brain. Achieving P2df=10 26 , GRIN2A surpassed all known PD susceptibility genes in significance in the GWAIS. In stratified GWAS, the GRIN2A signal was present in heavy coffeedrinkers (OR=0.43; P=6610 27 ) but not in light coffee-drinkers. The ap rioriReplication hypothesis that ‘‘Among heavy coffeedrinkers, rs4998386_T carriers have lower PD risk than rs4998386_CC carriers’’ was confirmed: ORReplication=0.59, PReplication=10 23 ;O R Pooled=0.51, PPooled=7610 28 . Compared to light coffee-drinkers with rs4998386_CC genotype, heavy coffee-drinkers with rs4998386_CC genotype had 18% lower risk (P=3610 23 ), whereas heavy coffee-drinkers with rs4998386_TC genotype had 59% lower risk (P=6610 213 ). Imputation revealed a block of SNPs that achieved P2df,5610 28 in GWAIS, and OR=0.41, P=3610 28 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.