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

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<5×10−8 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.

A Progressive Mouse Model of Parkinson's Disease: The Thy1-aSyn (“Line 61”) Mice

“…This view has now dramatically changed. Even though the role of accidental risk factors (e.g., traumatic brain injury) or environmental factors (e.g., exposure to agricultural pesticides or industrial solvents) is increasingly documented [9], it is clear that these environmental factors act in concert with genetic risk factors [10,11]. Furthermore, the identification of several mutations that cause familial forms of PD has revealed mechanisms shared by these rare disease forms and the much more common sporadic forms.…”

Promise of Pharmacogenomics for Drug Discovery, Treatment and Prevention of Parkinson's Disease. A Perspective

“…We were interested in identifying the genetic variations that were associated with enhanced or diminished effects of smoking/nicotine and caffeine on PD risk reduction, with the hope that they would be useful as PGx markers for prevention and treatment. We found that the caffeine effect is associated with polymorphisms in GRIN2A, which encodes the NMDA glutamate receptor subunit 2A [40], and that the nicotine effect is associated with polymorphisms in SV2C which encodes the synaptic vesicle protein 2C [41]. The significance of GRIN2A and SV2C in the central nervous system, the etiology of PD, and their intermediary roles in the effects of caffeine and nicotine on neurotransmission have been well-documented [46][47][48][49][50].…”

“…We conducted two genome-wide gene-drug interaction studies for PD; in one [40] the drug was caffeine, in the other [41] the drug was nicotine. Nicotine and caffeine are neuroprotective in animal models [42,43] and are robustly associated with reduced risk of PD in humans in epidemiological studies [44,45].…”

Bridging the Genetical Environmental Gap in Parkinson's Disease through Epigenetics

“…A collective study focusing on the effect of coffee consumption on Parkinson's Disease (PD) concluded that consumption of coffee is more protective amongst individuals with a particular genotype compared to another genotype [9]. Furthermore, multiple studies have synergistically concluded that the incidence of PD in cigarette smokers is less than nonsmokers, with the number of years of smoking, being closely linked to lowering the risk of PD among smokers [10].…”