Authors

Taye H. Hamza, New York State Department of Health Wadsworth Center
Honglei Chen, Research Triangle Park
Erin M. Hill-Burns, New York State Department of Health Wadsworth Center
Shannon L. Rhodes, University of California Los Angeles
Jennifer Montimurro, New York State Department of Health Wadsworth Center
Denise M. Kay, New York State Department of Health Wadsworth Center
Albert Tenesa, University of Edinburgh
Victoria I. Kusel, New York State Department of Health Wadsworth Center
Patricia Sheehan, New York State Department of Health Wadsworth Center
Muthukrishnan Eaaswarkhanth, New York State Department of Health Wadsworth Center
Dora Yearout, New York State Department of Health Wadsworth Center
Ali Samii, University of Washington
John W. Roberts, Virginia Mason Medical Center
Pinky Agarwal, Evergreen Hospital Medical Center
Yvette Bordelon, University of California Los Angeles
Yikyung Park, National Cancer Institute
Liyong Wang, University of Miami Miller School of Medicine
Jianjun Gao, Research Triangle Park
Jeffery M. Vance, University of Miami Miller School of Medicine
Kenneth S. Kendler, Virginia Commonwealth UniversityFollow
Silviu-Alin Bacanu, Virginia Commonwealth UniversityFollow
William K. Scott, University of Miami Miller School of Medicine
Beate Ritz, University of California Los Angeles
John Nutt, Oregon Health and Sciences University
Stweart A. Factor, Emory University School of Medicine
Cyrus P. Zabetian, University of Washington
Haydeh Payami, New York State Department of Health Wadsworth Center

Document Type

Article

Original Publication Date

2011

Journal/Book/Conference Title

PLOS ONE

Volume

7

DOI of Original Publication

10.1371/journal.pgen.1002237

Comments

Originally Published at http://dx.doi.org/10.1371/journal.pgen.1002237

Date of Submission

November 2014

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.

Author Summary

Parkinson's disease (PD), like most common disorders, involves interactions between genetic make-up and environmental exposures that are unique to each individual. Caffeinated-coffee consumption may protect some people from developing PD, although not all benefit equally. In a genome-wide search, we discovered that variations in the glutamate-receptor gene GRIN2Amodulate the risk of developing PD in heavy coffee drinkers. The study was hypothesis-free, that is, we cast a net across the entire genome allowing statistical significance to point us to a genetic variant, regardless of whether it fell in a genomic desert or an important gene. Fortuitously, the most significant finding was in a well-known gene, GRIN2A, which regulates brain signals that control movement and behavior. Our finding is important for three reasons: First, it is a proof of concept that studying genes and environment on the whole-genome scale is feasible, and this approach can identify important genes that are missed when environmental exposures are ignored. Second, the knowledge of interaction between GRIN2A, which is involved in neurotransmission in the brain, and caffeine, which is an adenosine-A2A-receptor antagonist, will stimulate new research towards understanding the cause and progression of PD. Third, the results may lead to personalized prevention of and treatment for PD.

Rights

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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VCU Psychiatry Publications

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