Genome-Wide Gene-Environment Study Identifies Glutamate Receptor Gene GRIN2A as a Parkinson's Disease Modifier Gene via Interaction with Coffee
Open accessAbstract
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 = 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: OR(Replication) = 0.59, P(Replication) = 10(-3); OR(Pooled) = 0.51, P(Pooled) = 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 P(2df)<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.
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There is little evidence for environmental modification of genotype effects, with coffee consumption and Parkinson's disease risk as a recent exception.
“Similarly, there is as yet little evidence for environmental modification of genotype effects: a recent example relating to the protective effect of coffee consumption and Parkinson’s disease risk provides an exception108.”
From Rare and common variants: twenty arguments (2012) · cites this paper as [108]
GWAS provide very little evidence for gene-environment or gene-gene interactions.
“It must be noted that there is very little evidence from GWAS for either GxE or GxG interactions108, but such effects could be mild at the level of individual associations and be below the power of detection.”
From Rare and common variants: twenty arguments (2012) · cites this paper as [108]
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Self-citation
- Authors
- Hamza, T. H., Chen, H., Hill-Burns, E. M., Rhodes, S. L., Montimurro, J., Kay, D. M., Tenesa, A., Kusel, V. I., Sheehan, P., Eaaswarkhanth, M., Yearout, D., Samii, A., Roberts, J. W., Agarwal, P., Bordelon, Y., Park, Y., Wang, L., Gao, J., Vance, J. M., Kendler, K. S., Bacanu, S.-A., Scott, W. K., Ritz, B., Nutt, J., Factor, S. A., Zabetian, C. P., & Payami, H.
- Affiliations
- New York State Department of Health (US)
- National Institute of Environmental Health Sciences (US)
- University of California, Los Angeles (US)
- Roslin Institute (GB)
- University of Washington (US)
- Virginia Mason Medical Center (US)
- Evergreen Health Medical Center (US)
- National Cancer Institute (US)
- University of Miami (US)
- Virginia Commonwealth University (US)
- Oregon Health & Science University (US)
- Emory University (US)
- Corresponding author
- Payami, Haydeh
- ORCID
- Hamza, Taye H.
- Chen, Honglei
- Rhodes, Shannon L.
- Kay, Denise M.
- Tenesa, Albert
- Sheehan, Patricia
- Eaaswarkhanth, Muthukrishnan
- Yearout, Dora
- 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
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-08-18
- Volume
- 7
- Issue
- 8
- Pages
- e1002237
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC3158052
- OpenAlex
- W2169657293
- Cited by
- 218
- References
- 54
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 10 · 2023: 9 · 2022: 11 · 2021: 10 · 2020: 19 · 2019: 12 · 2018: 17 · 2017: 11 · 2016: 17 · 2015: 23 · 2014: 24 · 2013: 27 · 2012: 20
- FWCI
- 14.62
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Genetics (publishedVersion, public-domain)
- Europe PMC (PubMed Central) (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (acceptedVersion, other-oa)
- VCU Scholars Compass (Virginia Commonwealth University) (submittedVersion, public-domain)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- U.S. Department of Veterans Affairs (I01 BX000531, 1I01BX000531)
- Michael J. Fox Foundation for Parkinson's Research
- National Institutes of Health (1z01es101986-03, HHSN268200782096C, NIEHS R01, Z01-ES101986)
- NODAI Genome Research Center, Tokyo University of Agriculture
- National Human Genome Research Institute (HHSN268200782096C)
- National Cancer Institute (Z01CP010196)
- National Institute of Neurological Disorders and Stroke (NS-038367, NS039764, R01NS036960, ES016732, R01 NS 36960, P50NS038367, R01NS067469, P50NS039764, NS36960)
- National Institute of Environmental Health Sciences (Z01-ES 101986, R01ES010544, P01ES016732, ES016732)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Pharmacology › Coffee research and impacts
- Keywords
- Parkinson's disease, GRIN2A, NMDA receptor, coffee consumption, gene-environment interaction, genetic susceptibility, glutamate receptors, excitatory neurotransmission, imputation, replication study
- MeSH terms
- Coffee, Female, Genotype, Humans, Male, Parkinson Disease, Risk Factors, Genome, Human, Case-Control Studies, Receptors, N-Methyl-D-Aspartate, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Gene-Environment Interaction
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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