ArticlePLoS genetics2011
Genome-wide gene-environment study identifies glutamate receptor gene GRIN2A as a Parkinson's disease modifier gene via interaction with coffee.
Article in PLoS genetics, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 123 papers, 8 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
123 citing papers in PubMed, 8 syntheses or guidelines pooled it, 224 citations in OpenAlex.
- Meta-analysis and in-silico functional characterization of the SNCA variant rs356220 in Parkinson's disease.Scientific reports · 2025Pooled it
- Habitual coffee consumption and cognitive function: a Mendelian randomization meta-analysis in up to 415,530 participants.Scientific reports · 2018Pooled it
- Coffee consumption is associated with DNA methylation levels of human blood.European journal of human genetics : EJHG · 2017Pooled it
- Meta-Analysis of Genome-Wide Association Studies with Correlated Individuals: Application to the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).Genetic epidemiology · 2016Pooled it
- Modulation of genetic associations with serum urate levels by body-mass-index in humans.PloS one · 2015Pooled it
- Post-GWAS gene-environment interplay in breast cancer: results from the Breast and Prostate Cancer Cohort Consortium and a meta-analysis on 79,000 women.Human molecular genetics · 2014Pooled it
- Genome-wide interaction study identifies RCBTB1 as a modifier for smoking effect on carotid intima-media thickness.Arteriosclerosis, thrombosis, and vascular biology · 2014Pooled it
- Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function.PLoS genetics · 2012Pooled it
- Disclosure of genetic information and change in dietary intake: a randomized controlled trial.PloS one · 2014Trial
- Caffeine consumption and risk of dyskinesia in CALM-PD.Movement disorders : official journal of the Movement Disorder Society · 2013Trial
- Caffeine and Progression of Parkinson Disease: A Deleterious Interaction With Creatine.Clinical neuropharmacologyTrial
- Lifestyle medicine for neuroprotection: evidence and implementation in Asian contexts.Journal of neural transmission (Vienna, Austria : 1996) · 2026Review
- Dual-Risk axis:Journal of Parkinson's disease · 2026Article
- Geometry based prediction of tau protein sites and motifs associated with misfolding and aggregation.Scientific reports · 2025Article
- Caffeine: A Multifunctional Efficacious Molecule with Diverse Health Implications and Emerging Delivery Systems.International journal of molecular sciences · 2024Review
- Microbiome-based therapeutics for Parkinson's disease.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2024Review
- Genome-wide association studies of coffee intake in UK/US participants of European ancestry uncover cohort-specific genetic associations.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2024Article
- The combined effect of lifestyle factors and polygenic scores on age at onset in Parkinson's disease.Scientific reports · 2024Article
- GluN2B subunit selective N-methyl-D-aspartate receptor ligands: Democratizing recent progress to assist the development of novel neurotherapeutics.Molecular diversity · 2024Review
- Mathematical topology and geometry-based classification of tauopathies.Scientific reports · 2024Article
63 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
27 authors at 14 institutions in 2 countries.
Funding
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 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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.