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 Con...
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2011
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oai:doaj.org-article:d9d8feb3c5a546248ccbec16104d890a2021-11-18T06:17:06ZGenome-wide gene-environment study identifies glutamate receptor gene GRIN2A as a Parkinson's disease modifier gene via interaction with coffee.1553-73901553-740410.1371/journal.pgen.1002237https://doaj.org/article/d9d8feb3c5a546248ccbec16104d890a2011-08-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21876681/?tool=EBIhttps://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Our 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.Taye H HamzaHonglei ChenErin M Hill-BurnsShannon L RhodesJennifer MontimurroDenise M KayAlbert TenesaVictoria I KuselPatricia SheehanMuthukrishnan EaaswarkhanthDora YearoutAli SamiiJohn W RobertsPinky AgarwalYvette BordelonYikyung ParkLiyong WangJianjun GaoJeffery M VanceKenneth S KendlerSilviu-Alin BacanuWilliam K ScottBeate RitzJohn NuttStewart A FactorCyrus P ZabetianHaydeh PayamiPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 7, Iss 8, p e1002237 (2011) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Genetics QH426-470 |
| spellingShingle |
Genetics QH426-470 Taye H Hamza Honglei Chen Erin M Hill-Burns Shannon L Rhodes Jennifer Montimurro Denise M Kay Albert Tenesa Victoria I Kusel Patricia Sheehan Muthukrishnan Eaaswarkhanth Dora Yearout Ali Samii John W Roberts Pinky Agarwal Yvette Bordelon Yikyung Park Liyong Wang Jianjun Gao Jeffery M Vance Kenneth S Kendler Silviu-Alin Bacanu William K Scott Beate Ritz John Nutt Stewart A Factor Cyrus P Zabetian Haydeh Payami Genome-wide gene-environment study identifies glutamate receptor gene GRIN2A as a Parkinson's disease modifier gene via interaction with coffee. |
| description |
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. |
| format |
article |
| author |
Taye H Hamza Honglei Chen Erin M Hill-Burns Shannon L Rhodes Jennifer Montimurro Denise M Kay Albert Tenesa Victoria I Kusel Patricia Sheehan Muthukrishnan Eaaswarkhanth Dora Yearout Ali Samii John W Roberts Pinky Agarwal Yvette Bordelon Yikyung Park Liyong Wang Jianjun Gao Jeffery M Vance Kenneth S Kendler Silviu-Alin Bacanu William K Scott Beate Ritz John Nutt Stewart A Factor Cyrus P Zabetian Haydeh Payami |
| author_facet |
Taye H Hamza Honglei Chen Erin M Hill-Burns Shannon L Rhodes Jennifer Montimurro Denise M Kay Albert Tenesa Victoria I Kusel Patricia Sheehan Muthukrishnan Eaaswarkhanth Dora Yearout Ali Samii John W Roberts Pinky Agarwal Yvette Bordelon Yikyung Park Liyong Wang Jianjun Gao Jeffery M Vance Kenneth S Kendler Silviu-Alin Bacanu William K Scott Beate Ritz John Nutt Stewart A Factor Cyrus P Zabetian Haydeh Payami |
| author_sort |
Taye H Hamza |
| title |
Genome-wide gene-environment study identifies glutamate receptor gene GRIN2A as a Parkinson's disease modifier gene via interaction with coffee. |
| title_short |
Genome-wide gene-environment study identifies glutamate receptor gene GRIN2A as a Parkinson's disease modifier gene via interaction with coffee. |
| title_full |
Genome-wide gene-environment study identifies glutamate receptor gene GRIN2A as a Parkinson's disease modifier gene via interaction with coffee. |
| title_fullStr |
Genome-wide gene-environment study identifies glutamate receptor gene GRIN2A as a Parkinson's disease modifier gene via interaction with coffee. |
| title_full_unstemmed |
Genome-wide gene-environment study identifies glutamate receptor gene GRIN2A as a Parkinson's disease modifier gene via interaction with coffee. |
| title_sort |
genome-wide gene-environment study identifies glutamate receptor gene grin2a as a parkinson's disease modifier gene via interaction with coffee. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2011 |
| url |
https://doaj.org/article/d9d8feb3c5a546248ccbec16104d890a |
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