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Genome-wide gene-environment study identifies glutamate receptor gene grin2a as a parkinson's disease modifier gene via interaction with coffee
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نویسنده
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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.
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منبع
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plos genetics - 2011 - دوره : 7 - شماره : 8
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چکیده
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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. © 2011 this is an open-access article.
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آدرس
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new york state department of health wadsworth center,albany,ny, United States, epidemiology branch,national institute of environmental health sciences,research triangle park,north carolina, United States, new york state department of health wadsworth center,albany,ny, United States, department of epidemiology,school of public health,university of california los angeles,los angeles,ca, United States, new york state department of health wadsworth center,albany,ny, United States, new york state department of health wadsworth center,albany,ny, United States, institute of genetics and molecular medicine and the roslin institute,university of edinburgh,edinburgh, United Kingdom, new york state department of health wadsworth center,albany,ny, United States, new york state department of health wadsworth center,albany,ny, United States, new york state department of health wadsworth center,albany,ny, United States, new york state department of health wadsworth center,albany,ny,united states,va puget sound health care system and department of neurology,university of washington,seattle,wa, United States, va puget sound health care system and department of neurology,university of washington,seattle,wa, United States, virginia mason medical center,seattle,wa, United States, booth gardner parkinson's care center,evergreen hospital medical center,kirkland,wa, United States, department of neurology,school of medicine,university of california los angeles,los angeles,ca, United States, nutritional epidemiology branch,divisions of cancer epidemiology and genetics,national cancer institute,bethesda,md, United States, dr. john t. macdonald foundation department of human genetics,john p. hussman institute for human genomics,university of miami miller school of medicine,miami,fl, United States, epidemiology branch,national institute of environmental health sciences,research triangle park,north carolina, United States, dr. john t. macdonald foundation department of human genetics,john p. hussman institute for human genomics,university of miami miller school of medicine,miami,fl, United States, virginia institute for psychiatric and behavioral genetics,department of psychiatry,virginia commonwealth university,richmond,va, United States, virginia institute for psychiatric and behavioral genetics,department of psychiatry,virginia commonwealth university,richmond,va, United States, dr. john t. macdonald foundation department of human genetics,john p. hussman institute for human genomics,university of miami miller school of medicine,miami,fl, United States, department of epidemiology,school of public health,university of california los angeles,los angeles,ca,united states,department of neurology,school of medicine,university of california los angeles,los angeles,ca,united states,department of environmental health sciences,center for occupational and environmental health,school of public health,university of california los angeles,los angeles,ca, United States, department of neurology,oregon health and sciences university,portland,or, United States, department of neurology,emory university school of medicine,atlanta,ga, United States, va puget sound health care system and department of neurology,university of washington,seattle,wa, United States, new york state department of health wadsworth center,albany,ny, United States
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Authors
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