Genome-Wide Gene-Environment Study Identifies Glutamate Receptor Gene GRIN2A as a Parkinson's Disease Modifier Gene via Interaction with Coffee

被引：164

作者：

Hamza, Taye H. ^{[1
]}

Chen, Honglei ^{[2
]}

Hill-Burns, Erin M. ^{[1
]}

Rhodes, Shannon L. ^{[3
]}

Montimurro, Jennifer ^{[1
]}

Kay, Denise M. ^{[1
]}

Tenesa, Albert ^{[4
]}

Kusel, Victoria I. ^{[1
]}

Sheehan, Patricia ^{[1
]}

Eaaswarkhanth, Muthukrishnan ^{[1
]}

Yearout, Dora ^{[1
,5
,6
]}

Samii, Ali ^{[5
,6
]}

Roberts, John W. ^{[7
]}

Agarwal, Pinky ^{[8
]}

Bordelon, Yvette ^{[9
]}

Park, Yikyung ^{[10
,11
]}

Wang, Liyong ^{[12
,13
]}

Gao, Jianjun ^{[2
]}

Vance, Jeffery M. ^{[12
,13
]}

Kendler, Kenneth S. ^{[14
]}

Bacanu, Silviu-Alin ^{[14
]}

Scott, William K. ^{[12
,13
]}

Ritz, Beate ^{[3
,9
,15
]}

Nutt, John ^{[16
]}

Factor, Stewart A. ^{[17
]}

Zabetian, Cyrus P. ^{[5
,6
]}

Payami, Haydeh ^{[1
]}

机构：

[1] New York State Dept Hlth, Wadsworth Ctr, Albany, NY USA

[2] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA

[3] Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90024 USA

[4] Univ Edinburgh, Roslin Inst, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland

[5] Univ Washington, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA

[6] Univ Washington, Dept Neurol, Seattle, WA 98195 USA

[7] Virginia Mason Med Ctr, Seattle, WA 98101 USA

[8] Evergreen Hosp, Med Ctr, Booth Gardner Parkinsons Care Ctr, Kirkland, WA USA

[9] Univ Calif Los Angeles, Sch Med, Dept Neurol, Los Angeles, CA 90024 USA

[10] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol, Bethesda, MD 20892 USA

[11] NCI, Nutr Epidemiol Branch, Div Genet, Bethesda, MD 20892 USA

[12] Univ Miami, Miller Sch Med, Dr John T Macdonald Fdn, Dept Human Genet, Miami, FL 33136 USA

[13] Univ Miami, Miller Sch Med, John P Hussman Inst Human Gen, Miami, FL 33136 USA

[14] Virginia Commonwealth Univ, Dept Psychiat, Virginia Inst Psychiat & Behav Genet, Richmond, VA USA

[15] Univ Calif Los Angeles, Sch Publ Hlth, Ctr Occupat & Environm Hlth, Dept Environm Hlth Sci, Los Angeles, CA 90024 USA

[16] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA

[17] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA

来源：

PLOS GENETICS | 2011年 / 7卷 / 08期

基金：

美国国家科学基金会; 美国国家卫生研究院;

关键词：

RISK-FACTORS; ASSOCIATION; SMOKING; CAFFEINE; MODEL; ONSET; ISTRADEFYLLINE; METAANALYSIS; VARIANTS; FAMILIES;

D O I：

10.1371/journal.pgen.1002237

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 = 6x10(-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, P-Replication = 10(-3); ORPooled = 0.51, P-Pooled = 7x10(-8). Compared to light coffee-drinkers with rs4998386_CC genotype, heavy coffee-drinkers with rs4998386_CC genotype had 18% lower risk (P = 3x10(-3)), whereas heavy coffee-drinkers with rs4998386_TC genotype had 59% lower risk (P = 6x10(-13)). Imputation revealed a block of SNPs that achieved P-2df<5x10(-8) in GWAIS, and OR = 0.41, P = 3x10(-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.

引用

页数：15

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