Lack of replication of the GRIN2A-by-coffee interaction in Parkinson disease.

Ismaïl Ahmed,Joanna M Biernacka,Lars Bertram,Demetrius M Maraganore,Federico M Farin,Tian Liu,Magali Nacfer,Johnni Hansen,Harvey Checkoway,Susan Searles Nielsen,Jørgen H Olsen,Claire Mulot,Fanny Artaud,Christina M Lill,Lisa G Gallagher,Alexis Elbaz,Christina Funch Lassen,Beate Ritz,Kari J Anderson ,Marie‐Anne Loriot ,Pei Chen Lee ,Sebastian M Armasu

doi:10.1371/journal.pgen.1004788

Abstract

Overview The etiology of Parkinson disease (PD) involves both genetic susceptibility and environmental exposures. In particular, coffee consumption is inversely associated with PD but the mechanisms underlying this intriguing association are unknown. According to a recent genome-wide gene–environment interaction study, the inverse coffee–PD association was two times stronger among carriers of the T allele of SNP rs4998386 in gene GRIN2A than in homozygotes for the C allele. We attempted to replicate this result in a similarly sized pooled analysis of 2,289 cases and 2,809 controls from four independent studies (Denmark, France, Seattle-United States (US), and Rochester-US) with detailed caffeinated coffee consumption data and rs4998386 genotypes. Using a variety of definitions of coffee drinking and statistical modeling techniques , we failed to replicate this interaction. Notably, whereas in the original study there was an association between rs4998386 and coffee consumption among controls, but not among cases, none of the datasets analyzed here indicated an association between rs4998386 and coffee consumption among controls. Based on large, well-characterized datasets independent from the original study, our results are not in favor of an interaction between caffeinated coffee consumption and rs4998386 for PD risk and suggest that the original finding may have been driven by an association of coffee consumption with rs4998386 in controls. The next years will likely see an increasing number of papers examining gene–environment interactions at the genome-wide level, which poses important methodological challenges. Our findings underline the need for a careful assessment of the findings of such studies.

Highlights

Genome-wide association studies (GWAS) have identified thousands of genetic risk variants for common diseases, which typically explain only a small proportion of the underlying heritability [1]
Analyses of gene–environment interactions can be performed through a variety of approaches [8], and, to better understand the findings presented by Hamza et al [7], we performed a re-analysis of their data by examining the association between coffee and rs4998386 separately in cases and controls (Table S1)
We found a strong positive association in controls between rs4998386-T and heavy coffee drinking (OR = 1.48, 95% confidence intervals (CI) = 1.23, 1.78, p = 361025), suggesting that GRIN2A-rs4998386-T is associated with an increased likelihood of drinking coffee among persons free of Parkinson disease (PD)

Summary

Introduction

Genome-wide association studies (GWAS) have identified thousands of genetic risk variants for common diseases, which typically explain only a small proportion of the underlying heritability [1]. PD is a good example of a disease for which numerous susceptibility loci [2] and putative risk or protective environmental factors [3] have been identified and may interact. There is robust epidemiological evidence that coffee consumption is inversely associated with PD independently of smoking [4]. Caffeine is hypothesized to account for this association because it is an adenosine A2A-receptor antagonist, and this family of agents has been shown to be neuroprotective and attenuate loss of Citation: Ahmed I, Lee P-C, Lill CM, Searles Nielsen S, Artaud F, et al (2014) Lack of Replication of the GRIN2A-by-Coffee Interaction in Parkinson Disease.

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