Non-additive genome-wide association scan reveals a new gene associated with habitual coffee consumption

Non-additive genome-wide association scan reveals a new gene associated with habitual coffee consumption

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Nicola Pirastu, Maarten Kooyman, Antonietta Robino, Ashley van der Spek, Luciano Navarini, Najaf Amin, Lennart C. Karssen, Cornelia M Van Duijn & Paolo Gasparini

Published online:

25 August 2016

Abstract

Coffee is one of the most consumed beverages world-wide and one of the primary sources of caffeine intake. Given its important health and economic impact, the underlying genetics of its consumption has been widely studied. Despite these efforts, much has still to be uncovered. In particular, the use of non-additive genetic models may uncover new information about the genetic variants driving coffee consumption. We have conducted a genome-wide association study in two Italian populations using additive, recessive and dominant models for analysis. This has uncovered a significant association in the PDSS2 gene under the recessive model that has been replicated in an independent cohort from the Netherlands (ERF). The identified gene has been shown to negatively regulate the expression of the caffeine metabolism genes and can thus be linked to coffee consumption. Further bioinformatics analysis of eQTL and histone marks from Roadmap data has evidenced a possible role of the identified SNPs in regulating PDSS2 gene expression through enhancers present in its intron. Our results highlight a novel gene which regulates coffee consumption by regulating the expression of the genes linked to caffeine metabolism. Further studies will be needed to clarify the biological mechanism which links PDSS2 and coffee consumption.

Introduction

Coffee is one of the most widely drunk beverages, being second only to water and tea1. Given that it contains many different physiologically active compounds such as caffeine, polyphenols (e.g., chlorogenic acids), niacin, N-methylpyridinium ion and others2, many studies have investigated its impact on health, finding associations with common disorders. For example, coffee consumption has been linked to protective effects on various common pathologies such as cardiovascular diseases3, hypertension4,5, Alzheimer’s and Parkinson’s diseases6,7, type 2 diabetes8,9,10, some types of cancer11,12 and hearing functions13, while it may predispose to others such as sleep disturbances14,15. The earliest studies on the genetic bases of coffee consumption can be dated back as far as the 1960’s with the first description of its heritability in Italy16, which has been estimated to range between 0.36 and 0.58 in twin studies. Different independent genome-wide association studies (GWAS) carried out mostly in Northern European populations have highlighted associations between coffee or caffeine consumption and several genes: CYP1A1-CYP1A217,18, AHR17 NRCAM and ULK318 while moderate association has been seen with the adenosine receptor A2, which is actually one of the effector proteins of caffeine17. More recently, a very large study comprising more than 120 thousand people has confirmed some of these (CYP1A1-CYP1A2 and AHR) while identifying 6 novel ones19. Despite these successes much of the heritability of coffee consumption still remains unexplained, part of which could be explained by the fact that the additive genetic model is almost always used in association studies, whereas, in fact, genes can exhibit recessive or dominant effects. It is in fact very well known that miss-specifying the genetic model will result in a considerable loss of power, especially under certain conditions20. For this reason we have decided do conduct a genome-wide association study looking for non-additive effects on two isolated populations of Italy in order to verify whether genes are affecting coffee consumption under these genetic models.

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http://www.nature.com/articles/srep31590

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