Genome-wide association and functional studies identify 46 novel loci for alcohol consumption and suggest common genetic mechanisms with neuropsychiatric disorders

Abstract

Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. We conducted a genome-wide association study (GWAS) of alcohol use in ~480,000 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 novel, common loci, and investigated their potential functional significance using magnetic resonance imaging data, gene expression and behavioral studies in Drosophila. Our results identify new genetic pathways associated with alcohol consumption and suggest common genetic mechanisms with several neuropsychiatric disorders including schizophrenia.Excessive alcohol consumption is a major public health problem that is responsible 1 for 2.2% and 6.8% age-standardized deaths for women and men respectively 1 . Most 2 genetic studies of alcohol use focus on alcohol dependency, although the burden of 3 alcohol-related disease mainly reflects a broader range of alcohol consumption 4 behaviors in a population 2 . Small reductions in alcohol intake could have major public 5 health benefits; a recent study reported that even moderate daily alcohol may have 6 significant impact on mortality 3 .

Recent Efforts to Dissect the Genetic Basis of Alcohol Use and Abuse

“…This association is one of the most consistently replicated findings in the field of psychiatric genetics, although the effects are clearly ancestry-specific (7). There appear to be multiple signals in this region, including ADH1C (17,18,(21)(22)(23)(24), ADH4 (18), ADH5 (21,23) and the METAP1/EIF4E region (21)(22)(23). The GSCAN consortium recently showed that there are at least 13 independent signals with minor allele frequencies over 0.001 at 4q23 (21).…”

“…The GWAS meta-analysis of AUDIT identified 10 associated risk loci (14). Large consortia were also formed to collate quantitative measures of alcohol use, including AlcGen (15) (17). The MVP study (18) also examined alcohol consumption, allowing for an explicit comparison between AUD and consumption in a single population; of the 18 loci detected in that study, 5 were common to both AUD diagnosis and alcohol consumption.…”

Fibroblast growth factor 21: an endocrine inhibitor of sugar and alcohol appetite

“…the relative proportion of one's diet derived from fat, carbohydrate and protein), it was reported that FGF21, a predominantly liver-derived hormone, suppresses intake of simple sugars and alcohol in mice and consumption of the artificial sweetener saccharin in primates (Talukdar et al 2016;von Holstein-Rathlou et al 2016). Since then, these findings have been replicated and generalized in mice and humans (Evangelou et al 2018;Frayling et al 2018;Meddens et al 2018;Sanchez-Roige et al 2018).…”

“…Since then, these findings have been replicated and generalized in mice and humans (Evangelou et al . ; Frayling et al . ; Meddens et al .…”

Altered actin filament dynamics in theDrosophilamushroom bodies lead to fast acquisition of alcohol consumption preference

“…However, the genes from these association studies often do not group into obvious over-represented categories of physiological function (e.g. Evangelou et al, 2018), leaving many of the molecular pathways of AUD obscure.…”