Alcohol Dependence Genetics: Lessons Learned From Genome-Wide Association Studies (GWAS) and Post-GWAS Analyses

Abstract

Background Alcohol dependence (AD) is a complex psychiatric disorder and a significant public health problem. Twin and family-based studies have consistently estimated its heritability to be approximately 50%, and many studies have sought to identify specific genetic variants associated with susceptibility to AD. These studies have been primarily linkage or candidate gene-based, and have been mostly unsuccessful in identifying replicable risk loci. Genome-wide association studies (GWAS) have improved the detection of specific loci associated with complex traits, including AD. However, findings from GWAS explain only a small proportion of phenotypic variance and alternative methods have been proposed to investigate the associations that do not meet strict genome-wide significance criteria. Methods This review summarizes all published AD GWAS and post-GWAS analyses that have sought to exploit GWAS data to identify AD-associated loci. Results Findings from AD GWAS have been largely inconsistent, with the exception of variants encoding the alcohol metabolizing enzymes. Analyses of GWAS data that go beyond single SNP association testing have demonstrated the polygenic nature of AD and the large contribution of common variants to risk, nominating novel genes and pathways for AD susceptibility. Conclusions Findings from AD GWAS and post-GWAS analyses have greatly increased our understanding of the genetic etiology of AD. However, it is clear that larger samples will be necessary to detect loci in addition to those that encode alcohol metabolizing enzymes, which may only be possible through consortium-based efforts. Post-GWAS approaches to studying the genetic influences on AD are increasingly common and could greatly increase our knowledge of both the genetic architecture of AD and the specific genes and pathways that influence risk.

Genetic studies of alcohol dependence in the context of the addiction cycle

“…It is beyond the scope of this review to detail methodological aspects of the published alcohol dependence GWAS. For a detailed description of GWAS study design and experimental details see (Hart and Kranzler, 2015). Briefly, the GWAS we discuss examine the DSM-IV defined phenotype of alcohol dependence using either case-control status of alcohol dependence as the primary phenotype or quantitative phenotypes derived from DSM-IV alcohol dependence (e.g., criterion factor score).…”

“…The first generation of GWAS of alcohol dependence in general have been viewed as yielding disappointing results due to various technical, practical and philosophical issues. Several excellent reviews have highlighted the general findings of these studies and have addressed prevalent GWAS challenges and limitations such as lack of sufficient statistical power due to small sample sizes, small individual gene effects, missing heritability, precision of phenotypes, and the overall lack of replication (Edenberg and Foroud, 2014; Hart and Kranzler, 2015; Tawa et al, 2016). Here we take a more optimistic approach by “mining” the existing GWAS results for logical biological function(s), despite largely non-significant statistical findings predicated (perhaps overly conservative, see (Kanai et al, 2016) by the need to correct for individual (presumably independent) tests of associations of ~1 million single-nucleotide polymorphisms (SNPs) throughout the genome.…”

Alcohol Misuse Across the Life Span: Insights From Developmental Studies in Behavior Genetics

“…The large sample sizes needed to detect such small effects have made it difficult to identify the genes involved. Notable exceptions include variants in genes that code for alcohol dehydrogenase and aldehyde dehydrogenase, which help metabolize alcohol (Hart & Kranzler, 2015). Some variants of these genes result in unpleasant side effects when drinking (nausea, facial flushing), leading to decreased alcohol consumption.…”

Bivariate genome-wide association analyses identified genetic pleiotropic effects for bone mineral density and alcohol drinking in Caucasians

“…A meta-analysis of 9382 participants in 42 case–control studies and two cross-sectional surveys implicated DRD2 Tag1A polymorphism at 11q23 as having a small but significant association with the risk of alcohol dependence [8]. Recently, through the study of the subjective effects of alcohol on individuals categorized as having intermediate phenotype alcohol disorders, several risk genes have been identified (such as genes encoding the classic opoid receptor, OPRM1 , the major inhibitory neurotransmitter in the central nervous system, GABA , and alcohol metabolizing enzymes, ALDH2 ) [9–11]. Some analyses of alcohol dependence genome-wide association studies (GWAS) and post-GWAS analyses are constantly emerging that seek to identify loci associated with alcohol dependence [11].…”