Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders

Abstract

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest GWAS to date of DSM-IV diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case/control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, N = 46,568; African; N = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; p = 9.8E-13) and African ancestries (rs2066702; p = 2.2E-9). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, ADHD, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and non-pathological drinking behaviors.

National Institute on Drug Abuse genomics consortium white paper: Coordinating efforts between human and animal addiction studies

“…Importance has been placed on the need to study different ethnic populations. To date, the PGC has validated previous studies that found a genetic variant that is related to metabolism that is involved in alcohol dependence 25 and has also identified potential genes that may be linked to OUD. The PGC is currently working on collaborations with other centers to increase sample size.…”

“…The genes responsible for underlying phenotypes vary across the different phases of addiction, and some of these genes are involved in the predisposition to other psychiatric disorders. 25 Additionally, OUD differs substantially from other SUDs, such as stimulant use disorder [26][27][28][29] at the behavioral and molecular levels. Because human samples derive from various time points throughout the addiction cycle and are not necessarily "pure," all of these observations should be considered in the analysis of GWASs.…”

“…These studies have proven quite promising for other psychiatric disorders 55 and SUD-related measures for nicotine 56,57 and alcohol. 25,58,59 However, very few GWASs of OUD 21,60-62 or other SUDs have been conducted. 53,63 Many of the limitations in published GWASs of SUDs are attributable to low sampling populations.…”

Genome‐wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward‐related ventral striatum activity in African‐ and European‐Americans

“…12 For instance, in the AA subsample, 80% power to detect a common variant (MAF ≥35%) is only expected for genotype relative risks ≥1.28, 77 which is fairly high for psychiatric disorders. First, despite interesting findings and the partially high risk sample design, our sample size is underpowered to detect the modest effect sizes typically associated with substance use disorders.…”

“…The common genetic architecture of dependence liability is also underscored by evidence from genome-wide association studies (GWAS) documenting genetic correlations between alcohol-related measures and cannabis and cigarette use. 11,12 Leveraging the common genetic architecture underlying general substance dependence liability to identify markers of dependence risk through GWAS would complement existing efforts targeting individual substances (eg, [12][13][14][15][16] ) to elucidate underlying etiologic risk factors for general and specific substance dependence liability.…”