Citation

White JD, Bierut LJ. Am. J. Psychiatry 2023; 180(8): 530-532.

Copyright

(Copyright © 2023, American Psychiatric Association)

DOI

10.1176/appi.ajp.20230456

PMID

37525606

Abstract

n this issue, Kember et al. (1) report an impressive undertaking to identify genetic contributors to both alcohol consumption and alcohol use disorder (AUD) in the largest study to date, both in terms of sample size and in terms of inclusion of non-European population groups. The authors also capitalize on the unique construction of the Million Veteran Program (MVP), with longitudinal data from alcohol consumption screenings and alcohol use disorder diagnoses in health records, to better refine phenotypes and analyses, something few other studies can accomplish. In these analyses, performed within and across ancestries, they report a notable 24 independent variants (19 loci) associated with alcohol consumption, quantified by Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) scores (2), and 26 independent variants (21 loci) associated with alcohol use disorder. The authors also perform gene-based associations, conduct mediation analyses, calculate genetic correlations, construct polygenic risk scores, and perform a phenome-wide association study in two external data sets: the Vanderbilt Biobank (BioVU) and the UK Biobank. Through these analyses, they conclude that differences in the associated loci, differences in genetic and phenotypic correlations, and nonmediating genetic variation support a conclusion that alcohol consumption and AUD have distinct underlying genetic architectures. We submit that, considered with other recent publications on the genetics of both alcohol use and disorder, the results presented by Kember et al. highlight the necessity of minimizing trait heterogeneity by reducing the misclassification of individuals who now abstain from alcohol but who have a lifetime history of alcohol use disorder. When trait heterogeneity is minimized, the overall genetic underpinnings of alcohol consumption and use disorder are, in composition and pattern, quite similar.

Given the heavy focus on genetic correlations as an indication of shared versus distinct genetic architectures for alcohol consumption and AUD, we think it prudent to give a brief overview of genetic correlations reported for these traits. Genetic correlations reported from twin studies suggested moderate to high correlations (rg range, 0.45-0.99) among several alcohol consumption traits and high correlations between alcohol consumption traits and problematic alcohol use (3, 4). Using cross-trait linkage disequilibrium score regression, reported genetic correlations between alcohol consumption traits and problematic alcohol use or alcohol use disorder have ranged widely (Table 1). In one of the earliest studies of individuals of European ancestry, the reported genetic correlation between AUDIT score and alcohol use disorder was negligible (rg=0.08) (5). Notice that several of the comparisons in Table 1 used the same cohorts or used the same trait (e.g., AUDIT-C score) in different cohorts, illustrating that seemingly innocuous differences in trait derivation and sample makeup can lead to large differences in estimated genetic correlations. Importantly, the study by Kember et al. compares alcohol consumption and alcohol use disorder measured in the same individuals, which eliminates biases in the estimated genetic correlations from sample selection and comorbid illness. When the authors focus analyses on those who report current drinking and exclude those who abstain from alcohol, 15% of whom have a lifetime history of alcohol use disorder, the genetic correlation between alcohol consumption and alcohol use disorder increases (rg=0.86-1), and the genetic correlations for individuals of African ancestry are very high (rg=0.98-1). These findings highlight that the genetic architecture of alcohol consumption and alcohol use disorder is primarily shared...

Language: en

Keywords

Humans; Alcohol; *Alcoholism/epidemiology/genetics; *Substance-Related Disorders/genetics; Alcohol Drinking/genetics; Genetics/Genomics; Phenotype; Substance-Related and Addictive Disorders