Molecular pathology selected abstracts

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Study of the genetics of problematic alcohol use

Problematic alcohol use is one of the leading causes of death and morbidity worldwide, contributing to 2.2 percent of deaths among females and 6.8 percent among males. It is characterized by alcohol use that leads to numerous adverse medical, psychiatric, and social issues. Alcohol use disorder has a genetic and an environmental component. Some studies have demonstrated a heritability of approximately 50 percent, and genomewide association studies (GWAS) have identified specific loci associated with it. Despite these advances, knowledge gaps exist. The loci previously identified by GWAS account for only five to 10 percent of heritability. Furthermore, many of the previous studies were performed on people of European ancestry, limiting applicability to the global population. The authors conducted a series of ancestry-specific GWAS of problematic alcohol use followed by a cross-ancestry meta-analysis. They examined 1,079,947 people from five ancestral groups and included 165,952 cases of problematic alcohol use. In the European ancestry group, which was the largest study population (N= 903,147), the ancestry-specific GWAS identified 85 variants at 75 loci that reached genomewide significance. Of these variants, 41 were in protein-coding genes, including five missense variants. Because of their smaller population sizes, the non-European ancestry-specific GWAS had fewer loci that reached genomewide significance, but they identified some independent variants associated with problematic alcohol use. In addition, many of the variants identified in the European ancestry GWAS had analogous variants in the other ancestry-specific GWAS. Combining ancestry-specific GWAS of problematic alcohol use and a cross-ancestry meta-analysis of all data sets, the authors identified 110 variants significantly associated with risk of problematic alcohol use. They then performed analyses to identify likely causal variants. Because problematic alcohol use is a psychiatric condition, the authors focused on genes enriched in brain tissue and associated with brain function. Through these relationships, the genes affected could be prioritized for potential causal relationships and future pharmacological studies. Overall, this multi-ancestry study elucidates the genetic underpinnings of problematic alcohol use disorder, demonstrates a shared genetic architecture across multiple ancestry groups, and identifies promising potential therapeutic targets.

Zhou H, Kember RL, Deak JD, et al. Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals. Nat Med. 2023;29:3184–3192.

Correspondence: Dr. Hang Zhou at hang.zhou@yale.edu or Dr. Joel Gelernter at joel.gelernter@yale.edu