Alcohol use disorder and body mass index show genetic pleiotropy and shared neural associations

Samantha G. Malone, Christal N. Davis, Zachary Piserchia, Michael R. Setzer, Sylvanus Toikumo, Hang Zhou, Emma L. Winterlind, Joel Gelernter, Amy Justice, Lorenzo Leggio, Christopher T. Rentsch, Henry R. Kranzler and Joshua C. Gray ()
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Samantha G. Malone: Department of Medical and Clinical Psychology
Christal N. Davis: Crescenz VA Medical Center
Zachary Piserchia: Department of Medical and Clinical Psychology
Michael R. Setzer: Department of Medical and Clinical Psychology
Sylvanus Toikumo: Crescenz VA Medical Center
Hang Zhou: Veterans Affairs Connecticut Healthcare System
Emma L. Winterlind: Department of Medical and Clinical Psychology
Joel Gelernter: Veterans Affairs Connecticut Healthcare System
Amy Justice: Veterans Affairs Connecticut Healthcare System
Lorenzo Leggio: National Institutes of Health
Christopher T. Rentsch: Yale University School of Medicine
Henry R. Kranzler: Crescenz VA Medical Center
Joshua C. Gray: Department of Medical and Clinical Psychology

Nature Human Behaviour, 2025, vol. 9, issue 5, 1056-1066

Abstract: Abstract Despite neurobiological overlap, alcohol use disorder (AUD) and body mass index (BMI) show minimal genetic correlation (rg), possibly due to mixed directions of shared variants. Here we applied MiXeR to investigate shared genetic architecture between AUD and BMI, conjunctional false discovery rate to detect shared loci and their directional effect, local analysis of (co)variant association for local rg, functional mapping and annotation to identify lead single-nucleotide polymorphisms, Genotype-Tissue Expression (GTEx) to examine tissue enrichment and BrainXcan to assess associations with brain phenotypes. MiXeR indicated 82.2% polygenic overlap, despite an rg of −0.03. The conjuctional false discovery rate method identified 132 shared lead single-nucleotide polymorphisms, with 53 novel, showing both concordant and discordant effects. GTEx analyses identified overexpression in multiple brain regions. Amygdala and caudate nucleus volumes were associated with AUD and BMI. Opposing variant effects explain the minimal rg between AUD and BMI, with implicated brain regions involved in executive function and reward, clarifying their polygenic overlap and neurobiological mechanisms.

Date: 2025
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DOI: 10.1038/s41562-025-02148-y

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