Background: The prevalence of co-occurring heavy alcohol consumption and obesity is increasing in the United States. Despite neurobiological overlap in the regulation of alcohol consumption and eating behavior, alcohol- and body mass index (BMI)-related phenotypes show no or minimal genetic correlation. We hypothesized that the lack of genetic correlation is due to mixed effect directions of variants shared by AUD and BMI. Methods: We applied MiXeR, to investigate shared genetic architecture between AUD and BMI in individuals of European ancestry. We used conjunctional false discovery rate (conjFDR) analysis to detect loci associated with both phenotypes and their directional effect, Functional Mapping and Annotation (FUMA) to identify lead single nucleotide polymorphisms (SNPs), Genotype-Tissue Expression (GTEx) samples to examine gene expression enrichment across tissue types, and BrainXcan to evaluate the shared associations of AUD and BMI with brain image-derived phenotypes. Results: MiXeR analysis indicated polygenic overlap of 80.9% between AUD and BMI, despite a genetic correlation (rg) of -.03. ConjFDR analysis yielded 56 lead SNPs with the same effect direction and 76 with the opposite direction. Of the 132 shared lead SNPs, 53 were novel for both AUD and BMI. GTEx analyses identified significant overexpression in the frontal cortex (BA9), hypothalamus, cortex, anterior cingulate cortex (BA24), hippocampus, and amygdala. Amygdala and caudate nucleus gray matter volumes were significantly associated with both AUD and BMI in BrainXcan analyses. Conclusions: More than half of variants significantly associated with AUD and BMI had opposite directions of effect for the traits, supporting our hypothesis that this is the basis for their lack of genetic correlation. Follow-up analyses identified brain regions implicated in executive functioning, reward, homeostasis, and food intake regulation. Together, these findings clarify the extensive polygenic overlap between AUD and BMI and elucidate several overlapping neurobiological mechanisms.

Disclosures: HRK is a member of advisory boards for Dicerna Pharmaceuticals, Sophrosyne Pharmaceuticals, Enthion Pharmaceuticals, and Clearmind Medicine; a consultant to Sobrera Pharmaceuticals; the recipient of research funding and medication supplies for an investigator-initiated study from Alkermes; and a member of the American Society of Clinical Psychopharmacologys Alcohol Clinical Trials Initiative, which was supported in the last three years by Alkermes, Dicerna, Ethypharm, Lundbeck, Mitsubishi, Otsuka, and Pear Therapeutics. JG and HRK hold U.S. patent 10,900,082 titled: Genotype-guided dosing of opioid agonists, issued 26 January 2021. JG is paid for editorial work for the journal Complex Psychiatry.

This work was supported by funding from the National Institute on Alcohol Abuse and Alcoholism (R01 AA030041 and R01 AA030056), the Department of Defense (HU0001-22-2-0066), and the Veterans Integrated Service Network 4 Mental Illness Research, Education and Clinical Center of the Crescenz Veterans Affairs Medical Center. LL is a federal employee and is supported by the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism Intramural Research Programs.

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The Uniformed Services Universitys Human Research Protections Program Office and determined the project to be considered research not involving human subjects per 32 CFR 219.102(e)(1), and applicable DoD policy guidance. As such, this protocol does not require Institutional Review Board (IRB) review.

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BMI summary statistics were downloaded from: https://portals.broadinstitute.org/collaboration/giant/index.php/GIANT_consortium_data_files AUD summary statistics (excluding UKB) were provided by the MVP SUD consortium.