A phenome-wide association and Mendelian randomisation study of alcohol use variants in a diverse cohort comprising over 3 million individuals

Mariela V Jennings; José Jaime Martínez-Magaña; Natasia S Courchesne-Krak; Renata B Cupertino; Laura Vilar-Ribó; Sevim B Bianchi; Alexander S Hatoum; Elizabeth G Atkinson; Paola Giusti-Rodriguez; Janitza L Montalvo-Ortiz; Joel Gelernter; María Soler Artigas; 23andMe, Inc. Research Team; Sarah L Elson; Howard J Edenberg; Pierre Fontanillas; Abraham A Palmer; Sandra Sanchez-Roige

doi:10.1016/j.ebiom.2024.105086

A phenome-wide association and Mendelian randomisation study of alcohol use variants in a diverse cohort comprising over 3 million individuals

EBioMedicine. 2024 Apr 2:105086. doi: 10.1016/j.ebiom.2024.105086. Online ahead of print.

Authors

Mariela V Jennings¹, José Jaime Martínez-Magaña², Natasia S Courchesne-Krak¹, Renata B Cupertino¹, Laura Vilar-Ribó³, Sevim B Bianchi¹, Alexander S Hatoum⁴, Elizabeth G Atkinson⁵, Paola Giusti-Rodriguez⁶, Janitza L Montalvo-Ortiz⁷, Joel Gelernter⁸, María Soler Artigas⁹; 23andMe, Inc. Research Team¹⁰; Sarah L Elson¹⁰, Howard J Edenberg¹¹, Pierre Fontanillas¹⁰, Abraham A Palmer¹², Sandra Sanchez-Roige¹³

Collaborators

23andMe, Inc. Research Team:
Stella Aslibekyan, Adam Auton, Elizabeth Babalola, Robert K Bell, Jessica Bielenberg, Katarzyna Bryc, Emily Bullis, Daniella Coker, Gabriel Cuellar Partida, Devika Dhamija, Sayantan Das, Sarah L Elson, Nicholas Eriksson, Teresa Filshtein, Alison Fitch, Kipper Fletez-Brant, Pierre Fontanillas, Will Freyman, Julie M Granka, Karl Heilbron, Alejandro Hernandez, Barry Hicks, David A Hinds, Ethan M Jewett, Yunxuan Jiang, Katelyn Kukar, Alan Kwong, Keng-Han Lin, Bianca A Llamas, Maya Lowe, Jey C McCreight, Matthew H McIntyre, Steven J Micheletti, Meghan E Moreno, Priyanka Nandakumar, Dominique T Nguyen, Elizabeth S Noblin, Jared O'Connell, Aaron A Petrakovitz, G David Poznik, Alexandra Reynoso, Morgan Schumacher, Anjali J Shastri, Janie F Shelton, Jingchunzi Shi, Suyash Shringarpure, Qiaojuan Jane Su, Susana A Tat, Christophe Toukam Tchakouté, Vinh Tran, Joyce Y Tung, Xin Wang, Wei Wang, Catherine H Weldon, Peter Wilton, Corinna D Wong

Affiliations

¹ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
² Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, Orange, West Haven, CT, USA.
³ Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain; Department of Mental Health, Hospital Universitari Vall d'Hebron, Barcelona, Spain; Biomedical Network Research Centre on Mental Health (CIBERSAM), Madrid, Spain.
⁴ Department of Psychology & Brain Sciences, Washington University in St. Louis, St Louis, MO, USA.
⁵ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
⁶ Department of Psychiatry, University of Florida College of Medicine, Gainesville, FL, USA.
⁷ Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, Orange, West Haven, CT, USA; National Center of Posttraumatic Stress Disorder, VA CT Healthcare Center, West Haven, CT, USA.
⁸ VA CT Healthcare Center, Department Psychiatry, West Haven, CT, USA; Departments Psychiatry, Genetics, and Neuroscience, Yale Univ. School of Medicine, New Haven, CT, USA.
⁹ Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain; Department of Mental Health, Hospital Universitari Vall d'Hebron, Barcelona, Spain; Biomedical Network Research Centre on Mental Health (CIBERSAM), Madrid, Spain; Department of Genetics, Microbiology, and Statistics, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain.
¹⁰ 23andMe, Inc., Sunnyvale, CA, USA.
¹¹ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
¹² Department of Psychiatry, University of California San Diego, La Jolla, CA, USA; Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA.
¹³ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA; Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA; Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, TN, USA. Electronic address: sanchezroige@ucsd.edu.

PMID: 38580523
DOI: 10.1016/j.ebiom.2024.105086

Abstract

Background: Alcohol consumption is associated with numerous negative social and health outcomes. These associations may be direct consequences of drinking, or they may reflect common genetic factors that influence both alcohol consumption and other outcomes.

Methods: We performed exploratory phenome-wide association studies (PheWAS) of three of the best studied protective single nucleotide polymorphisms (SNPs) in genes encoding ethanol metabolising enzymes (ADH1B: rs1229984-T, rs2066702-A; ADH1C: rs698-T) using up to 1109 health outcomes across 28 phenotypic categories (e.g., substance-use, mental health, sleep, immune, cardiovascular, metabolic) from a diverse 23andMe cohort, including European (N ≤ 2,619,939), Latin American (N ≤ 446,646) and African American (N ≤ 146,776) populations to uncover new and perhaps unexpected associations. These SNPs have been consistently implicated by both candidate gene studies and genome-wide association studies of alcohol-related behaviours but have not been investigated in detail for other relevant phenotypes in a hypothesis-free approach in such a large cohort of multiple ancestries. To provide insight into potential causal effects of alcohol consumption on the outcomes significant in the PheWAS, we performed univariable two-sample and one-sample Mendelian randomisation (MR) analyses.

Findings: The minor allele rs1229984-T, which is protective against alcohol behaviours, showed the highest number of PheWAS associations across the three cohorts (N = 232, European; N = 29, Latin American; N = 7, African American). rs1229984-T influenced multiple domains of health. We replicated associations with alcohol-related behaviours, mental and sleep conditions, and cardio-metabolic health. We also found associations with understudied traits related to neurological (migraines, epilepsy), immune (allergies), musculoskeletal (fibromyalgia), and reproductive health (preeclampsia). MR analyses identified evidence of causal effects of alcohol consumption on liability for 35 of these outcomes in the European cohort.

Interpretation: Our work demonstrates that polymorphisms in genes encoding alcohol metabolising enzymes affect multiple domains of health beyond alcohol-related behaviours. Understanding the underlying mechanisms of these effects could have implications for treatments and preventative medicine.

Funding: MVJ, NCK, SBB, SSR and AAP were supported by T32IR5226 and 28IR-0070. SSR was also supported by NIDA DP1DA054394. NCK and RBC were also supported by R25MH081482. ASH was supported by funds from NIAAA K01AA030083. JLMO was supported by VA 1IK2CX002095. JLMO and JJMM were also supported by NIDA R21DA050160. JJMM was also supported by the Kavli Postdoctoral Award for Academic Diversity. EGA was supported by K01MH121659 from the NIMH/NIH, the Caroline Wiess Law Fund for Research in Molecular Medicine and the ARCO Foundation Young Teacher-Investigator Fund at Baylor College of Medicine. MSA was supported by the Instituto de Salud Carlos III and co-funded by the European Union Found: Fondo Social Europeo Plus (FSE+) (P19/01224, PI22/00464 and CP22/00128).

Keywords: ADH1B; ADH1C; Alcohol; Metabolising enzyme genes; PheWAS; rs1229984.

Abstract

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