Journal Article

Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals

Hougaard, David M., Mallard, Travis T., Johnson, Jessica, Hatoum, Alexander S., Gillespie, Nathan A., Agrawal, Arpana, Zhou, Hang, Whitfield, John B., Galimberti, Marco, Gordon, Scott, Smoller, Jordan W., Kranzler, Henry R., Huckins, Laura M., Yuan, Kai, Nielsen, Trine Tollerup, Byrne, Enda M., Toikumo, Sylvanus, Medland, Sarah E., Davis, Lea K., Xu, Jiayi, Dao, Cecilia, Johnston, Keira J. A., Demontis, Ditte, Xu, Ke, Krystal, John H., Overstreet, Cassie, Edenberg, Howard J., Justice, Amy C., Johnson, Emma C., Zhao, Hongyu, Deak, Joseph D., Farajzadeh, Leila, Stein, Murray B., Børglum, Anders D., Hickie, Ian B., Gaziano, J. Michael, Heath, Andrew C., Wang, Lu, Gelernter, Joel, Sanchez-Roige, Sandra, Kember, Rachel L., Lind, Penelope A., Martin, Nicholas G., Ge, Tian, Xu, Heng, Levey, Daniel F., Madden, Pamela A. F., Lee, Hyunjoon

2023

Overview

Problematic alcohol use (PAU), a trait that combines alcohol use disorder and alcohol-related problems assessed with a questionnaire, is a leading cause of death and morbidity worldwide. Here we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals (European, N  = 903,147; African, N  = 122,571; Latin American, N  = 38,962; East Asian, N  = 13,551; and South Asian, N  = 1,716 ancestries). We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine mapping improved the identification of likely causal variants. Prioritizing genes through gene expression and chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by a computational drug repurposing analysis. Cross-ancestry polygenic risk scores showed better performance of association in independent samples than single-ancestry polygenic risk scores. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. This study advances our knowledge of the genetic etiology of PAU, and these findings may bring possible clinical applicability of genetics insights—together with neuroscience, biology and data science—closer. A multi-ancestry genome-wide association study of problematic alcohol use in one million individuals identified 110 risk variants and shows that multi-ancestry polygenic scores improve risk prediction compared with single-ancestry scores

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/205/2138 / 692/699/476/5 / Alcohol use / Alcoholism - genetics / Alcohols / Biomedical and Life Sciences / Biomedicine / Cancer Research / Chromatin / Computational neuroscience / Gene expression / Gene mapping / Genes / Genetic Predisposition to Disease / Genetics / Genome-wide association studies / Genome-Wide Association Study / Genomes / Humans / Infectious Diseases / Metabolic Diseases / Molecular Medicine / Morbidity / Neurosciences / Phenotype / Polygenic inheritance / Polymorphism, Single Nucleotide / Racial Groups / Substance use