Alcohol misuse (AM) is highly prevalent and harmful, with theorized subgroups differing on internalizing and externalizing dimensions. Despite known heterogeneity, genome-wide association studies (GWAS) are usually conducted on unidimensional phenotypes. These approaches have identified important genes related to AM but fail to capture a large part of the heritability, even with recent increases in sample sizes. This study aimed to address phenotypic heterogeneity in GWAS to aid gene finding and to uncover the etiology of different types of AM. Genetic and phenotypic data from 410,414 unrelated individuals of multiple ancestry groups (primarily European) in the UK Biobank were obtained. Mixture modeling was applied to measures of alcohol misuse and internalizing/externalizing psychopathology to uncover phenotypically homogenous subclasses, which were carried forward to GWAS and functional annotation. A four-class model emerged with “low risk”, “internalizing—light/non-drinkers”, “heavy alcohol use—low impairment”, and “broad high risk” classes. SNP heritability ranged from 3 to 18% and both known AM signals and novel signals were captured by genomic risk loci. Class comparisons showed distinct patterns of regional brain tissue enrichment and genetic correlations with internalizing and externalizing phenotypes. Despite some limitations, this study demonstrated the utility of genetic research on homogenous subclasses. Not only were novel genetic signals identified that might be used for follow-up studies, but addressing phenotypic heterogeneity allows for the discovery and investigation of differential genetic vulnerabilities in the development of AM, which is an important step towards the goal of personalized medicine.
| Original language | English |
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| Pages (from-to) | 4225-4233 |
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| Number of pages | 9 |
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| Journal | Molecular Psychiatry |
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| Volume | 28 |
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| Issue number | 10 |
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| Early online date | 25 Jul 2023 |
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| DOIs | |
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| Publication status | Published - Oct 2023 |
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This research was funded by a grant to J.E.S. from the Amsterdam Neuroscience Alliance Project. J.E.S. was additionally supported by a VENI (201G-064) grant from The Netherlands Organization for Scientific Research (NWO). D.P. was funded by the NWO (VICI 453-14-005), NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012), and a European Research Council advanced grant (Grant No, ERC-2018-AdG GWAS2FUNC 834057). The research has been conducted using the UK Biobank Resource (application no. 16406). We would like to thank the many UK Biobank participants and staff. Analyses were carried out on the Genetic Cluster Computer hosted by the Dutch National computing and Networking Services SURFsara. Spit for Science has been supported by Virginia Commonwealth University, P20 AA017828, R37AA011408, K02AA018755, P50 AA022537, and K01AA024152 from the National Institute on Alcohol Abuse and Alcoholism, and UL1RR031990 from the National Center for Research Resources and National Institutes of Health Roadmap for Medical Research. This research was also supported by the Center for the Study of Tobacco Products at Virginia Commonwealth University. The content is solely the responsibility of the authors and does not necessarily represent the views of the NIH or the FDA. Data from this study are available to qualified researchers via dbGaP (phs001754.v4.p2) or via [email protected] to qualified researchers who provide the appropriate signed data use agreement. We would like to thank Dr. Danielle Dick for founding and directing the Spit for Science Registry from 2011–2022, and the Spit for Science participants for making this study a success, as well as the many University faculty, students, and staff who contributed to the design and implementation of the project. Secondary analyses included data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by the Veterans Administration (VA) Million Veteran Program (MVP). The authors thank the staff, researchers, and volunteers, who have contributed to MVP, and especially participants who previously served their country in the military and now generously agreed to enroll in the study. (See https://www.research.va.gov/mvp/ for more details). The citation for MVP is Gaziano, J.M. et al. Million Veteran Program: A mega-biobank to study genetic influences on health and disease. J Clin Epidemiol 70, 214-23 (2016).
This research was funded by a grant to J.E.S. from the Amsterdam Neuroscience Alliance Project. J.E.S. was additionally supported by a VENI (201G-064) grant from The Netherlands Organization for Scientific Research (NWO). D.P. was funded by the NWO (VICI 453-14-005), NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012), and a European Research Council advanced grant (Grant No, ERC-2018-AdG GWAS2FUNC 834057). The research has been conducted using the UK Biobank Resource (application no. 16406). We would like to thank the many UK Biobank participants and staff. Analyses were carried out on the Genetic Cluster Computer hosted by the Dutch National computing and Networking Services SURFsara. Spit for Science has been supported by Virginia Commonwealth University, P20 AA017828, R37AA011408, K02AA018755, P50 AA022537, and K01AA024152 from the National Institute on Alcohol Abuse and Alcoholism, and UL1RR031990 from the National Center for Research Resources and National Institutes of Health Roadmap for Medical Research. This research was also supported by the Center for the Study of Tobacco Products at Virginia Commonwealth University. The content is solely the responsibility of the authors and does not necessarily represent the views of the NIH or the FDA. Data from this study are available to qualified researchers via dbGaP (phs001754.v4.p2) or via [email protected] to qualified researchers who provide the appropriate signed data use agreement. We would like to thank Dr. Danielle Dick for founding and directing the Spit for Science Registry from 2011–2022, and the Spit for Science participants for making this study a success, as well as the many University faculty, students, and staff who contributed to the design and implementation of the project. Secondary analyses included data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by the Veterans Administration (VA) Million Veteran Program (MVP). The authors thank the staff, researchers, and volunteers, who have contributed to MVP, and especially participants who previously served their country in the military and now generously agreed to enroll in the study. (See https://www.research.va.gov/mvp/ for more details). The citation for MVP is Gaziano, J.M. et al. Million Veteran Program: A mega-biobank to study genetic influences on health and disease. J Clin Epidemiol 70, 214-23 (2016).