TY - JOUR
T1 - Investigating genetically stratified subgroups to better understand the etiology of alcohol misuse
AU - Data collection
AU - Thijssen, Anaïs B.
AU - Registry management
AU - Chartier, Karen
AU - Amstadter, Ananda
AU - Dick, Danielle M.
AU - Genotypic data processing and cleaning
AU - Data cleaning and management
AU - Lilley, Emily
AU - Gelzinis, Renolda
AU - Morris, Anne
AU - Bountress, Katie
AU - Adkins, Amy E.
AU - Thomas, Nathaniel
AU - Neale, Zoe
AU - Pedersen, Kimberly
AU - Bannard, Thomas
AU - Cho, Seung B.
AU - Barr, Peter
AU - Byers, Holly
AU - Berenz, Erin C.
AU - Caraway, Erin
AU - Clifford, James S.
AU - Cooke, Megan
AU - Do, Elizabeth
AU - Edwards, Alexis C.
AU - Goyal, Neeru
AU - Hack, Laura M.
AU - Halberstadt, Lisa J.
AU - Hawn, Sage
AU - Kuo, Sally
AU - Lasko, Emily
AU - Lend, Jennifer
AU - Lind, Mackenzie
AU - Long, Elizabeth
AU - Martelli, Alexandra
AU - Meyers, Jacquelyn L.
AU - Mitchell, Kerry
AU - Moore, Ashlee
AU - Moscati, Arden
AU - Nasim, Aashir
AU - Opalesky, Jill
AU - Overstreet, Cassie
AU - Pais, A. Christian
AU - Raldiris, Tarah
AU - Salvatore, Jessica
AU - Savage, Jeanne
AU - Smith, Rebecca
AU - Sosnowski, David
AU - Su, Jinni
AU - Walker, Chloe
AU - Walsh, Marcie
AU - Willoughby, Teresa
AU - Woodroof, Madison
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85182859828&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/37488169
U2 - https://doi.org/10.1038/s41380-023-02174-0
DO - https://doi.org/10.1038/s41380-023-02174-0
M3 - Article
C2 - 37488169
SN - 1359-4184
JO - Molecular psychiatry
JF - Molecular psychiatry
ER -