Investigating genetically stratified subgroups to better understand the etiology of alcohol misuse.
Journal
Molecular psychiatry
ISSN: 1476-5578
Titre abrégé: Mol Psychiatry
Pays: England
ID NLM: 9607835
Informations de publication
Date de publication:
25 Jul 2023
25 Jul 2023
Historique:
received:
28
02
2023
accepted:
28
06
2023
revised:
15
06
2023
pubmed:
25
7
2023
medline:
25
7
2023
entrez:
24
7
2023
Statut:
aheadofprint
Résumé
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.
Identifiants
pubmed: 37488169
doi: 10.1038/s41380-023-02174-0
pii: 10.1038/s41380-023-02174-0
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : U.S. Department of Health & Human Services | NIH | National Institute on Alcohol Abuse and Alcoholism (NIAAA)
ID : R37AA011408
Organisme : U.S. Department of Health & Human Services | NIH | National Institute on Alcohol Abuse and Alcoholism (NIAAA)
ID : K02AA018755
Organisme : U.S. Department of Health & Human Services | NIH | National Institute on Alcohol Abuse and Alcoholism (NIAAA)
ID : P50AA022537
Organisme : U.S. Department of Health & Human Services | NIH | National Institute on Alcohol Abuse and Alcoholism (NIAAA)
ID : K01AA024152
Organisme : U.S. Department of Health & Human Services | NIH | National Institute on Alcohol Abuse and Alcoholism (NIAAA)
ID : P20AA017828, R37AA011408, K02AA018755, P50AA022537, K01AA024152
Organisme : Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organisation for Scientific Research)
ID : VENI.201G-064
Organisme : Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organisation for Scientific Research)
ID : VICI.453-14-005
Organisme : Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organisation for Scientific Research)
ID : 024.004.012
Organisme : Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organisation for Scientific Research)
ID : VICI 453-14-005
Organisme : EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)
ID : ERC-2018-AdG GWAS2FUNC 834057
Organisme : U.S. Department of Health & Human Services | NIH | National Center for Research Resources (NCRR)
ID : UL1RR031990
Organisme : U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (NIDA)
ID : U54DA036105
Investigateurs
Karen Chartier
(K)
Ananda Amstadter
(A)
Danielle M Dick
(DM)
Emily Lilley
(E)
Renolda Gelzinis
(R)
Anne Morris
(A)
Katie Bountress
(K)
Amy E Adkins
(AE)
Nathaniel Thomas
(N)
Zoe Neale
(Z)
Kimberly Pedersen
(K)
Thomas Bannard
(T)
Seung B Cho
(SB)
Peter Barr
(P)
Holly Byers
(H)
Erin C Berenz
(EC)
Erin Caraway
(E)
James S Clifford
(JS)
Megan Cooke
(M)
Elizabeth Do
(E)
Alexis C Edwards
(AC)
Neeru Goyal
(N)
Laura M Hack
(LM)
Lisa J Halberstadt
(LJ)
Sage Hawn
(S)
Sally Kuo
(S)
Emily Lasko
(E)
Jennifer Lend
(J)
Mackenzie Lind
(M)
Elizabeth Long
(E)
Alexandra Martelli
(A)
Jacquelyn L Meyers
(JL)
Kerry Mitchell
(K)
Ashlee Moore
(A)
Arden Moscati
(A)
Aashir Nasim
(A)
Jill Opalesky
(J)
Cassie Overstreet
(C)
A Christian Pais
(AC)
Tarah Raldiris
(T)
Jessica Salvatore
(J)
Jeanne Savage
(J)
Rebecca Smith
(R)
David Sosnowski
(D)
Jinni Su
(J)
Chloe Walker
(C)
Marcie Walsh
(M)
Teresa Willoughby
(T)
Madison Woodroof
(M)
Jia Yan
(J)
Cuie Sun
(C)
Brandon Wormley
(B)
Brien Riley
(B)
Fazil Aliev
(F)
Roseann Peterson
(R)
Bradley T Webb
(BT)
Informations de copyright
© 2023. The Author(s).
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