Refining the scope of genetic influences on alcohol misuse through environmental stratification and gene-environment interaction.
SES
alcohol
genome‐wide environment interaction
stratified GWAS
trauma
Journal
Alcohol, clinical & experimental research
ISSN: 2993-7175
Titre abrégé: Alcohol Clin Exp Res (Hoboken)
Pays: United States
ID NLM: 9918609780906676
Informations de publication
Date de publication:
28 Aug 2024
28 Aug 2024
Historique:
revised:
30
07
2024
received:
14
03
2024
accepted:
30
07
2024
medline:
31
8
2024
pubmed:
31
8
2024
entrez:
28
8
2024
Statut:
aheadofprint
Résumé
Gene-environment interaction (G × E) is likely an important influence shaping individual differences in alcohol misuse (AM), yet it has not been extensively studied in molecular genetic research. In this study, we use a series of genome-wide gene-environment interaction (GWEIS) and in silico annotation methods with the aim of improving gene identification and biological understanding of AM. We carried out GWEIS for four AM phenotypes in the large UK Biobank sample (N = 360,314), with trauma exposure and socioeconomic status (SES) as moderators of the genetic effects. Exploratory analyses compared stratified genome-wide association (GWAS) and GWEIS modeling approaches. We applied functional annotation, gene- and gene-set enrichment, and polygenic score analyses to interpret the GWEIS results. GWEIS models showed few genetic variants with significant interaction effects across gene-environment pairs. Enrichment analyses identified moderation by SES of the genes NOXA1, DLGAP1, and UBE2L3 on drinking quantity and the gene IFIT1B on drinking frequency. Except for DLGAP1, these genes have not previously been linked to AM. The most robust results (GWEIS interaction p = 4.59e-09) were seen for SES moderating the effects of variants linked to immune-related genes on a pattern of drinking with versus without meals. Our results highlight several genes and a potential mechanism of immune system functioning behind the moderating effect of SES on the genetic influences on AM. Although GWEIS seems to be a preferred approach over stratified GWAS, modeling G × E effects at the molecular level remains a challenge even in large samples. Understanding these effects will require substantial effort and more in-depth phenotypic measurement.
Sections du résumé
BACKGROUND
BACKGROUND
Gene-environment interaction (G × E) is likely an important influence shaping individual differences in alcohol misuse (AM), yet it has not been extensively studied in molecular genetic research. In this study, we use a series of genome-wide gene-environment interaction (GWEIS) and in silico annotation methods with the aim of improving gene identification and biological understanding of AM.
METHODS
METHODS
We carried out GWEIS for four AM phenotypes in the large UK Biobank sample (N = 360,314), with trauma exposure and socioeconomic status (SES) as moderators of the genetic effects. Exploratory analyses compared stratified genome-wide association (GWAS) and GWEIS modeling approaches. We applied functional annotation, gene- and gene-set enrichment, and polygenic score analyses to interpret the GWEIS results.
RESULTS
RESULTS
GWEIS models showed few genetic variants with significant interaction effects across gene-environment pairs. Enrichment analyses identified moderation by SES of the genes NOXA1, DLGAP1, and UBE2L3 on drinking quantity and the gene IFIT1B on drinking frequency. Except for DLGAP1, these genes have not previously been linked to AM. The most robust results (GWEIS interaction p = 4.59e-09) were seen for SES moderating the effects of variants linked to immune-related genes on a pattern of drinking with versus without meals.
CONCLUSIONS
CONCLUSIONS
Our results highlight several genes and a potential mechanism of immune system functioning behind the moderating effect of SES on the genetic influences on AM. Although GWEIS seems to be a preferred approach over stratified GWAS, modeling G × E effects at the molecular level remains a challenge even in large samples. Understanding these effects will require substantial effort and more in-depth phenotypic measurement.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIAAA NIH HHS
ID : K01AA024152
Pays : United States
Organisme : NIAAA NIH HHS
ID : K02AA018755
Pays : United States
Organisme : NIAAA NIH HHS
ID : P20AA017828
Pays : United States
Organisme : NIAAA NIH HHS
ID : P50AA022537
Pays : United States
Organisme : NIAAA NIH HHS
ID : R37AA011408
Pays : United States
Organisme : Virginia Commonwealth University
Organisme : Nederlandse Organisatie voor Wetenschappelijk Onderzoek
ID : VI.VENI.201G-064
Organisme : Nederlandse Organisatie voor Wetenschappelijk Onderzoek
ID : 024.004.012
Organisme : NIH HHS
Pays : United States
Organisme : NCRR NIH HHS
ID : UL1RR031990
Pays : United States
Investigateurs
Karen Chartier
(K)
Ananda Amstadter
(A)
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)
Amy E Adkins
(AE)
Kimberly Pedersen
(K)
Peter Barr
(P)
Holly Byers
(H)
Erin C Berenz
(EC)
Erin Caraway
(E)
Seung B Cho
(SB)
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)
Zoe Neale
(Z)
Jill Opalesky
(J)
Cassie Overstreet
(C)
A Christian Pais
(AC)
Kimberly Pedersen
(K)
Tarah Raldiris
(T)
Jessica Salvatore
(J)
Rebecca Smith
(R)
David Sosnowski
(D)
Jinni Su
(J)
Nathaniel Thomas
(N)
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
© 2024 The Author(s). Alcohol, Clinical and Experimental Research published by Wiley Periodicals LLC on behalf of Research Society on Alcohol.
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