Examining the Effect of Genes on Depression as Mediated by Smoking and Modified by Sex-Reference-Cited by-同舟云学术

Examining the Effect of Genes on Depression as Mediated by Smoking and Modified by Sex

Published:2024-04-27 Issue:5 Volume:15 Page:565
ISSN:2073-4425
Container-title:Genes
language:en
Short-container-title:Genes

Author:

Voorhies Kirsten¹,Hecker Julian²,Lee Sanghun³^ORCID,Hahn Georg⁴^ORCID,Prokopenko Dmitry⁵^ORCID,McDonald Merry-Lynn⁶⁷⁸,Wu Alexander C.⁹,Wu Ann¹^ORCID,Hokanson John E.¹⁰,Cho Michael H.²,Lange Christoph¹¹,Hoth Karin F.¹²,Lutz Sharon M.¹¹¹

Affiliation:

1. Department of Population Medicine, Harvard Pilgrim Health Care Institute, Boston, MA 02215, USA

2. Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA

3. Division of Medicine, Department of Medical Consilience, Graduate School, Dankook University, Yongin 16890, Republic of Korea

4. Brigham and Women’s Hospital, Division of Pharmacoepidemiology and Pharmacoeconomics, and Department of Medicine, Harvard Medical School, Boston, MA 02120, USA

5. Genetics and Aging Research Unit and the McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA

6. Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL 35233, USA

7. Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA

8. Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35233, USA

9. Harvard College, Cambridge, MA 02138, USA

10. Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA

11. Department of Biostatistics, T.H. Chan School of Public Health, Harvard University, Boston, MA 02115, USA

12. Department of Psychiatry and Iowa Neuroscience Institute, University of Iowa, Iowa City, IA 52242, USA

Abstract

Depression is heritable, differs by sex, and has environmental risk factors such as cigarette smoking. However, the effect of single nucleotide polymorphisms (SNPs) on depression through cigarette smoking and the role of sex is unclear. In order to examine the association of SNPs with depression and smoking in the UK Biobank with replication in the COPDGene study, we used counterfactual-based mediation analysis to test the indirect or mediated effect of SNPs on broad depression through the log of pack-years of cigarette smoking, adjusting for age, sex, current smoking status, and genetic ancestry (via principal components). In secondary analyses, we adjusted for age, sex, current smoking status, genetic ancestry (via principal components), income, education, and living status (urban vs. rural). In addition, we examined sex-stratified mediation models and sex-moderated mediation models. For both analyses, we adjusted for age, current smoking status, and genetic ancestry (via principal components). In the UK Biobank, rs6424532 [LOC105378800] had a statistically significant indirect effect on broad depression through the log of pack-years of cigarette smoking (p = 4.0 × 10−4) among all participants and a marginally significant indirect effect among females (p = 0.02) and males (p = 4.0 × 10−3). Moreover, rs10501696 [GRM5] had a marginally significant indirect effect on broad depression through the log of pack-years of cigarette smoking (p = 0.01) among all participants and a significant indirect effect among females (p = 2.2 × 10−3). In the secondary analyses, the sex-moderated indirect effect was marginally significant for rs10501696 [GRM5] on broad depression through the log of pack-years of cigarette smoking (p = 0.01). In the COPDGene study, the effect of an SNP (rs10501696) in GRM5 on depressive symptoms and medication was mediated by log of pack-years (p = 0.02); however, no SNPs had a sex-moderated mediated effect on depressive symptoms. In the UK Biobank, we found SNPs in two genes [LOC105378800, GRM5] with an indirect effect on broad depression through the log of pack-years of cigarette smoking. In addition, the indirect effect for GRM5 on broad depression through smoking may be moderated by sex. These results suggest that genetic regions associated with broad depression may be mediated by cigarette smoking and this relationship may be moderated by sex.

Funder

National Institute of Mental Health

National Heart, Lung, & Blood Institute

Publisher

MDPI AG

Link

https://www.mdpi.com/2073-4425/15/5/565/pdf

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