Evidence of causal effect of major depression on alcohol dependence: findings from the psychiatric genomics consortium
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Abstract
Background: Despite established clinical associations among major depression (MD), alcohol dependence (AD), and alcohol consumption (AC), the nature of the causal relationship between them is not completely understood. We leveraged genome-wide data from the Psychiatric Genomics Consortium (PGC) and UK Biobank to test for the presence of shared genetic mechanisms and causal relationships among MD, AD, and AC. Methods: Linkage disequilibrium score regression and Mendelian randomization (MR) were performed using genome-wide data from the PGC (MD: 135 458 cases and 344 901 controls; AD: 10 206 cases and 28 480 controls) and UK Biobank (AC-frequency: 438 308 individuals; AC-quantity: 307 098 individuals). Results: Positive genetic correlation was observed between MD and AD (rg MD−AD = + 0.47, P = 6.6 × 10 −10 ). AC-quantity showed positive genetic correlation with both AD (rg AD−AC quantity = + 0.75, P = 1.8 × 10 −14 ) and MD (rg MD−AC quantity = + 0.14, P = 2.9 × 10 −7 ), while there was negative correlation of AC-frequency with MD (rg MD−AC frequency = −0.17, P = 1.5 × 10 −10 ) and a non-significant result with AD. MR analyses confirmed the presence of pleiotropy among these four traits. However, the MD-AD results reflect a mediated-pleiotropy mechanism (i.e. causal relationship) with an effect of MD on AD (beta = 0.28, P = 1.29 × 10 −6 ). There was no evidence for reverse causation. Conclusion: This study supports a causal role for genetic liability of MD on AD based on genetic datasets including thousands of individuals. Understanding mechanisms underlying MD-AD comorbidity addresses important public health concerns and has the potential to facilitate prevention and intervention efforts.
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Recent work has suggested a potentially genetic causal link between chronotype and odds of developing depressive symptoms, and similar findings have been reported for smoking or alcohol abuse and depression.
“For example, recent work has suggested that there is a potentially genetic causal link between chronotype and odds of developing depressive symptoms [38] and similar findings have been reported for smoking [39] or alcohol abuse [40] and depression.”
From Neandertal introgression partitions the genetic landscape of neuropsychiatric disorders and associated behavioral phenotypes (2022) · cites this paper as [40]
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- Authors
- Polimanti, R., Peterson, R. E., Ong, J.-S., MacGregor, S., Edwards, A. C., Clarke, T.-K., Frank, J., Gerring, Z., Gillespie, N. A., Lind, P. A., Maes, H. H., Martin, N. G., Mbarek, H., Medland, S. E., Streit, F., Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Agrawal, A., Edenberg, H. J., Kendler, K. S., Lewis, C. M., Sullivan, P. F., Wray, N. R., Gelernter, J., & Derks, E. M.
- Affiliations
- Yale University (US)
- Virginia Commonwealth University (US)
- QIMR Berghofer Medical Research Institute (AU)
- University of Edinburgh (GB)
- Heidelberg University (DE)
- Amsterdam Public Health (NL)
- Indiana University Indianapolis (US)
- King's College London (GB)
- University of North Carolina at Chapel Hill (US)
- The University of Queensland (AU)
- Corresponding author
- Polimanti, Renato
- ORCID
- Polimanti, Renato
- Peterson, Roseann E.
- Ong, Jue-Sheng
- MacGregor, Stuart
- Edwards, Alexis C.
- Clarke, Toni-Kim
- Frank, Josef
- Gerring, Zachary
- Gillespie, Nathan A.
- Lind, Penelope A.
- Maes, Hermine H.
- Martin, Nicholas G.
- Mbarek, Hamdi
- Medland, Sarah E.
- Streit, Fabian
- Edenberg, Howard J.
- Kendler, Kenneth S.
- Lewis, Cathryn M.
- Sullivan, Patrick F.
- Wray, Naomi R.
- Gelernter, Joel
- Derks, Eske M.
- Venue
- Psychological Medicine
- Publisher
- Cambridge University Press (CUP)
- Published
- 2019-04-01
- Volume
- 49
- Issue
- 07
- Pages
- 1218-1226
- ISSN
- 0033-2917 (ISSN-L)
- 1469-8978
- PMC
- PMC6565601
- OpenAlex
- W2952677689
- Cited by
- 108
- References
- 49
- Citations by year
- 2026: 12 · 2025: 11 · 2024: 16 · 2023: 12 · 2022: 18 · 2021: 18 · 2020: 11 · 2019: 7 · 2018: 3
- FWCI
- 8.11
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Psychological Medicine (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- VU Research Portal (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- HAL (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- SUNY Digital Repository Support (State University of New York System) (submittedVersion, cc-by-nc-nd)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- IUScholarWorks (Indiana University) (submittedVersion)
- Purdue University Indianapolis (Indiana University) (submittedVersion)
- Funders
- American Foundation for Suicide Prevention
- South London and Maudsley NHS Foundation Trust
- National Institute for Health and Care Research
- Department of Health and Social Care
- King's College London
- Vrije Universiteit Amsterdam
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO 480‐05‐003, 480- 05-003)
- National Institutes of Health
- Medical Research Council (MR/K026992/1, MC_UU_00007/10)
- National Institute on Alcohol Abuse and Alcoholism (U01AA008401, U10AA008401)
- National Institute on Aging (U24AG021886)
- National Institute of Mental Health (MH094421, U01MH109528, U01MH085520, K01MH113848, U01MH109536, MH109532, U01MH094421, MH109528, U01MH109532)
- National Institute on Drug Abuse (R00DA023549, MH109532)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Keywords
- major depressive disorder, alcoholism, alcohol consumption, causal relationship, genetic correlation, pleiotropy, drinking frequency, reverse causality
- MeSH terms
- Adult, Aged, Alcoholism, Major Depressive Disorder, Female, United Kingdom, Humans, Male, Middle Aged, Cohort Studies, Linkage Disequilibrium, Comorbidity, Causality, Genomics, Genome-Wide Association Study, Genetic Association Studies, Mendelian Randomization Analysis
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