Polygenic Scores for Major Depressive Disorder and Risk of Alcohol Dependence
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Importance: Major depressive disorder (MDD) and alcohol dependence (AD) are heritable disorders with significant public health burdens, and they are frequently comorbid. Common genetic factors that influence the co-occurrence of MDD and AD have been sought in family, twin, and adoption studies, and results to date have been promising but inconclusive. Objective: To examine whether AD and MDD overlap genetically, using a polygenic score approach. Design, Settings, and Participants: Association analyses were conducted between MDD polygenic risk score (PRS) and AD case-control status in European ancestry samples from 4 independent genome-wide association study (GWAS) data sets: the Collaborative Study on the Genetics of Alcoholism (COGA); the Study of Addiction, Genetics, and Environment (SAGE); the Yale-Penn genetic study of substance dependence; and the National Health and Resilience in Veterans Study (NHRVS). Results from a meta-analysis of MDD (9240 patients with MDD and 9519 controls) from the Psychiatric Genomics Consortium were applied to calculate PRS at thresholds from P < .05 to P ≤ .99 in each AD GWAS data set. Main Outcomes and Measures: Association between MDD PRS and AD. Results: Participants analyzed included 788 cases (548 [69.5%] men; mean [SD] age, 38.2 [10.8] years) and 522 controls (151 [28.9.%] men; age [SD], 43.9 [11.6] years) from COGA; 631 cases (333 [52.8%] men; age [SD], 35.0 [7.7] years) and 756 controls (260 [34.4%] male; age [SD] 36.1 [7.7] years) from SAGE; 2135 cases (1375 [64.4%] men; age [SD], 39.4 [11.5] years) and 350 controls (126 [36.0%] men; age [SD], 43.5 [13.9] years) from Yale-Penn; and 317 cases (295 [93.1%] men; age [SD], 59.1 [13.1] years) and 1719 controls (1545 [89.9%] men; age [SD], 64.5 [13.3] years) from NHRVS. Higher MDD PRS was associated with a significantly increased risk of AD in all samples (COGA: best P = 1.7 × 10-6, R2 = 0.026; SAGE: best P = .001, R2 = 0.01; Yale-Penn: best P = .035, R2 = 0.0018; and NHRVS: best P = .004, R2 = 0.0074), with stronger evidence for association after meta-analysis of the 4 samples (best P = 3.3 × 10-9). In analyses adjusted for MDD status in 3 AD GWAS data sets, similar patterns of association were observed (COGA: best P = 7.6 × 10-6, R2 = 0.023; Yale-Penn: best P = .08, R2 = 0.0013; and NHRVS: best P = .006, R2 = 0.0072). After recalculating MDD PRS using MDD GWAS data sets without comorbid MDD-AD cases, significant evidence was observed for an association between the MDD PRS and AD in the meta-analysis of 3 GWAS AD samples without MDD cases (best P = .007). Conclusions and Relevance: These results suggest that shared genetic susceptibility contributes modestly to MDD and AD comorbidity. Individuals with elevated polygenic risk for MDD may also be at risk for AD.
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Taken together with evidence from other recent genomic studies and null correlations for other GWAS of alcohol consumption, but not for measures of problem drinking (e.g., AUDIT-P), these findings suggest that major depression may primarily share genetic liability with alcohol use at pathological levels.
“Taken together with evidence from other recent genomic studies37, and null correlations for other GWAS of alcohol consumption, but not for measures of problem drinking (e.g., AUDIT-P), these findings suggest that major depression may primarily share genetic liability with alcohol use at pathological levels.”
From Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders (2018) · cites this paper as [37]
This genetic correlation is strongest for aspects of negative mood, including neuroticism and major depression, as also seen in twin studies and through recent specific molecular evidence for pleiotropy.
“This correlation is strongest for aspects of negative mood, including neuroticism and major depression, as also seen in twin studies35,36 and through recent specific molecular evidence for pleiotropy37,38.”
From Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders (2018) · cites this paper as [37]
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- Authors
- Andersen, A. M., Pietrzak, R. H., Kranzler, H. R., Ma, L., Zhou, H., Liu, X., Kramer, J., Kuperman, S., Edenberg, H. J., Nurnberger, J. I., Rice, J. P., Tischfield, J. A., Goate, A., Foroud, T. M., Meyers, J. L., Porjesz, B., Dick, D. M., Hesselbrock, V., Boerwinkle, E., Southwick, S. M., Krystal, J. H., Weissman, M. M., Levinson, D. F., Potash, J. B., Gelernter, J., & Han, S.
- Affiliations
- University of Iowa (US)
- Yale University (US)
- Philadelphia VA Medical Center (US)
- University of Maryland, College Park (US)
- The University of Texas Health Science Center at Houston (US)
- Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City
- Indiana University Indianapolis (US)
- Department of Psychiatry, Indiana University School of Medicine, Indianapolis
- Washington University in St. Louis (US)
- Rutgers, The State University of New Jersey (US)
- Icahn School of Medicine at Mount Sinai (US)
- Indiana University School of Medicine (US)
- SUNY Downstate Health Sciences University (US)
- Department of Psychiatry and Behavioral Sciences, State University of New York Downstate Medical Center, Brooklyn
- Virginia Commonwealth University (US)
- University of Connecticut (US)
- New York State Psychiatric Institute (US)
- Stanford Medicine (US)
- Corresponding author
- Han, Shizhong
- ORCID
- Andersen, Allan M.
- Pietrzak, Robert H.
- Kranzler, Henry R.
- Ma, Li
- Zhou, Hang
- Liu, Xiaoming
- Kramer, John
- Edenberg, Howard J.
- Rice, John P.
- Tischfield, Jay A.
- Goate, Alison
- Foroud, Tatiana M.
- Meyers, Jacquelyn L.
- Dick, Danielle M.
- Hesselbrock, Victor
- Boerwinkle, Eric
- Southwick, Steven M.
- Krystal, John H.
- Weissman, Myrna M.
- Levinson, Douglas F.
- Potash, James B.
- Gelernter, Joel
- Han, Shizhong
- Venue
- JAMA Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2017-11-01
- Volume
- 74
- Issue
- 11
- Pages
- 1153
- ISSN
- 2168-622X (ISSN-L)
- PMC
- PMC5710224
- OpenAlex
- W2750021882
- Cited by
- 90
- References
- 71
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 8 · 2023: 11 · 2022: 8 · 2021: 11 · 2020: 16 · 2019: 11 · 2018: 13 · 2017: 2
- FWCI
- 1.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Psychiatry (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Purdue University Indianapolis (Indiana University) (submittedVersion)
- Columbia Academic Commons (Columbia University)
- Funders
- U.S. Department of Veterans Affairs
- Eli Lilly and Company
- Pfizer
- Yale University
- American Academy of Child and Adolescent Psychiatry (K12DA000357)
- University of Pennsylvania
- Johns Hopkins University (HHSN268200782096C, U01HG004438, N01-HG-65403)
- Indivior
- American Society of Clinical Psychopharmacology
- H. Lundbeck A/S
- National Institutes of Health (HHSN268200782096C, AA008401, N01‐HG‐65403, CA089392, UL1TR001863)
- Roy J. and Lucille A. Carver College of Medicine, University of Iowa
- National Center for PTSD, U.S. Department of Veterans Affairs
- National Institute on Alcohol Abuse and Alcoholism (R01 AA 11330, R01AA024486, AA008401, R01AA022994, U10AA008401)
- National Institute on Aging (P50AG005138)
- National Institute on Drug Abuse (K01DA037914, R01DA013423, HHSN268200782096C, DA013423, K12DA000357)
- National Human Genome Research Institute (U01HG004422, U01HG004446, U01HG004438)
- National Cancer Institute (P01CA089392)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- major depressive disorder, alcoholism, polygenic risk score, genetic overlap, comorbidities, psychiatric genetics, European ancestry, shared genetic risk
- MeSH terms
- Adult, Alcoholism, Major Depressive Disorder, Depressive Disorder, Major, Female, Humans, Male, Middle Aged, United States, Comorbidity, Genetic Predisposition to Disease, Multifactorial Inheritance, White People, Genome-Wide Association Study
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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