Polygenic Scores for Major Depressive Disorder and Risk of Alcohol Dependence.
- Authors
- Andersen, Allan M; Pietrzak, Robert H; Kranzler, Henry R; Ma, Li; Zhou, Hang; Liu, Xiaoming; Kramer, John; Kuperman, Samuel; Edenberg, Howard J; Nurnberger, John I; Rice, John P; Tischfield, Jay A; Goate, Alison; Foroud, Tatiana M; Meyers, Jacquelyn L; Porjesz, Bernice; 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
- Year
- 2017
- Journal
- JAMA psychiatry
- PMID
- 28813562
- DOI
- 10.1001/jamapsychiatry.2017.2269
- PMCID
- PMC5710224
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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