Allan M Andersen1, Robert H Pietrzak2,3, Henry R Kranzler4,5, Li Ma6, Hang Zhou3, Xiaoming Liu7, John Kramer1, Samuel Kuperman1, Howard J Edenberg8, John I Nurnberger9, John P Rice10, Jay A Tischfield11, Alison Goate12, Tatiana M Foroud13, Jacquelyn L Meyers14, Bernice Porjesz14, Danielle M Dick15, Victor Hesselbrock16, Eric Boerwinkle7, Steven M Southwick2,3, John H Krystal2,3, Myrna M Weissman17,18,19, Douglas F Levinson20, James B Potash1,21,22, Joel Gelernter2,3, Shizhong Han1,22. 1. Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City. 2. US Department of Veterans Affairs (VA) National Center for Posttraumatic Stress Disorder, Clinical Neurosciences Division, VA Connecticut Healthcare System, West Haven. 3. Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut. 4. Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia. 5. Mental Illness, Research, Education and Clinical Center of Veterans Integrated Service Network 4, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania. 6. Department of Animal and Avian Sciences, University of Maryland, College Park. 7. Human Genetics Center, University of Texas Health Science Center at Houston. 8. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis. 9. Department of Psychiatry, Indiana University School of Medicine, Indianapolis. 10. Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri. 11. Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers University, Piscataway. 12. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York. 13. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis. 14. Department of Psychiatry and Behavioral Sciences, State University of New York Downstate Medical Center, Brooklyn. 15. Departments of Psychology and Human and Molecular Genetics, Virginia Commonwealth University, Richmond. 16. Department of Psychiatry, University of Connecticut School of Medicine, Farmington. 17. Division of Epidemiology, New York State Psychiatric Institute, New York. 18. Department of Psychiatry, Columbia University, College of Physicians and Surgeons, New York, New York. 19. Columbia University, Mailman School of Public Health, New York, New York. 20. Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California. 21. Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City. 22. now with the Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland.
Abstract
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.
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.
Authors: Guo-Bo Chen; Sang Hong Lee; Matthew R Robinson; Maciej Trzaskowski; Zhi-Xiang Zhu; Thomas W Winkler; Felix R Day; Damien C Croteau-Chonka; Andrew R Wood; Adam E Locke; Zoltán Kutalik; Ruth J F Loos; Timothy M Frayling; Joel N Hirschhorn; Jian Yang; Naomi R Wray; Peter M Visscher Journal: Eur J Hum Genet Date: 2016-08-24 Impact factor: 4.246
Authors: S I Shyn; J Shi; J B Kraft; J B Potash; J A Knowles; M M Weissman; H A Garriock; J S Yokoyama; P J McGrath; E J Peters; W A Scheftner; W Coryell; W B Lawson; D Jancic; P V Gejman; A R Sanders; P Holmans; S L Slager; D F Levinson; S P Hamilton Journal: Mol Psychiatry Date: 2009-12-29 Impact factor: 15.992
Authors: Rosa M Crum; Ramin Mojtabai; Samuel Lazareck; James M Bolton; Jennifer Robinson; Jitender Sareen; Kerry M Green; Elizabeth A Stuart; Lareina La Flair; Anika A H Alvanzo; Carla L Storr Journal: JAMA Psychiatry Date: 2013-07 Impact factor: 21.596
Authors: Caitlin E Carey; Arpana Agrawal; Kathleen K Bucholz; Sarah M Hartz; Michael T Lynskey; Elliot C Nelson; Laura J Bierut; Ryan Bogdan Journal: Front Genet Date: 2016-08-15 Impact factor: 4.599
Authors: Brienna M Fogle; Jack Tsai; Natalie Mota; Ilan Harpaz-Rotem; John H Krystal; Steven M Southwick; Robert H Pietrzak Journal: Front Psychiatry Date: 2020-12-09 Impact factor: 4.157
Authors: Jill Alexandra Rabinowitz; Rashelle Musci; Adam Milam; Kelly Benke; Danielle Sisto; Nicholas S Ialongo; Brion S Maher; George Uhl; Gail Rosenbaum; Beth Reboussin Journal: J Stud Alcohol Drugs Date: 2019-01 Impact factor: 2.582
Authors: Joel Gelernter; Hang Zhou; Yaira Z Nuñez; Apiwat Mutirangura; Robert T Malison; Rasmon Kalayasiri Journal: Alcohol Clin Exp Res Date: 2018-03-13 Impact factor: 3.455
Authors: Hang Zhou; Renato Polimanti; Bao-Zhu Yang; Qian Wang; Shizhong Han; Richard Sherva; Yaira Z Nuñez; Hongyu Zhao; Lindsay A Farrer; Henry R Kranzler; Joel Gelernter Journal: JAMA Psychiatry Date: 2017-12-01 Impact factor: 21.596
Authors: Jill A Rabinowitz; Rashelle J Musci; Beth Reboussin; Adam J Milam; Kelly S Benke; George R Uhl; Danielle Y Sisto; Nicholas S Ialongo; Brion S Maher Journal: Dev Psychopathol Date: 2020-05
Authors: Honghuang Lin; Fan Wang; Andrew J Rosato; Lindsay A Farrer; David C Henderson; Huiping Zhang Journal: Epigenomics Date: 2020-06-04 Impact factor: 4.778