Polygenic Scores for Major Depressive Disorder and Risk of Alcohol Dependence

Allan M. Andersen, Robert H. Pietrzak, Henry R. Kranzler, Li Ma, Hang Zhou, Xiaoming Liu, John Kramer, Samuel Kuperman, Howard Edenberg, John Nurnberger, John P. Rice, Jay A. Tischfield, Alison Goate, Tatiana Foroud, Jacquelyn L. Meyers, Bernice Porjesz, Danielle M. Dick, Victor Hesselbrock, Eric Boerwinkle, Steven M. SouthwickJohn H. Krystal, Myrna M. Weissman, Douglas F. Levinson, James B. Potash, Joel Gelernter, Shizhong Han

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1153-1160
Number of pages8
JournalJAMA Psychiatry
Volume74
Issue number11
DOIs
StatePublished - Nov 1 2017

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Major Depressive Disorder
Alcoholism
Genome-Wide Association Study
Veterans
Meta-Analysis
Health
Twin Studies
Genetic Predisposition to Disease
Genomics

ASJC Scopus subject areas

  • Psychiatry and Mental health

Cite this

Andersen, A. M., Pietrzak, R. H., Kranzler, H. R., Ma, L., Zhou, H., Liu, X., ... Han, S. (2017). Polygenic Scores for Major Depressive Disorder and Risk of Alcohol Dependence. JAMA Psychiatry, 74(11), 1153-1160. https://doi.org/10.1001/jamapsychiatry.2017.2269

Polygenic Scores for Major Depressive Disorder and Risk of Alcohol Dependence. / Andersen, Allan M.; Pietrzak, Robert H.; Kranzler, Henry R.; Ma, Li; Zhou, Hang; Liu, Xiaoming; Kramer, John; Kuperman, Samuel; Edenberg, Howard; Nurnberger, John; Rice, John P.; Tischfield, Jay A.; Goate, Alison; Foroud, Tatiana; 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.

In: JAMA Psychiatry, Vol. 74, No. 11, 01.11.2017, p. 1153-1160.

Research output: Contribution to journalArticle

Andersen, AM, Pietrzak, RH, Kranzler, HR, Ma, L, Zhou, H, Liu, X, Kramer, J, Kuperman, S, Edenberg, H, Nurnberger, J, Rice, JP, Tischfield, JA, Goate, A, Foroud, T, Meyers, JL, Porjesz, B, Dick, DM, Hesselbrock, V, Boerwinkle, E, Southwick, SM, Krystal, JH, Weissman, MM, Levinson, DF, Potash, JB, Gelernter, J & Han, S 2017, 'Polygenic Scores for Major Depressive Disorder and Risk of Alcohol Dependence', JAMA Psychiatry, vol. 74, no. 11, pp. 1153-1160. https://doi.org/10.1001/jamapsychiatry.2017.2269
Andersen AM, Pietrzak RH, Kranzler HR, Ma L, Zhou H, Liu X et al. Polygenic Scores for Major Depressive Disorder and Risk of Alcohol Dependence. JAMA Psychiatry. 2017 Nov 1;74(11):1153-1160. https://doi.org/10.1001/jamapsychiatry.2017.2269
Andersen, Allan M. ; Pietrzak, Robert H. ; Kranzler, Henry R. ; Ma, Li ; Zhou, Hang ; Liu, Xiaoming ; Kramer, John ; Kuperman, Samuel ; Edenberg, Howard ; Nurnberger, John ; Rice, John P. ; Tischfield, Jay A. ; Goate, Alison ; Foroud, Tatiana ; 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. / Polygenic Scores for Major Depressive Disorder and Risk of Alcohol Dependence. In: JAMA Psychiatry. 2017 ; Vol. 74, No. 11. pp. 1153-1160.
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title = "Polygenic Scores for Major Depressive Disorder and Risk of Alcohol Dependence",
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.",
author = "Andersen, {Allan M.} and Pietrzak, {Robert H.} and Kranzler, {Henry R.} and Li Ma and Hang Zhou and Xiaoming Liu and John Kramer and Samuel Kuperman and Howard Edenberg and John Nurnberger and Rice, {John P.} and Tischfield, {Jay A.} and Alison Goate and Tatiana Foroud and Meyers, {Jacquelyn L.} and Bernice Porjesz and Dick, {Danielle M.} and Victor Hesselbrock and Eric Boerwinkle and Southwick, {Steven M.} and Krystal, {John H.} and Weissman, {Myrna M.} and Levinson, {Douglas F.} and Potash, {James B.} and Joel Gelernter and Shizhong Han",
year = "2017",
month = "11",
day = "1",
doi = "10.1001/jamapsychiatry.2017.2269",
language = "English (US)",
volume = "74",
pages = "1153--1160",
journal = "JAMA Psychiatry",
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TY - JOUR

T1 - Polygenic Scores for Major Depressive Disorder and Risk of Alcohol Dependence

AU - Andersen, Allan M.

AU - Pietrzak, Robert H.

AU - Kranzler, Henry R.

AU - Ma, Li

AU - Zhou, Hang

AU - Liu, Xiaoming

AU - Kramer, John

AU - Kuperman, Samuel

AU - Edenberg, Howard

AU - Nurnberger, John

AU - Rice, John P.

AU - Tischfield, Jay A.

AU - Goate, Alison

AU - Foroud, Tatiana

AU - Meyers, Jacquelyn L.

AU - Porjesz, Bernice

AU - Dick, Danielle M.

AU - Hesselbrock, Victor

AU - Boerwinkle, Eric

AU - Southwick, Steven M.

AU - Krystal, John H.

AU - Weissman, Myrna M.

AU - Levinson, Douglas F.

AU - Potash, James B.

AU - Gelernter, Joel

AU - Han, Shizhong

PY - 2017/11/1

Y1 - 2017/11/1

N2 - 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.

AB - 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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