Evidence of causal effect of major depression on alcohol dependence

Findings from the psychiatric genomics consortium

Renato Polimanti, Roseann E. Peterson, Jue Sheng Ong, Stuart MacGregor, Alexis C. Edwards, Toni Kim Clarke, Josef Frank, Zachary Gerring, Nathan A. Gillespie, Penelope A. Lind, Hermine H. Maes, Nicholas G. Martin, Hamdi Mbarek, Sarah E. Medland, Fabian Streit, Arpana Agrawal, Howard Edenberg, Kenneth S. Kendler, Cathryn M. Lewis, Patrick F. Sullivan & 3 others Naomi R. Wray, Joel Gelernter, Eske M. Derks

Research output: Contribution to journalArticle

Abstract

BackgroundDespite 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.MethodsLinkage 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).ResultsPositive 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.ConclusionThis 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.

Original languageEnglish (US)
JournalPsychological Medicine
DOIs
StatePublished - Jan 1 2019

Fingerprint

Genomics
Alcoholism
Psychiatry
Depression
Alcohol Drinking
Mendelian Randomization Analysis
Genome
Random Allocation
Causality
Comorbidity
Public Health

Keywords

  • Alcohol consumption
  • alcohol dependence
  • genetic correlation
  • genome-wide association
  • major depression
  • Mendelian randomization

ASJC Scopus subject areas

  • Applied Psychology
  • Psychiatry and Mental health

Cite this

Evidence of causal effect of major depression on alcohol dependence : Findings from the psychiatric genomics consortium. / 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; Agrawal, Arpana; Edenberg, Howard; Kendler, Kenneth S.; Lewis, Cathryn M.; Sullivan, Patrick F.; Wray, Naomi R.; Gelernter, Joel; Derks, Eske M.

In: Psychological Medicine, 01.01.2019.

Research output: Contribution to journalArticle

Polimanti, R, Peterson, RE, Ong, JS, MacGregor, S, Edwards, AC, Clarke, TK, Frank, J, Gerring, Z, Gillespie, NA, Lind, PA, Maes, HH, Martin, NG, Mbarek, H, Medland, SE, Streit, F, Agrawal, A, Edenberg, H, Kendler, KS, Lewis, CM, Sullivan, PF, Wray, NR, Gelernter, J & Derks, EM 2019, 'Evidence of causal effect of major depression on alcohol dependence: Findings from the psychiatric genomics consortium', Psychological Medicine. https://doi.org/10.1017/S0033291719000667
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 ; Agrawal, Arpana ; Edenberg, Howard ; Kendler, Kenneth S. ; Lewis, Cathryn M. ; Sullivan, Patrick F. ; Wray, Naomi R. ; Gelernter, Joel ; Derks, Eske M. / Evidence of causal effect of major depression on alcohol dependence : Findings from the psychiatric genomics consortium. In: Psychological Medicine. 2019.
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abstract = "BackgroundDespite 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.MethodsLinkage 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).ResultsPositive 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.ConclusionThis 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.",
keywords = "Alcohol consumption, alcohol dependence, genetic correlation, genome-wide association, major depression, Mendelian randomization",
author = "Renato Polimanti and Peterson, {Roseann E.} and Ong, {Jue Sheng} and Stuart MacGregor and Edwards, {Alexis C.} and Clarke, {Toni Kim} and Josef Frank and Zachary Gerring and Gillespie, {Nathan A.} and Lind, {Penelope A.} and Maes, {Hermine H.} and Martin, {Nicholas G.} and Hamdi Mbarek and Medland, {Sarah E.} and Fabian Streit and Arpana Agrawal and Howard Edenberg and Kendler, {Kenneth S.} and Lewis, {Cathryn M.} and Sullivan, {Patrick F.} and Wray, {Naomi R.} and Joel Gelernter and Derks, {Eske M.}",
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T1 - Evidence of causal effect of major depression on alcohol dependence

T2 - Findings from the psychiatric genomics consortium

AU - Polimanti, Renato

AU - Peterson, Roseann E.

AU - Ong, Jue Sheng

AU - MacGregor, Stuart

AU - Edwards, Alexis C.

AU - Clarke, Toni Kim

AU - Frank, Josef

AU - Gerring, Zachary

AU - Gillespie, Nathan A.

AU - Lind, Penelope A.

AU - Maes, Hermine H.

AU - Martin, Nicholas G.

AU - Mbarek, Hamdi

AU - Medland, Sarah E.

AU - Streit, Fabian

AU - Agrawal, Arpana

AU - Edenberg, Howard

AU - Kendler, Kenneth S.

AU - Lewis, Cathryn M.

AU - Sullivan, Patrick F.

AU - Wray, Naomi R.

AU - Gelernter, Joel

AU - Derks, Eske M.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - BackgroundDespite 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.MethodsLinkage 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).ResultsPositive 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.ConclusionThis 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.

AB - BackgroundDespite 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.MethodsLinkage 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).ResultsPositive 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.ConclusionThis 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.

KW - Alcohol consumption

KW - alcohol dependence

KW - genetic correlation

KW - genome-wide association

KW - major depression

KW - Mendelian randomization

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