Evidence of causal effect of major depression on alcohol dependence: findings from the psychiatric genomics consortium

Major Depressive Disorder Working Group of 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 J Edenberg, Kenneth S Kendler, Cathryn M Lewis & 14 others Patrick F Sullivan, Naomi R Wray, Joel Gelernter, Eske M Derks, Abdel Abdellaoui, C.V. Dolan, J.J. Hottenga, C.M. Middeldorp, M.G. Nivard, Danielle Posthuma, Gonneke Willemsen, D.I. Boomsma, Eco JC de Geus, R.S.L. Ligthart

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

BACKGROUND: Despite 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.

METHODS: Linkage 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).

RESULTS: Positive genetic correlation was observed between MD and AD (rgMD-AD = + 0.47, P = 6.6 × 10-10). AC-quantity showed positive genetic correlation with both AD (rgAD-AC quantity = + 0.75, P = 1.8 × 10-14) and MD (rgMD-AC quantity = + 0.14, P = 2.9 × 10-7), while there was negative correlation of AC-frequency with MD (rgMD-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.

CONCLUSION: This 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.

LanguageEnglish
Pages1218-1226
Number of pages9
JournalPsychological Medicine
Volume49
Issue number7
DOIs
Publication statusPublished - May 2019

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

Cite this

@article{e2be74b41b0f4e94ad14c3ff333cb6a5,
title = "Evidence of causal effect of major depression on alcohol dependence: findings from the psychiatric genomics consortium",
abstract = "BACKGROUND: Despite 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.METHODS: Linkage 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).RESULTS: Positive genetic correlation was observed between MD and AD (rgMD-AD = + 0.47, P = 6.6 × 10-10). AC-quantity showed positive genetic correlation with both AD (rgAD-AC quantity = + 0.75, P = 1.8 × 10-14) and MD (rgMD-AC quantity = + 0.14, P = 2.9 × 10-7), while there was negative correlation of AC-frequency with MD (rgMD-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.CONCLUSION: This 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.",
author = "{Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium} and Renato Polimanti and Peterson, {Roseann E} and Jue-Sheng Ong and Stuart MacGregor and Edwards, {Alexis C} and Toni-Kim Clarke 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 Edenberg, {Howard J} and Kendler, {Kenneth S} and Lewis, {Cathryn M} and Sullivan, {Patrick F} and Wray, {Naomi R} and Joel Gelernter and Derks, {Eske M} and Abdel Abdellaoui and C.V. Dolan and J.J. Hottenga and C.M. Middeldorp and M.G. Nivard and Danielle Posthuma and Gonneke Willemsen and D.I. Boomsma and {de Geus}, {Eco JC} and R.S.L. Ligthart",
year = "2019",
month = "5",
doi = "10.1017/S0033291719000667",
language = "English",
volume = "49",
pages = "1218--1226",
journal = "Psychological Medicine",
issn = "0033-2917",
publisher = "Cambridge University Press",
number = "7",

}

Evidence of causal effect of major depression on alcohol dependence : findings from the psychiatric genomics consortium. / Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; Abdellaoui, Abdel; Dolan, C.V.; Hottenga, J.J.; Middeldorp, C.M.; Nivard, M.G.; Posthuma, Danielle; Willemsen, Gonneke; Boomsma, D.I.; de Geus, Eco JC; Ligthart, R.S.L.

In: Psychological Medicine, Vol. 49, No. 7, 05.2019, p. 1218-1226.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - Evidence of causal effect of major depression on alcohol dependence

T2 - Psychological Medicine

AU - Major Depressive Disorder Working Group of 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 J

AU - Kendler, Kenneth S

AU - Lewis, Cathryn M

AU - Sullivan, Patrick F

AU - Wray, Naomi R

AU - Gelernter, Joel

AU - Derks, Eske M

AU - Abdellaoui, Abdel

AU - Dolan, C.V.

AU - Hottenga, J.J.

AU - Middeldorp, C.M.

AU - Nivard, M.G.

AU - Posthuma, Danielle

AU - Willemsen, Gonneke

AU - Boomsma, D.I.

AU - de Geus, Eco JC

AU - Ligthart, R.S.L.

PY - 2019/5

Y1 - 2019/5

N2 - BACKGROUND: Despite 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.METHODS: Linkage 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).RESULTS: Positive genetic correlation was observed between MD and AD (rgMD-AD = + 0.47, P = 6.6 × 10-10). AC-quantity showed positive genetic correlation with both AD (rgAD-AC quantity = + 0.75, P = 1.8 × 10-14) and MD (rgMD-AC quantity = + 0.14, P = 2.9 × 10-7), while there was negative correlation of AC-frequency with MD (rgMD-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.CONCLUSION: This 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 - BACKGROUND: Despite 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.METHODS: Linkage 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).RESULTS: Positive genetic correlation was observed between MD and AD (rgMD-AD = + 0.47, P = 6.6 × 10-10). AC-quantity showed positive genetic correlation with both AD (rgAD-AC quantity = + 0.75, P = 1.8 × 10-14) and MD (rgMD-AC quantity = + 0.14, P = 2.9 × 10-7), while there was negative correlation of AC-frequency with MD (rgMD-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.CONCLUSION: This 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.

U2 - 10.1017/S0033291719000667

DO - 10.1017/S0033291719000667

M3 - Article

VL - 49

SP - 1218

EP - 1226

JO - Psychological Medicine

JF - Psychological Medicine

SN - 0033-2917

IS - 7

ER -