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 J. Edenberg; Kenneth S. Kendler; Cathryn M. Lewis; Patrick F. Sullivan; Naomi R. Wray; Joel Gelernter; Eske M. Derks

doi:10.1017/S0033291719000667

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 J. Edenberg, Kenneth S. Kendler, Cathryn M. Lewis, Patrick F. SullivanNaomi R. Wray, Joel Gelernter, Eske M. Derks

Research output: Contribution to journal › Article › peer-review

76 Scopus citations

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.

Original language	English
Pages (from-to)	1218-1226
Number of pages	9
Journal	Psychological Medicine
Volume	49
Issue number	7
DOIs	https://doi.org/10.1017/S0033291719000667
State	Published - 1 May 2019
Externally published	Yes

Keywords

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

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10.1017/S0033291719000667

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Polimanti, R., Peterson, R. E., Ong, J. S., MacGregor, S., Edwards, A. C., Clarke, T. K., Frank, J., Gerring, Z., Gillespie, N. A., Lind, P. A., Maes, H. H., Martin, N. G., Mbarek, H., Medland, S. E., Streit, F., Agrawal, A., Edenberg, H. J., Kendler, K. S., Lewis, C. M., ... Derks, E. M. (2019). Evidence of causal effect of major depression on alcohol dependence: Findings from the psychiatric genomics consortium. Psychological Medicine, 49(7), 1218-1226. https://doi.org/10.1017/S0033291719000667

@article{ae78f3f83feb4c57a7d7a40e9c09a2db,

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.",

keywords = "Alcohol consumption, Mendelian randomization, alcohol dependence, genetic correlation, genome-wide association, major depression",

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 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.}",

note = "Publisher Copyright: {\textcopyright} 2019 Cambridge University Press.",

year = "2019",

month = may,

day = "1",

doi = "10.1017/S0033291719000667",

language = "English",

volume = "49",

pages = "1218--1226",

journal = "Psychological Medicine",

issn = "0033-2917",

publisher = "Cambridge University Press",

number = "7",

}

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, HJ, 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, vol. 49, no. 7, pp. 1218-1226. https://doi.org/10.1017/S0033291719000667

TY - JOUR

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 J.

AU - Kendler, Kenneth S.

AU - Lewis, Cathryn M.

AU - Sullivan, Patrick F.

AU - Wray, Naomi R.

AU - Gelernter, Joel

AU - Derks, Eske M.

PY - 2019/5/1

Y1 - 2019/5/1

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.

KW - Alcohol consumption

KW - Mendelian randomization

KW - alcohol dependence

KW - genetic correlation

KW - genome-wide association

KW - major depression

UR - http://www.scopus.com/inward/record.url?scp=85063776914&partnerID=8YFLogxK

U2 - 10.1017/S0033291719000667

DO - 10.1017/S0033291719000667

M3 - Article

C2 - 30929657

AN - SCOPUS:85063776914

SN - 0033-2917

VL - 49

SP - 1218

EP - 1226

JO - Psychological Medicine

JF - Psychological Medicine

IS - 7

ER -

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

Abstract

Keywords

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