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 & 3 others Naomi R. Wray, Joel Gelernter, Eske M. Derks

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.

Original languageEnglish
Pages (from-to)1218-1226
Number of pages9
JournalPsychological Medicine
Volume49
Issue number7
Early online date1 Apr 2019
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

Keywords

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

Cite this

Polimanti, R., Peterson, R. E., Ong, J. S., MacGregor, S., Edwards, A. C., Clarke, T. K., ... 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
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 J. ; 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 ; Vol. 49, No. 7. pp. 1218-1226.
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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.",
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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.}",
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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

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

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 - 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

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.

KW - Alcohol consumption

KW - alcohol dependence

KW - genetic correlation

KW - genome-wide association

KW - major depression

KW - Mendelian randomization

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