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

Published online by Cambridge University Press:  01 April 2019

Renato Polimanti*
Affiliation:
Department of Psychiatry, Yale University School of Medicine and VA CT Healthcare Center, West Haven, Connecticut, USA
Roseann E. Peterson
Affiliation:
Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, USA
Jue-Sheng Ong
Affiliation:
Statistical Genetics, QIMR Berghofer, Brisbane, Australia
Stuart MacGregor
Affiliation:
Statistical Genetics, QIMR Berghofer, Brisbane, Australia
Alexis C. Edwards
Affiliation:
Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, USA
Toni-Kim Clarke
Affiliation:
Division of Psychiatry, University of Edinburgh, Edinburgh, UK
Josef Frank
Affiliation:
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Baden-Württemberg, Germany
Zachary Gerring
Affiliation:
Translational Neurogenomics, QIMR Berghofer, Brisbane, Australia
Nathan A. Gillespie
Affiliation:
Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, USA
Penelope A. Lind
Affiliation:
Psychiatric Genetics, QIMR Berghofer, Brisbane, Australia
Hermine H. Maes
Affiliation:
Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, USA Department of Human and Molecular Genetics, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA
Nicholas G. Martin
Affiliation:
Genetic Epidemiology, QIMR Berghofer, Brisbane, Australia
Hamdi Mbarek
Affiliation:
Department of Biological Psychology & EMGO + Institute for Health and Care Research, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
Sarah E. Medland
Affiliation:
Psychiatric Genetics, QIMR Berghofer, Brisbane, Australia
Fabian Streit
Affiliation:
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Baden-Württemberg, Germany
Arpana Agrawal
Affiliation:
Department of Psychiatry, Washington University School of Medicine, Saint Louis, Missouri, USA
Howard J. Edenberg
Affiliation:
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
Kenneth S. Kendler
Affiliation:
Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, USA
Cathryn M. Lewis
Affiliation:
Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's CollegeLondon, UK
Patrick F. Sullivan
Affiliation:
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Naomi R. Wray
Affiliation:
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia Queensland Brain Institute, The University of Queensland, Brisbane, Australia
Joel Gelernter
Affiliation:
Department of Psychiatry, Yale University School of Medicine and VA CT Healthcare Center, West Haven, Connecticut, USA Departments of Genetics and Neuroscience, Yale University School of Medicine, New Haven, Connecticut,USA
Eske M. Derks
Affiliation:
Translational Neurogenomics, QIMR Berghofer, Brisbane, Australia
Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium
Affiliation:
Department of Psychiatry, Yale University School of Medicine and VA CT Healthcare Center, West Haven, Connecticut, USA Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, USA Statistical Genetics, QIMR Berghofer, Brisbane, Australia Division of Psychiatry, University of Edinburgh, Edinburgh, UK Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Baden-Württemberg, Germany Translational Neurogenomics, QIMR Berghofer, Brisbane, Australia Department of Human and Molecular Genetics, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA Psychiatric Genetics, QIMR Berghofer, Brisbane, Australia Genetic Epidemiology, QIMR Berghofer, Brisbane, Australia Department of Biological Psychology & EMGO + Institute for Health and Care Research, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands 23andMe, Inc., Mountain View, California, USA Department of Psychiatry, Washington University School of Medicine, Saint Louis, Missouri, USA Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's CollegeLondon, UK Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia Queensland Brain Institute, The University of Queensland, Brisbane, Australia Departments of Genetics and Neuroscience, Yale University School of Medicine, New Haven, Connecticut,USA
Substance Use Disorder Working Group of the Psychiatric Genomics Consortium
Affiliation:
Department of Psychiatry, Yale University School of Medicine and VA CT Healthcare Center, West Haven, Connecticut, USA Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, USA Statistical Genetics, QIMR Berghofer, Brisbane, Australia Division of Psychiatry, University of Edinburgh, Edinburgh, UK Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Baden-Württemberg, Germany Translational Neurogenomics, QIMR Berghofer, Brisbane, Australia Department of Human and Molecular Genetics, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA Psychiatric Genetics, QIMR Berghofer, Brisbane, Australia Genetic Epidemiology, QIMR Berghofer, Brisbane, Australia Department of Biological Psychology & EMGO + Institute for Health and Care Research, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands 23andMe, Inc., Mountain View, California, USA Department of Psychiatry, Washington University School of Medicine, Saint Louis, Missouri, USA Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's CollegeLondon, UK Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia Queensland Brain Institute, The University of Queensland, Brisbane, Australia Departments of Genetics and Neuroscience, Yale University School of Medicine, New Haven, Connecticut,USA
23andMe Research Team
Affiliation:
23andMe, Inc., Mountain View, California, USA
*
Author for correspondence: Renato Polimanti, E-mail: renato.polimanti@yale.edu

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.

Type
Original Articles
Copyright
Copyright © Cambridge University Press 2019 

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Footnotes

*

Joint first authors

Full list of Major Depressive Disorder Working Group members appears in Acknowledgments and Supplemental Material

Full list of Substance Use Disorder Working Group members appears in Acknowledgments and Supplemental Material

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