Renato Polimanti1, Roseann E Peterson2, Jue-Sheng Ong3, Stuart MacGregor3, Alexis C Edwards2, Toni-Kim Clarke4, Josef Frank5, Zachary Gerring6, Nathan A Gillespie2, Penelope A Lind7, Hermine H Maes2, Nicholas G Martin8, Hamdi Mbarek9, Sarah E Medland7, Fabian Streit5, Arpana Agrawal10, Howard J Edenberg11, Kenneth S Kendler2, Cathryn M Lewis12, Patrick F Sullivan13, Naomi R Wray14, Joel Gelernter1, Eske M Derks6. 1. Department of Psychiatry,Yale University School of Medicine and VA CT Healthcare Center,West Haven, Connecticut,USA. 2. Department of Psychiatry,Virginia Institute for Psychiatric and Behavioral Genetics,Virginia Commonwealth University, Richmond, Virginia,USA. 3. Statistical Genetics,QIMR Berghofer, Brisbane,Australia. 4. Division of Psychiatry,University of Edinburgh,Edinburgh,UK. 5. Department of Genetic Epidemiology in Psychiatry,Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University,Mannheim, Baden-Württemberg,Germany. 6. Translational Neurogenomics, QIMR Berghofer,Brisbane,Australia. 7. Psychiatric Genetics, QIMR Berghofer,Brisbane,Australia. 8. Genetic Epidemiology, QIMR Berghofer,Brisbane,Australia. 9. Department of Biological Psychology & EMGO + Institute for Health and Care Research,Vrije Universiteit Amsterdam, Amsterdam,the Netherlands. 10. Department of Psychiatry,Washington University School of Medicine,Saint Louis, Missouri,USA. 11. Department of Biochemistry and Molecular Biology,Indiana University School of Medicine,Indianapolis, Indiana,USA. 12. Social, Genetic and Developmental Psychiatry Centre,Institute of Psychiatry, Psychology & Neuroscience, King's CollegeLondon,UK. 13. Department of Medical Epidemiology and Biostatistics,Karolinska Institutet,Stockholm,Sweden. 14. Institute for Molecular Bioscience, The University of Queensland,Brisbane,Australia.
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.
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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