Evidence of causal effect of major depression on alcohol dependence: findings from the psychiatric genomics consortium
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Polimanti, Renato | Peterson, Roseann | Ong, Jue-Sheng | Macgregor, Stuart | Edwards, Alexis | Clarke, Toni-Kim | Frank, Josef | Gerring, Zachary | Gillespie, Nathan | Lind, Penelope | Maes, Hermine | Martin, Nicholas | Mbarek, Hamdi | Medland, Sarah | Streit, Fabian | Agrawal, Arpana | Edenberg, Howard | Kendler, Kenneth | Lewis, Cathryn | Sullivan, Patrick | Wray, Naomi | Gelernter, Joel | Derks, Eske | Wray, Naomi R. | Ripke, Stephan | Mattheisen, Manuel | Trzaskowski, Maciej | Byrne, Enda M. | Abdellaoui, Abdel | Adams, Mark J. | Agerbo, Esben | Air, Tracy M. | Andlauer, Till M. F. | Bacanu, Silviu-Alin | Bækvad-Hansen, Marie | Beekman, Aartjan F. T. | Bigdeli, Tim B. | Binder, Elisabeth B. | Blackwood, Douglas R. H. | Bryois, Julien | Buttenschøn, Henriette N. | Bybjerg-Grauholm, Jonas | Cai, Na | Castelao, Enrique | Christensen, Jane Hvarregaard | Coleman, Jonathan I. R. | Colodro-Conde, Lucía | Couvy-Duchesne, Baptiste | Craddock, Nick | Crawford, Gregory E. | Crowley, Cheynna A. | Dashti, Hassan S. | Davies, Gail | Deary, Ian J. | Degenhardt, Franziska | Derks, Eske M. | Direk, Nese | Dolan, Conor V. | Dunn, Erin C. | Eley, Thalia C. | Eriksson, Nicholas | Escott-Price, Valentina | Kiadeh, Farnush Hassan Farhadi | Finucane, Hilary K. | Forstner, Andreas J. | Gaspar, Héléna A. | Gill, Michael | Giusti-Rodríguez, Paola | Goes, Fernando S. | Gordon, Scott D. | Grove, Jakob | Hall, Lynsey S. | Hannon, Eilis | Hansen, Christine Søholm | Hansen, Thomas F. | Herms, Stefan | Hickie, Ian B. | Hoffmann, Per | Homuth, Georg | Horn, Carsten | Hottenga, Jouke-Jan | Hougaard, David M. | Hu, Ming | Hyde, Craig L. | Ising, Marcus | Jansen, Rick | Jin, Fulai | Jorgenson, Eric | Knowles, James A. | Kohane, Isaac S. | Kraft, Julia | Kretzschmar, Warren W. | Krogh, Jesper | Kutalik, Zoltán | Lane, Jacqueline M. | Li, Yihan | Li, Yun | Lind, Penelope A. | Liu, Xiaoxiao | Lu, Leina | Macintyre, Donald J. | Mackinnon, Dean F. | Maier, Robert M. | Maier, Wolfgang | Marchini, Jonathan | Mcgrath, Patrick | Mcguffin, Peter | Medland, Sarah E. | Mehta, Divya | Middeldorp, Christel M. | Mihailov, Evelin | Milaneschi, Yuri | Milani, Lili | Mill, Jonathan | Mondimore, Francis M. | Montgomery, Grant W. | Mostafavi, Sara | Mullins, Niamh | Nauck, Matthias | Ng, Bernard | Nivard, Michel G. | Nyholt, Dale R. | O’reilly, Paul F. | Oskarsson, Hogni | Owen, Michael J. | Painter, Jodie N. | Pedersen, Carsten Bøcker | Pedersen, Marianne Giørtz | Peterson, Roseann E. | Pettersson, Erik | Peyrot, Wouter J. | Pistis, Giorgio | Posthuma, Danielle | Purcell, Shaun M. | Quiroz, Jorge A. | Qvist, Per | Rice, John P. | Riley, Brien P. | Rivera, Margarita | Mirza, Saira Saeed | Saxena, Richa | Schoevers, Robert | Schulte, Eva C. | Shen, Ling | Shi, Jianxin | Shyn, Stanley I. | Sigurdsson, Engilbert | Sinnamon, Grant B. C. | Smit, Johannes H. | Smith, Daniel J. | Stefansson, Hreinn | Steinberg, Stacy | Stockmeier, Craig A. | Strohmaier, Jana | Tansey, Katherine E. | Teismann, Henning | Teumer, Alexander | Thompson, Wesley | Thomson, Pippa A. | Thorgeirsson, Thorgeir E. | Tian, Chao | Traylor, Matthew | Treutlein, Jens | Trubetskoy, Vassily | Uitterlinden, André G. | Umbricht, Daniel | Auwera, Sandra van Der | Hemert, Albert M. Van | Viktorin, Alexander | Visscher, Peter M. | Wang, Yunpeng | Webb, Bradley T. | Weinsheimer, Shantel Marie | Wellmann, Jürgen | Willemsen, Gonneke | Witt, Stephanie H. | Wu, Yang | Xi, Hualin S. | Yang, Jian | Zhang, Futao | Arolt, Volker | Baune, Bernhard T. | Berger, Klaus | Boomsma, Dorret I. | Cichon, Sven | Dannlowski, Udo | Geus, E. C. J. De | Depaulo, J. Raymond | Domenici, Enrico | Domschke, Katharina | Esko, Tõnu | Grabe, Hans J. | Hamilton, Steven P. | Hayward, Caroline | Heath, Andrew C. | Hinds, David A. | Kendler, Kenneth S. | Kloiber, Stefan | Lewis, Glyn | Li, Qingqin S. | Lucae, Susanne | Madden, Pamela F. A. | Magnusson, Patrik K. | Martin, Nicholas G. | Mcintosh, Andrew M. | Metspalu, Andres | Mors, Ole | Mortensen, Preben Bo | Müller-Myhsok, Bertram | Nordentoft, Merete | Nöthen, Markus M. | O’donovan, Michael C. | Paciga, Sara A. | Pedersen, Nancy L. | Penninx, Brenda W. J. H. | Perlis, Roy H. | Porteous, David J. | Potash, James B. | Preisig, Martin | Rietschel, Marcella | Schaefer, Catherine | Schulze, Thomas G. | Smoller, Jordan W. | Stefansson, Kari | Tiemeier, Henning | Uher, Rudolf | Völzke, Henry | Weissman, Myrna M. | Werge, Thomas | Winslow, Ashley R. | Lewis, Cathryn M. | Levinson, Douglas F. | Breen, Gerome | Børglum, Anders D. | Sullivan, Patrick F. | Walters, Raymond K. | Johnson, Emma C. | Mcclintick, Jeanette N. | Adkins, Amy E. | Aliev, Fazil | Batzler, Anthony | Bertelsen, Sarah | Biernacka, Joanna M. | Chen, Li-Shiun | Chou, Yi-Ling | Docherty, Anna R. | Edwards, Alexis C. | Fontanillas, Pierre | Foo, Jerome C. | Fox, Louis | Giegling, Ina | Gordon, Scott | Hack, Laura M. | Hartmann, Annette M. | Hartz, Sarah M. | Heilmann-Heimbach, Stefanie | Hodgkinson, Colin | Hottenga, Jouke Jan | Kennedy, Martin A. | Alanne-Kinnunen, Mervi | Konte, Bettina | Lahti, Jari | Lahti-Pulkkinen, Marius | Lai, Dongbing | Ligthart, Lannie | Loukola, Anu | Maher, Brion S. | Mcqueen, Matthew B. | Meyers, Jacquelyn L. | Palviainen, Teemu | Pearson, John F. | Ripatti, Samuli | Ryu, Euijung | Saccone, Nancy L. | Salvatore, Jessica E. | Sanchez-Roige, Sandra | Schwandt, Melanie | Sherva, Richard | Thomas, Nathaniel | Wang, Jen-Chyong | Wedow, Robbee | Wetherill, Leah | Wills, Amanda G. | Boardman, Jason D. | Chen, Danfeng | Choi, Doo-Sup | Copeland, William E. | Culverhouse, Robert C. | Dahmen, Norbert | Degenhardt, Louisa | Domingue, Benjamin W. | Elson, Sarah L. | Frye, Mark A. | Gäbel, Wolfgang | Keyes, Margaret | Kiefer, Falk | Kramer, John | Kuperman, Samuel | Lynskey, Michael T. | Mann, Karl | Männistö, Satu | Murray, Alison D. | Nurnberger, John I. | Palotie, Aarno | Preuss, Ulrich | Räikkönen, Katri | Reynolds, Maureen D | Ridinger, Monika | Scherbaum, Norbert | Schuckit, Marc A. | Soyka, Michael | Witt, Stephanie | Wodarz, Norbert | Zill, Peter | Adkins, Daniel E. | Boden, Joseph M. | Bierut, Laura J. | Brown, Sandra A. | Bucholz, Kathleen K. | Costello, E. Jane | Wit, Harriet De | Diazgranados, Nancy | Dick, Danielle M. | Eriksson, Johan G. | Farrer, Lindsay A. | Foroud, Tatiana M. | Goate, Alison M. | Goldman, David | Grucza, Richard A. | Hancock, Dana | Harris, Kathleen Mullan | Hesselbrock, Victor | Hewitt, John K. | Hopfer, Christian J. | Horwood, John | Iacono, William | Johnson, Eric O. | Kaprio, Jaakko A. | Karpyak, Victor M. | Kranzler, Henry R. | Krauter, Kenneth | Lichtenstein, Paul | Mcgue, Matt | Mackillop, James | Madden, Pamela A. F. | Maes, Hermine H. | Magnusson, Patrik | Nelson, Elliot C. | Palmer, Abraham A. | Porjesz, Bernice | Rose, Richard | Rujescu, Dan | Shen, Pei-Hong | Silberg, Judy | Stallings, Michael C. | Tarter, Ralph E. | Vanyukov, Michael M. | Vrieze, Scott | Wall, Tamara L. | Whitfield, John B. | Zhao, Hongyu | Neale, Benjamin M. | Edenberg, Howard J. | Agee, Michelle | Alipanahi, Babak | Auton, Adam | Bell, Robert K. | Bryc, Katarzyna | Furlotte, Nicholas A. | Huber, Karen E. | Kleinman, Aaron | Litterman, Nadia K. | Mcintyre, Matthew H. | Mountain, Joanna L. | Noblin, Elizabeth S. | Northover, Carrie A.M. | Pitts, Steven J. | Sathirapongsasuti, J. Fah | Sazonova, Olga V. | Shelton, Janie F. | Shringarpure, Suyash | Tung, Joyce Y. | Vacic, Vladimir | Wilson, Catherine H.
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CCSD ; Cambridge University Press (CUP) -
International audience.
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.
