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Abstract
Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
Details
Title
Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology
Author
Mullins, Niamh; Forstner, Andreas J; O'Connell, Kevin S; Coombes, Brandon; Coleman, Jonathan R I; Qiao, Zhen; Als, Thomas D; Bigdeli, Tim B; Børte, Sigrid; Bryois, Julien; Charney, Alexander W; Drange, Ole Kristian; Gandal, Michael J; Hagenaars, Saskia P; Ikeda, Masashi; Kamitaki, Nolan; Kim, Minsoo; Krebs, Kristi; Panagiotaropoulou, Georgia; Schilder, Brian M; Sloofman, Laura G; Steinberg, Stacy; Trubetskoy, Vassily; Winsvold, Bendik S; Won, Hong-Hee; Abramova, Liliya; Adorjan, Kristina; Agerbo, Esben; Al Eissa, Mariam; Albani, Diego; Alliey-Rodriguez, Ney; Anjorin, Adebayo; Antilla, Verneri; Antoniou, Anastasia; Awasthi, Swapnil; Baek, Ji Hyun; Bækvad-Hansen, Marie; Bass, Nicholas; Bauer, Michael; Beins, Eva C; Bergen, Sarah E; Birner, Armin; Pedersen, Carsten Bøcker; Bøen, Erlend; Boks, Marco P; Bosch, Rosa; Brum, Murielle; Brumpton, Ben M; Brunkhorst-Kanaan, Nathalie; Budde, Monika; Bybjerg-Grauholm, Jonas; Byerley, William; Cairns, Murray; Casas, Miquel; Cervantes, Pablo; Clarke, Toni-Kim; Cruceanu, Cristiana; Cuellar-Barboza, Alfredo; Cunningham, Julie; Curtis, David; Czerski, Piotr M; Dale, Anders M; Dalkner, Nina; David, Friederike S; Degenhardt, Franziska; Djurovic, Srdjan; Dobbyn, Amanda L; Douzenis, Athanassios; Elvsåshagen, Torbjørn; ESCOTT-PRICE, Valentina; Ferrier, I Nicol; Fiorentino, Alessia; Foroud, Tatiana M; Forty, Liz; Frank, Josef; Frei, Oleksandr; Freimer, Nelson B; Frisén, Louise; Gade, Katrin; Garnham, Julie; Gelernter, Joel; Pedersen, Marianne Giørtz; Gizer, Ian R; Gordon, Scott D; Gordon-Smith, Katherine; Greenwood, Tiffany A; Grove, Jakob; Guzman-Parra, José; Ha, Kyooseob; Haraldsson, Magnus; Hautzinger, Martin; Heilbronner, Urs; Hellgren, Dennis; Herms, Stefan; Hoffmann, Per; Holmans, Peter A; Huckins, Laura; Jamain, Stéphane; Johnson, Jessica S; Kalman, Janos L; Kamatani, Yoichiro; Kennedy, James L; Kittel-Schneider, Sarah; Knowles, James A; Kogevinas, Manolis; Koromina, Maria; Kranz, Thorsten M; Kranzler, Henry R; Kubo, Michiaki; Kupka, Ralph; Kushner, Steven A; Lavebratt, Catharina; Lawrence, Jacob; Leber, Markus; Lee, Heon-Jeong; Lee, Phil H; Levy, Shawn E; Lewis, Catrin; Liao, Calwing; Lucae, Susanne; Lundberg, Martin; Macintyre, Donald J; Magnusson, Sigurdur H; Maier, Wolfgang; Maihofer, Adam; Malaspina, Dolores; Maratou, Eirini; Martinsson, Lina; Mattheisen, Manuel; McCarroll, Steven A; McGregor, Nathaniel W; McGuffin, Peter; McKay, James D; Medeiros, Helena; Medland, Sarah E; Millischer, Vincent; Montgomery, Grant W; Moran, Jennifer L; Morris, Derek W; Mühleisen, Thomas W; O'Brien, Niamh; O'Donovan, Claire; Loohuis, Loes M Olde; Oruc, Lilijana; Papiol, Sergi; Pardiñas, Antonio F; Perry, Amy; Pfennig, Andrea; Porichi, Evgenia; Potash, James B; Quested, Digby; Raj, Towfique; Rapaport, Mark H; Depaulo, J Raymond; Regeer, Eline J; Rice, John P; Rivas, Fabio; Rivera, Margarita; Roth, Julian; Roussos, Panos; Ruderfer, Douglas M; SÁNCHEZ-MORA, Cristina; Schulte, Eva C; Senner, Fanny; Sharp, Sally; Shilling, Paul D; Sigurdsson, Engilbert; Sirignano, Lea; Slaney, Claire; Smeland, Olav B; Smith, Daniel J; Sobell, Janet L; Hansen, Christine Søholm; Artigas, Maria Soler; Spijker, Anne T; Stein, Dan J; Strauss, John S; Świątkowska, Beata; Terao, Chikashi; Thorgeirsson, Thorgeir E; Toma, Claudio; Tooney, Paul; Tsermpini, Evangelia-Eirini; Vawter, Marquis P; Vedder, Helmut; Walters, James T R; Witt, Stephanie H; Xi, Simon; Xu, Wei; Mei, Jessica; Yang, Kay; Young, Allan H; Young, Hannah; Zandi, Peter P; Zhou, Hang; Zillich, Lea; Adolfsson, Rolf; Agartz, Ingrid; Alda, Martin; Alfredsson, Lars; Babadjanova, Gulja; Backlund, Lena; Baune, Bernhard T; Bellivier, Frank; Bengesser, Susanne; Berrettini, Wade H; Blackwood, Douglas H R; Boehnke, Michael; Børglum, Anders D; Breen, Gerome; Carr, Vaughan J; Catts, Stanley; Corvin, Aiden; Craddock, Nicholas; Dannlowski, Udo; Dikeos, Dimitris; Esko, Tonu; Etain, Bruno; Ferentinos, Panagiotis; Frye, Mark; Fullerton, Janice M; Gawlik, Micha; Gershon, Elliot S; Goes, Fernando S; Green, Melissa J; Grigoroiu-Serbanescu, Maria; Hauser, Joanna; Henskens, Frans; Hillert, Jan; Hong, Kyung Sue; Hougaard, David M; Hultman, Christina M; Hveem, Kristian; Iwata, Nakao; Jablensky, Assen V; Jones, Ian; Jones, Lisa A; Kahn, René S; Kelsoe, John R; Kirov, George; Landén, Mikael; Leboyer, Marion; Lewis, Cathryn M; Li, Qingqin S; Lissowska, Jolanta; Lochner, Christine; Loughland, Carmel; Martin, Nicholas G; Mathews, Carol A; Mayoral, Fermin; McElroy, Susan L; McIntosh, Andrew M; McMahon, Francis J; Melle, Ingrid; Michie, Patricia; Milani, Lili; Mitchell, Philip B; Morken, Gunnar; Mors, Ole; Mortensen, Preben Bo; Mowry, Bryan; Müller-Myhsok, Bertram; Myers, Richard M; Neale, Benjamin M; Nievergelt, Caroline M; Nordentoft, Merete; Nöthen, Markus M; O'Donovan, Michael C; Oedegaard, Ketil J; Olsson, Tomas; Owen, Michael J; Paciga, Sara A; Pantelis, Chris; Pato, Carlos; Pato, Michele T; Patrinos, George P; Perlis, Roy H; Posthuma, Danielle; Ramos-Quiroga, Josep Antoni; Reif, Andreas; Reininghaus, Eva Z; Ribasés, Marta; Rietschel, Marcella; Ripke, Stephan; Rouleau, Guy A; Saito, Takeo; Schall, Ulrich; Schalling, Martin; Schofield, Peter R; Schulze, Thomas G; Scott, Laura J; Scott, Rodney J; Serretti, Alessandro; Weickert, Cynthia Shannon; Smoller, Jordan W; Stefansson, Hreinn; Stefansson, Kari; Stordal, Eystein; Streit, Fabian; Sullivan, Patrick F; Turecki, Gustavo; Vaaler, Arne E; Vieta, Eduard; Vincent, John B; Waldman, Irwin D; Weickert, Thomas W; Werge, Thomas; Wray, Naomi R; Zwart, JOHN-ANKER; Biernacka, Joanna M; Nurnberger, John I; Cichon, Sven; Edenberg, Howard J; Stahl, Eli A; McQuillin, Andrew; Di Florio, Arianna; Ophoff, Roel A; Andreassen, Ole A
Pages
817-2,829A-829D
Section
ARTICLES
Publication year
2021
Publication date
Jun 2021
ISSN
10614036
e-ISSN
15461718
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2540566045
Copyright
Copyright Nature Publishing Group Jun 2021