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Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

Authors :
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
Bøcker Pedersen, Carsten
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
Giørtz Pedersen, Marianne
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
Olde Loohuis, Loes M.
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.
Søholm Hansen, Christine
Soler Artigas, Maria
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
Yang, Jessica Mei 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, Tõnu
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
Shannon Weickert, Cynthia
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.
Source :
Nature Genetics; June 2021, Vol. 53 Issue: 6 p817-829, 13p
Publication Year :
2021

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

Language :
English
ISSN :
10614036 and 15461718
Volume :
53
Issue :
6
Database :
Supplemental Index
Journal :
Nature Genetics
Publication Type :
Periodical
Accession number :
ejs56378084
Full Text :
https://doi.org/10.1038/s41588-021-00857-4