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Cited by 1,517Bipolar Disorder and TreatmentGenetic Associations and EpidemiologySchizophrenia research and treatment

The DOI matches its Crossref record; 117 of the 129 references it cites were found in a registry or an index.

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

Open access
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, HUNT All-In Psychiatry, 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.·2021·Nature Genetics
DOI 10.1038/s41588-021-00857-4PMC PMC8192451

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Abstract

Abstract Bipolar disorder (BD) is a heritable mental illness with complex etiology. We performed a genome-wide association study (GWAS) of 41,917 BD cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. BD 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 eQTL data implicated 15 genes robustly linked to BD via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of BD subtypes indicated high but imperfect genetic correlation between BD type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of BD, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

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Authors
Mullins, N., Forstner, A. J., O’Connell, K. S., Coombes, B., Coleman, J. R. I., Qiao, Z., Als, T. D., Bigdeli, T. B., Børte, S., Bryois, J., Charney, A. W., Drange, O. K., Gandal, M. J., Hagenaars, S. P., Ikeda, M., Kamitaki, N., Kim, M., Krebs, K., Panagiotaropoulou, G., Schilder, B. M., Sloofman, L. G., Steinberg, S., Trubetskoy, V., Winsvold, B. S., Won, H.-H., Abramova, L., Adorjan, K., Agerbo, E., Al Eissa, M., Albani, D., Alliey-Rodriguez, N., Anjorin, A., Antilla, V., Antoniou, A., Awasthi, S., Baek, J. H., Bækvad-Hansen, M., Bass, N., Bauer, M., Beins, E. C., Bergen, S. E., Birner, A., Bøcker Pedersen, C., Bøen, E., Boks, M. P., Bosch, R., Brum, M., Brumpton, B. M., Brunkhorst-Kanaan, N., Budde, M., Bybjerg-Grauholm, J., Byerley, W., Cairns, M., Casas, M., Cervantes, P., Clarke, T.-K., Cruceanu, C., Cuellar-Barboza, A., Cunningham, J., Curtis, D., Czerski, P. M., Dale, A. M., Dalkner, N., David, F. S., Degenhardt, F., Djurovic, S., Dobbyn, A. L., Douzenis, A., Elvsåshagen, T., Escott-Price, V., Ferrier, I. N., Fiorentino, A., Foroud, T. M., Forty, L., Frank, J., Frei, O., Freimer, N. B., Frisén, L., Gade, K., Garnham, J., Gelernter, J., Giørtz Pedersen, M., Gizer, I. R., Gordon, S. D., Gordon-Smith, K., Greenwood, T. A., Grove, J., Guzman-Parra, J., Ha, K., Haraldsson, M., Hautzinger, M., Heilbronner, U., Hellgren, D., Herms, S., Hoffmann, P., Holmans, P. A., Huckins, L., Jamain, S., Johnson, J. S., Kalman, J. L., Kamatani, Y., Kennedy, J. L., Kittel-Schneider, S., Knowles, J. A., Kogevinas, M., Koromina, M., Kranz, T. M., Kranzler, H. R., Kubo, M., Kupka, R., Kushner, S. A., Lavebratt, C., Lawrence, J., Leber, M., Lee, H.-J., Lee, P. H., Levy, S. E., Lewis, C., Liao, C., Lucae, S., Lundberg, M., MacIntyre, D. J., Magnusson, S. H., Maier, W., Maihofer, A., Malaspina, D., Maratou, E., Martinsson, L., Mattheisen, M., McCarroll, S. A., McGregor, N. W., McGuffin, P., McKay, J. D., Medeiros, H., Medland, S. E., Millischer, V., Montgomery, G. W., Moran, J. L., Morris, D. W., Mühleisen, T. W., O’Brien, N., O’Donovan, C., Olde Loohuis, L. M., Oruc, L., Papiol, S., Pardiñas, A. F., Perry, A., Pfennig, A., Porichi, E., Potash, J. B., Quested, D., Raj, T., Rapaport, M. H., DePaulo, J. R., Regeer, E. J., Rice, J. P., Rivas, F., Rivera, M., Roth, J., Roussos, P., Ruderfer, D. M., Sánchez-Mora, C., Schulte, E. C., Senner, F., Sharp, S., Shilling, P. D., Sigurdsson, E., Sirignano, L., Slaney, C., Smeland, O. B., Smith, D. J., Sobell, J. L., Søholm Hansen, C., Soler Artigas, M., Spijker, A. T., Stein, D. J., Strauss, J. S., Świątkowska, B., Terao, C., Thorgeirsson, T. E., Toma, C., Tooney, P., Tsermpini, E.-E., Vawter, M. P., Vedder, H., Walters, J. T. R., Witt, S. H., Xi, S., Xu, W., Yang, J. M. K., Young, A. H., Young, H., Zandi, P. P., Zhou, H., Zillich, L., Psychiatry, H. A.-I., Adolfsson, R., Agartz, I., Alda, M., Alfredsson, L., Babadjanova, G., Backlund, L., Baune, B. T., Bellivier, F., Bengesser, S., Berrettini, W. H., Blackwood, D. H. R., Boehnke, M., Børglum, A. D., Breen, G., Carr, V. J., Catts, S., Corvin, A., Craddock, N., Dannlowski, U., Dikeos, D., Esko, T., Etain, B., Ferentinos, P., Frye, M., Fullerton, J. M., Gawlik, M., Gershon, E. S., Goes, F. S., Green, M. J., Grigoroiu-Serbanescu, M., Hauser, J., Henskens, F., Hillert, J., Hong, K. S., Hougaard, D. M., Hultman, C. M., Hveem, K., Iwata, N., Jablensky, A. V., Jones, I., Jones, L. A., Kahn, R. S., Kelsoe, J. R., Kirov, G., Landén, M., Leboyer, M., Lewis, C. M., Li, Q. S., Lissowska, J., Lochner, C., Loughland, C., Martin, N. G., Mathews, C. A., Mayoral, F., McElroy, S. L., McIntosh, A. M., McMahon, F. J., Melle, I., Michie, P., Milani, L., Mitchell, P. B., Morken, G., Mors, O., Mortensen, P. B., Mowry, B., Müller-Myhsok, B., Myers, R. M., Neale, B. M., Nievergelt, C. M., Nordentoft, M., Nöthen, M. M., O’Donovan, M. C., Oedegaard, K. J., Olsson, T., Owen, M. J., Paciga, S. A., Pantelis, C., Pato, C., Pato, M. T., Patrinos, G. P., Perlis, R. H., Posthuma, D., Ramos-Quiroga, J. A., Reif, A., Reininghaus, E. Z., Ribasés, M., Rietschel, M., Ripke, S., Rouleau, G. A., Saito, T., Schall, U., Schalling, M., Schofield, P. R., Schulze, T. G., Scott, L. J., Scott, R. J., Serretti, A., Shannon Weickert, C., Smoller, J. W., Stefansson, H., Stefansson, K., Stordal, E., Streit, F., Sullivan, P. F., Turecki, G., Vaaler, A. E., Vieta, E., Vincent, J. B., Waldman, I. D., Weickert, T. W., Werge, T., Wray, N. R., Zwart, J.-A., Biernacka, J. M., Nurnberger, J. I., Cichon, S., Edenberg, H. J., Stahl, E. A., McQuillin, A., Di Florio, A., Ophoff, R. A., & Andreassen, O. A.
Affiliations
  • Icahn School of Medicine at Mount Sinai (US)
  • University of Bonn (DE)
  • Oslo University Hospital (NO)
  • Mayo Clinic (US)
  • King's College London (GB)
  • The University of Queensland (AU)
  • Aarhus University (DK)
  • SUNY Downstate Health Sciences University (US)
  • Karolinska Institutet (SE)
  • Norwegian University of Science and Technology (NO)
  • University of California, Los Angeles (US)
  • Fujita Health University (JP)
  • Broad Institute (US)
  • University of Tartu (EE)
  • Stiftung Charité (DE)
  • deCODE Genetics (Iceland) (IS)
  • Samsung (South Korea) (KR)
  • Mental Health Research Center of Russian Academy of Medical Sciences (RU)
  • Institut für Psychiatrische Phänomik und Genomik (DE)
  • Mario Negri Institute for Pharmacological Research (IT)
  • Berkshire Healthcare NHS Foundation Trust (GB)
  • National and Kapodistrian University of Athens (GR)
  • Samsung Medical Center (KR)
  • University College London (GB)
  • University Hospital Carl Gustav Carus (DE)
  • Medical University of Graz (AT)
  • Diakonhjemmet Hospital (NO)
  • University Medical Center Utrecht (NL)
  • Universitat Autònoma de Barcelona (ES)
  • University Hospital Frankfurt (DE)
  • University of California, San Francisco (US)
  • University of Newcastle Australia (AU)
  • McGill University Health Centre (CA)
  • University of Edinburgh (GB)
  • Queen Mary University of London (GB)
  • Poznan University of Medical Sciences (PL)
  • University of California San Diego (US)
  • Newcastle University (GB)
  • Indiana University Indianapolis (US)
  • Cardiff University (GB)
  • Heidelberg University (DE)
  • Universitätsmedizin Göttingen (DE)
  • Dalhousie University (CA)
  • Yale University (US)
  • University of Missouri (US)
  • QIMR Berghofer Medical Research Institute (AU)
  • Seoul National University (KR)
  • National University Hospital of Iceland (IS)
  • University of Tübingen (DE)
  • Inserm (FR)
  • RIKEN Center for Integrative Medical Sciences (JP)
  • Centre for Addiction and Mental Health (CA)
  • Barcelona Institute for Global Health (ES)
  • University of Patras (GR)
  • Philadelphia VA Medical Center (US)
  • GGZ inGeest (NL)
  • Erasmus MC (NL)
  • Karolinska University Hospital (SE)
  • North East London NHS Foundation Trust (GB)
  • University Hospital Cologne (DE)
  • Korea University (KR)
  • Harvard University (US)
  • HudsonAlpha Institute for Biotechnology (US)
  • Montreal Neurological Institute and Hospital (CA)
  • Max Planck Institute of Psychiatry (DE)
  • Stellenbosch University (ZA)
  • Centre international de recherche sur le cancer (FR)
  • Ollscoil na Gaillimhe – University of Galway (IE)
  • Forschungszentrum Jülich (DE)
  • University of Worcester (GB)
  • Johns Hopkins University (US)
  • Oxford Health NHS Foundation Trust (GB)
  • Emory University (US)
  • Washington University in St. Louis (US)
  • Instituto de Investigación Biomédica de Málaga (ES)
  • Universidad de Granada (ES)
  • Universitätsklinikum Würzburg (DE)
  • Vanderbilt University Medical Center (US)
  • University of Southern California (US)
  • PsyQ (NL)
  • South African Medical Research Council (ZA)
  • Nofer Institute of Occupational Medicine (PL)
  • University of California, Irvine (US)
  • University of Toronto (CA)
  • National Health Service (GB)
  • Umeå University (SE)
  • University of Pennsylvania (US)
  • University of Michigan (US)
  • Trinity College Dublin (IE)
  • UNSW Sydney (AU)
  • University of Chicago (US)
  • Statens Serum Institut (DK)
  • The University of Western Australia (AU)
  • The Maria Sklodowska-Curie National Research Institute of Oncology (PL)
  • University of Florida (US)
  • Lindner Center of HOPE (US)
  • National Institute of Mental Health (US)
  • University of Oslo (NO)
  • Massachusetts General Hospital (US)
  • University of Copenhagen (DK)
  • Haukeland University Hospital (NO)
  • Pfizer (United States) (US)
  • The University of Melbourne (AU)
  • Neuroscience Research Australia (AU)
  • University of North Carolina at Chapel Hill (US)
  • St Olav's University Hospital (NO)
  • Centro de Investigación Biomédica en Red de Salud Mental (ES)
  • SUNY Upstate Medical University (US)
Corresponding author
  • Mullins, Niamh
  • Andreassen, Ole A.
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2021-05-17
Volume
53
Issue
6
Pages
817-829
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/s41588-021-00857-4
PMC
PMC8192451
OpenAlex
W3162259891
Cited by
1,517
References
129
Citations by year
2026: 232 · 2025: 369 · 2024: 387 · 2023: 255 · 2022: 204 · 2021: 68
FWCI
41.13
Type
journal article
Language
en
Open access
Licence
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  • Nature Genetics (publishedVersion, other-oa)
  • medRxiv (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
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  • VU Research Portal (publishedVersion, other-oa)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
  • PubMed Central (acceptedVersion)
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  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (acceptedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion, other-oa)
  • ScholarWorks @ UTRGV (The University of Texas Rio Grande Valley) (submittedVersion, other-oa)
  • Worcester Research and Publications (University of Worcester) (submittedVersion, other-oa)
  • UWA Profiles and Research Repository (UWA) (submittedVersion, other-oa)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • HAL (submittedVersion, other-oa)
  • Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
  • UCL Discovery (University College London) (submittedVersion)
  • Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion)
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  • Hirsla (Landspítali University Hospital) (submittedVersion)
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Funders
U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (U01 MH109528, U01 MH094421, U01 MH085520)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Keywords
bipolar disorder, genome-wide association study, genetic susceptibility loci, prefrontal cortex, hippocampus, expression quantitative trait loci, melanin-concentrating hormone receptor 1, furin, bipolar disorder subtypes, genetic correlation, drug repurposing, European ancestry
MeSH terms
Bipolar Disorder, Chromosomes, Human, Humans, Major Histocompatibility Complex, Phenotype, Risk Factors, Genome, Human, Case-Control Studies, Genetic Predisposition to Disease, Multifactorial Inheritance, Quantitative Trait Loci, Genome-Wide Association Study

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