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

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...

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Published in:	Nature genetics Vol. 53; no. 6; pp. 817 - 829
Main Authors:	Mullins, Niamh, O’Connell, Kevin S., Coleman, Jonathan R. I., Qiao, Zhen, Bigdeli, Tim B., Hagenaars, Saskia P., Krebs, Kristi, Panagiotaropoulou, Georgia, Schilder, Brian M., Sloofman, Laura G., Winsvold, Bendik S., Al Eissa, Mariam, Albani, Diego, Alliey-Rodriguez, Ney, Antoniou, Anastasia, Beins, Eva C., Boks, Marco P., Brum, Murielle, Byerley, William, Cairns, Murray, Cervantes, Pablo, Cuellar-Barboza, Alfredo, Czerski, Piotr M., Djurovic, Srdjan, Douzenis, Athanassios, Foroud, Tatiana M., Giørtz Pedersen, Marianne, Gordon-Smith, Katherine, Grove, Jakob, Guzman-Parra, José, Haraldsson, Magnus, Herms, Stefan, Hoffmann, Per, Holmans, Peter A., Huckins, Laura, Johnson, Jessica S., Kalman, Janos L., Knowles, James A., Koromina, Maria, Kranzler, Henry R., Lee, Phil H., Lewis, Catrin, Lundberg, Martin, MacIntyre, Donald J., Magnusson, Sigurdur H., Maier, Wolfgang, Medland, Sarah E., Moran, Jennifer L., O’Brien, Niamh, Olde Loohuis, Loes M., Oruc, Lilijana, Papiol, Sergi, Pardiñas, Antonio F., Perry, Amy, Sánchez-Mora, Cristina, Sharp, Sally, Spijker, Anne T., Stein, Dan J., Strauss, John S., Tooney, Paul, Tsermpini, Evangelia-Eirini, Vedder, Helmut, Walters, James T. R., Witt, Stephanie H., Babadjanova, Gulja, Blackwood, Douglas H. R., Carr, Vaughan J., Dannlowski, Udo, Dikeos, Dimitris, Etain, Bruno, Frye, Mark, Gershon, Elliot S., Goes, Fernando S., Grigoroiu-Serbanescu, Maria, Hougaard, David M., Hveem, Kristian, Jablensky, Assen V., Kirov, George, Lewis, Cathryn M., Loughland, Carmel, Martin, Nicholas G., McElroy, Susan L., Melle, Ingrid, Milani, Lili, Nievergelt, Caroline M., Nöthen, Markus M., O’Donovan, Michael C., Oedegaard, Ketil J., Olsson, Tomas, Perlis, Roy H., Ribasés, Marta, Rouleau, Guy A., Schalling, Martin, Schulze, Thomas G., Serretti, Alessandro, Smoller, Jordan W., Stefansson, Kari, Stordal, Eystein, Vieta, Eduard, Nurnberger, John I.
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01.06.2021 Nature Publishing Group
Subjects:	45 45/43 631/208/205/2138 692/699/476/1333 Agriculture Anesthetics Animal Genetics and Genomics Antipsychotics Biomedical and Life Sciences Biomedicine Bipolar Disorder Bipolar Disorder - genetics Calcium Calcium channel blockers Calcium channels Cancer Research Case-Control Studies Chromosomes, Human Chromosomes, Human - genetics Consortia Diagnosis educational-attainment Etiology Furin Gene expression Gene Function Gene loci Gene mapping Genes Genetic aspects Genetic Predisposition to Disease Genetics & Heredity Genome, Human Genome-wide association studies Genome-Wide Association Study Genomes Genomics genotype imputation Human Genetics Human health and pathology Humans identification ld score regression Life Sciences loci Major Histocompatibility Complex Major Histocompatibility Complex - genetics Mental disorders Meta-analysis Multifactorial Inheritance Multifactorial Inheritance - genetics Neurosciences Neurovetenskaper Phenotype polygenicity Population Prefrontal cortex prevalence Psychiatrics and mental health Psychotropic drugs Quantitative Trait Loci Quantitative Trait Loci - genetics risk Risk Factors schizophrenia spectrum disorder Australia North America Europe
ISSN:	1061-4036, 1546-1718, 1546-1718
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Summary:	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. Genome-wide association analyses of 41,917 bipolar disorder cases and 371,549 controls of European ancestry provide new insights into the etiology of this disorder and identify novel therapeutic leads and potential opportunities for drug repurposing.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 PMCID: PMC8192451
ISSN:	1061-4036 1546-1718 1546-1718
DOI:	10.1038/s41588-021-00857-4