Fine-mapping genomic loci refines bipolar disorder risk genes

Koromina M, Ravi A, Panagiotaropoulou G, Schilder BM, Humphrey J, Braun A, Bidgeli T, Chatzinakos C, Coombes BJ, Kim J, Liu X, Terao C, O’Connell KS, Adams MJ, Adolfsson R, Alda M, Alfredsson L, Andlauer TF, Andreassen OA, Antoniou A, Baune BT, Bengesser S, Biernacka J, Boehnke M, Bosch R, Cairns MJ, Carr VJ, Casas M, Catts S, Cichon S, Corvin A, Craddock N, Dafnas K, Dalkner N, Dannlowski U, Degenhardt F, Di Florio A, Dikeos D, Fellendorf FT, Ferentinos P, Forstner AJ, Forty L, Frye M, Fullerton JM, Gawlik M, Gizer IR, Gordon-Smith K, Green MJ, Grigoroiu-Serbanescu M, Guzman-Parra J, Hahn T, Henskens F, Hillert J, Jablensky AV, Jones L, Jones I, Jonsson L, Kelsoe JR, Kircher T, Kirov G, Kittel-Schneider S, Kogevinas M, Landén M, Leboyer M, Lenger M, Lissowska J, Lochner C, Loughland C, MacIntyre DJ, Martin NG, Maratou E, Mathews CA, Mayoral F, McElroy SL, McGregor NW, McIntosh A, McQuillin A, Michie P, Mitchell PB, Moutsatsou P, Mowry B, Müller-Myhsok B, Myers RM, Nenadić I, Nievergelt CM, Nöthen MM, Nurnberger J, ’Donovan MO, ’Donovan CO, Ophoff RA, Owen MJ, Pantelis C, Pato C, Pato MT, Patrinos GP, Pawlak JM, Perlis RH, Porichi E, Posthuma D, Ramos-Quiroga JA, Reif A, Reininghaus EZ, Ribasés M, Rietschel M, Schall U, Schofield PR, Schulze TG, Scott L, Scott RJ, Serretti A, Smoller JW, Świątkowska B, Soler Artigas M, Stein DJ, Streit F, Toma C, Tooney P, Vawter MP, Vieta E, Vincent JB, Waldman ID, Weickert CS, Weickert T, Witt SH, Hong KS, Ikeda M, Iwata N, Won HH, Edenberg HJ, Ripke S, Raj T, Coleman JR, Mullins N (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Book Volume: 28

Pages Range: 1393-1403

Journal Issue: 7

DOI: 10.1038/s41593-025-01998-z

Abstract

Bipolar disorder is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 bipolar disorder risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci and prioritized 17 likely causal SNPs for bipolar disorder. We mapped these SNPs to genes and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci and results from rare variant exome sequencing in bipolar disorder. Convergent lines of evidence supported the roles of genes involved in neurotransmission and neurodevelopment, including SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, FKBP2, RASGRP1, FURIN, FES, MED24 and THRA among others in bipolar disorder. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance of bipolar disorder polygenic risk scores across diverse populations and present a high-throughput fine-mapping pipeline.

Involved external institutions

University of Stellenbosch / Universiteit van Stellenbosch South Africa (ZA) Karolinska Institute Sweden (SE) University of Edinburgh United Kingdom (GB) University of Western Australia (UWA) Australia (AU) University Of Worcester United Kingdom (GB) University of Queensland Australia (AU) University of New South Wales (UNSW) Australia (AU) University of Newcastle (UoN) Australia (AU) National and Kapodistrian University of Athens Greece (GR) Westfälische Wilhelms-Universität (WWU) Münster Germany (DE) Universitätsklinikum Bonn Germany (DE) Indiana University – Purdue University Indianapolis United States (USA) (US) Dalhousie University Canada (CA) Cardiff University United Kingdom (GB) Poznan University of Medical Sciences / Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu Poland (PL) Medizinische Universität Graz Austria (AT) Mayo Clinic United States (USA) (US) University of Michigan United States (USA) (US) Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) Spain (ES) Vrije Universiteit Amsterdam (VU) / University Amsterdam Netherlands (NL) Universitätsklinikum Frankfurt am Main (KGU) Germany (DE) Universitätsklinikum Mannheim / University Medical Centre Mannheim (Universitätsmedizin Mannheim) Germany (DE) Nofer Institute of Occupational Medicine (NIOM) Poland (PL) Universität Basel Switzerland (CH) Trinity College Dublin Ireland (IE) University of Cape Town (UCT) South Africa (ZA) University of California Irvine United States (USA) (US) Charité - Universitätsmedizin Berlin Germany (DE) King’s College London United Kingdom (GB) University of Missouri-Columbia (Mizzou) United States (USA) (US) Neuroscience Research Australia NeuRA Australia (AU) University of Gothenburg / Göteborgs universitet Sweden (SE) University of California, San Diego (UC San Diego, UCSD) United States (USA) (US) Philipps-Universität Marburg Germany (DE) Universitätsklinikum Würzburg Germany (DE) Instituto de Salud Global de Barcelona (ISGlobal) Spain (ES) Paris-Est Créteil University / Université Paris-Est Créteil Val-de-Marne (UPEC) / Université Paris XII-Val-de-Marne / University Paris 12 Marne la Vallée France (FR) Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie Poland (PL) IMS RIKEN Center for Integrative Medical Sciences Japan (JP) Kore University of Enna / Università degli Studi di Enna Kore Italy (IT) Eli and Edythe L. Broad Institute of MIT and Harvard United States (USA) (US) Universitat de Barcelona (UB) / University of Barcelona Spain (ES) Icahn School of Medicine at Mount Sinai United States (USA) (US) University College London (UCL) United Kingdom (GB) Max-Planck-Institut für Psychiatrie (Deutsche Forschungsanstalt für Psychiatrie) Germany (DE) HudsonAlpha United States (USA) (US) The Jane and Terry Semel Institute for Neuroscience and Human Behavior United States (USA) (US) Harvard University United States (USA) (US) Cardiovascular Research Foundation United States (USA) (US) University of Florida United States (USA) (US) Lindner Center of HOPE United States (USA) (US) Sungkyunkwan University (SKKU) Korea, Republic of (KR) Oslo University Hospital / Oslo Universitetssykehus Rikshospitalet Norway (NO) Umeå University Sweden (SE) Centre for Addiction and Mental Health (CAMH) Canada (CA) Emory University United States (USA) (US) University of British Columbia Canada (CA) Fujita Health University Japan (JP) Klinikum rechts der Isar Germany (DE) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU)

How to cite

APA:

Koromina, M., Ravi, A., Panagiotaropoulou, G., Schilder, B.M., Humphrey, J., Braun, A.,... Mullins, N. (2025). Fine-mapping genomic loci refines bipolar disorder risk genes. Nature Neuroscience, 28(7), 1393-1403. https://doi.org/10.1038/s41593-025-01998-z

MLA:

Koromina, Maria, et al. "Fine-mapping genomic loci refines bipolar disorder risk genes." Nature Neuroscience 28.7 (2025): 1393-1403.

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