Koromina Maria, Ravi Ashvin, Panagiotaropoulou Georgia, Schilder Brian M, Humphrey Jack, Braun Alice, Bidgeli Tim, Chatzinakos Chris, Coombes Brandon J, Kim Jaeyoung, Liu Xiaoxi, Terao Chikashi, O'Connell Kevin S, Adams Mark J, Adolfsson Rolf, Alda Martin, Alfredsson Lars, Andlauer Till F M, Andreassen Ole A, Antoniou Anastasia, Baune Bernhard T, Bengesser Susanne, Biernacka Joanna, Boehnke Michael, Bosch Rosa, Cairns Murray J, Carr Vaughan J, Casas Miquel, Catts Stanley, Cichon Sven, Corvin Aiden, Craddock Nicholas, Dafnas Konstantinos, Dalkner Nina, Dannlowski Udo, Degenhardt Franziska, Di Florio Arianna, Dikeos Dimitris, Fellendorf Frederike Tabea, Ferentinos Panagiotis, Forstner Andreas J, Forty Liz, Frye Mark, Fullerton Janice M, Gawlik Micha, Gizer Ian R, Gordon-Smith Katherine, Green Melissa J, Grigoroiu-Serbanescu Maria, Guzman-Parra José, Hahn Tim, Henskens Frans, Hillert Jan, Jablensky Assen V, Jones Lisa, Jones Ian, Jonsson Lina, Kelsoe John R, Kircher Tilo, Kirov George, Kittel-Schneider Sarah, Kogevinas Manolis, Landén Mikael, Leboyer Marion, Lenger Melanie, Lissowska Jolanta, Lochner Christine, Loughland Carmel, MacIntyre Donald J, Martin Nicholas G, Maratou Eirini, Mathews Carol A, Mayoral Fermin, McElroy Susan L, McGregor Nathaniel W, McIntosh Andrew, McQuillin Andrew, Michie Patricia, Mitchell Philip B, Moutsatsou Paraskevi, Mowry Bryan, Müller-Myhsok Bertram, Myers Richard M, Nenadić Igor, Nievergelt Caroline M, Nöthen Markus M, Nurnberger John, 'Donovan Michael O, 'Donovan Claire O, Ophoff Roel A, Owen Michael J, Pantelis Christos, Pato Carlos, Pato Michele T, Patrinos George P, Pawlak Joanna M, Perlis Roy H, Porichi Evgenia, Posthuma Danielle, Ramos-Quiroga Josep Antoni, Reif Andreas, Reininghaus Eva Z, Ribasés Marta, Rietschel Marcella, Schall Ulrich, Schofield Peter R, Schulze Thomas G, Scott Laura, Scott Rodney J, Serretti Alessandro, Smoller Jordan W, Świątkowska Beata, Soler Artigas Maria, Stein Dan J, Streit Fabian, Toma Claudio, Tooney Paul, Vawter Marquis P, Vieta Eduard, Vincent John B, Waldman Irwin D, Weickert Cynthia Shannon, Weickert Thomas, Witt Stephanie H, Hong Kyung Sue, Ikeda Masashi, Iwata Nakao, Won Hong-Hee, Edenberg Howard J, Ripke Stephan, Raj Towfique, Coleman Jonathan R I, Mullins Niamh
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York City, NY, USA.
Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York City, NY, USA.
Nat Neurosci. 2025 Jun 25. doi: 10.1038/s41593-025-01998-z.
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.
双相情感障碍是一种病因复杂的遗传性精神疾病。虽然已发表的最大规模全基因组关联研究确定了64个双相情感障碍风险位点，但这些位点内的因果单核苷酸多态性（SNP）和基因仍不清楚。我们对这些位点应用了一系列统计和功能精细定位方法，并确定了17个可能导致双相情感障碍的因果SNP。我们将这些SNP定位到基因，并通过整合变异注释、脑细胞类型表观基因组注释、脑数量性状位点以及双相情感障碍罕见变异外显子测序结果，研究了它们可能的功能后果。多条证据支持了参与神经传递和神经发育的基因的作用，包括SCN2A、TRANK1、DCLK3、INSYN2B、SYNE1、THSD7A、CACNA1B、TUBBP5、FKBP2、RASGRP1、FURIN、FES、MED24和THRA等在双相情感障碍中的作用。这些是进行功能实验以了解生物学机制和治疗潜力的有希望的候选者。此外，我们证明精细定位效应大小可以提高双相情感障碍多基因风险评分在不同人群中的性能，并提出了一种高通量精细定位流程。
