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Fine-mapping genomic loci refines bipolar disorder risk genes

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...

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Main Authors: Koromina, Maria (Author) , Ravi, Ashvin (Author) , Panagiotaropoulou, Georgia (Author) , Schilder, Brian M. (Author) , Humphrey, Jack (Author) , Braun, Alice (Author) , Bidgeli, Tim (Author) , Chatzinakos, Chris (Author) , Coombes, Brandon J. (Author) , Kim, Jaeyoung (Author) , Liu, Xiaoxi (Author) , Terao, Chikashi (Author) , O’Connell, Kevin S. (Author) , Adams, Mark J. (Author) , Adolfsson, Rolf (Author) , Alda, Martin (Author) , Alfredsson, Lars (Author) , Andlauer, Till F. M. (Author) , Andreassen, Ole A. (Author) , Antoniou, Anastasia (Author) , Baune, Bernhard T. (Author) , Bengesser, Susanne (Author) , Biernacka, Joanna (Author) , Boehnke, Michael (Author) , Bosch, Rosa (Author) , Cairns, Murray J. (Author) , Carr, Vaughan J. (Author) , Casas, Miquel (Author) , Catts, Stanley (Author) , Cichon, Sven (Author) , Corvin, Aiden (Author) , Craddock, Nicholas (Author) , Dafnas, Konstantinos (Author) , Dalkner, Nina (Author) , Dannlowski, Udo (Author) , Degenhardt, Franziska (Author) , Di Florio, Arianna (Author) , Dikeos, Dimitris (Author) , Fellendorf, Frederike Tabea (Author) , Ferentinos, Panagiotis (Author) , Forstner, Andreas J. (Author) , Forty, Liz (Author) , Frye, Mark (Author) , Fullerton, Janice M. (Author) , Gawlik, Micha (Author) , Gizer, Ian R. (Author) , Gordon-Smith, Katherine (Author) , Green, Melissa J. (Author) , Grigoroiu-Serbanescu, Maria (Author) , Guzman-Parra, José (Author) , Hahn, Tim (Author) , Henskens, Frans (Author) , Hillert, Jan (Author) , Jablensky, Assen V. (Author) , Jones, Lisa (Author) , Jones, Ian (Author) , Jonsson, Lina (Author) , Kelsoe, John R. (Author) , Kircher, Tilo (Author) , Kirov, George (Author) , Kittel-Schneider, Sarah (Author) , Kogevinas, Manolis (Author) , Landén, Mikael (Author) , Leboyer, Marion (Author) , Lenger, Melanie (Author) , Lissowska, Jolanta (Author) , Lochner, Christine (Author) , Loughland, Carmel (Author) , MacIntyre, Donald J. (Author) , Martin, Nicholas G. (Author) , Maratou, Eirini (Author) , Mathews, Carol A. (Author) , Mayoral, Fermin (Author) , McElroy, Susan L. (Author) , McGregor, Nathaniel W. (Author) , McIntosh, Andrew (Author) , McQuillin, Andrew (Author) , Michie, Patricia (Author) , Mitchell, Philip B. (Author) , Moutsatsou, Paraskevi (Author) , Mowry, Bryan (Author) , Müller-Myhsok, Bertram (Author) , Myers, Richard M. (Author) , Nenadić, Igor (Author) , Nievergelt, Caroline M. (Author) , Nöthen, Markus M. (Author) , Nurnberger, John (Author) , ’Donovan, Michael O. (Author) , ’Donovan, Claire O. (Author) , Ophoff, Roel A. (Author) , Owen, Michael J. (Author) , Pantelis, Christos (Author) , Pato, Carlos (Author) , Pato, Michele T. (Author) , Patrinos, George P. (Author) , Pawlak, Joanna M. (Author) , Perlis, Roy H. (Author) , Porichi, Evgenia (Author) , Posthuma, Danielle (Author) , Ramos-Quiroga, Josep Antoni (Author) , Reif, Andreas (Author) , Reininghaus, Eva Z. (Author) , Ribasés, Marta (Author) , Rietschel, Marcella (Author) , Schall, Ulrich (Author) , Schofield, Peter R. (Author) , Schulze, Thomas G. (Author) , Scott, Laura (Author) , Scott, Rodney J. (Author) , Serretti, Alessandro (Author) , Smoller, Jordan W. (Author) , Świątkowska, Beata (Author) , Soler Artigas, Maria (Author) , Stein, Dan J. (Author) , Streit, Fabian (Author) , Toma, Claudio (Author) , Tooney, Paul (Author) , Vawter, Marquis P. (Author) , Vieta, Eduard (Author) , Vincent, John B. (Author) , Waldman, Irwin D. (Author) , Weickert, Cynthia Shannon (Author) , Weickert, Thomas (Author) , Witt, Stephanie (Author) , Hong, Kyung Sue (Author) , Ikeda, Masashi (Author) , Iwata, Nakao (Author) , Won, Hong-Hee (Author) , Edenberg, Howard J. (Author) , Ripke, Stephan (Author) , Raj, Towfique (Author) , Coleman, Jonathan R. I. (Author) , Mullins, Niamh (Author)
Format: Article (Journal)
Language:English
Published: 25 June 2025
In: Nature neuroscience
Year: 2025, Volume: 28, Issue: 7, Pages: 1393-1403
ISSN:1546-1726
DOI:10.1038/s41593-025-01998-z
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41593-025-01998-z
Verlag, kostenfrei, Volltext: http://www.nature.com/articles/s41593-025-01998-z
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Author Notes:Maria Koromina, Ashvin Ravi, Georgia Panagiotaropoulou, Brian M. Schilder, Jack Humphrey, Alice Braun, Tim Bidgeli, Chris Chatzinakos, Brandon J. Coombes, Jaeyoung Kim, Xiaoxi Liu, Chikashi Terao, Kevin S. O’Connell, Mark J. Adams, Rolf Adolfsson, Martin Alda, Lars Alfredsson, Till F.M. Andlauer, Ole A. Andreassen, Anastasia Antoniou, Bernhard T. Baune, Susanne Bengesser, Joanna Biernacka, Michael Boehnke, Rosa Bosch, Murray J. Cairns, Vaughan J. Carr, Miquel Casas, Stanley Catts, Sven Cichon, Aiden Corvin, Nicholas Craddock, Konstantinos Dafnas, Nina Dalkner, Udo Dannlowski, Franziska Degenhardt, Arianna Di Florio, Dimitris Dikeos, Frederike Tabea Fellendorf, Panagiotis Ferentinos, Andreas J. Forstner, Liz Forty, Mark Frye, Janice M. Fullerton, Micha Gawlik, Ian R. Gizer, Katherine Gordon-Smith, Melissa J. Green, Maria Grigoroiu-Serbanescu, José Guzman-Parra, Tim Hahn, Frans Henskens, Jan Hillert, Assen V. Jablensky, Lisa Jones, Ian Jones, Lina Jonsson, John R. Kelsoe, Tilo Kircher, George Kirov, Sarah Kittel-Schneider, Manolis Kogevinas, Mikael Landén, Marion Leboyer, Melanie Lenger, Jolanta Lissowska, Christine Lochner, Carmel Loughland, Donald J. MacIntyre, Nicholas G. Martin, Eirini Maratou, Carol A. Mathews, Fermin Mayoral, Susan L. McElroy, Nathaniel W. McGregor, Andrew McIntosh, Andrew McQuillin, Patricia Michie, Philip B. Mitchell, Paraskevi Moutsatsou, Bryan Mowry, Bertram Müller-Myhsok, Richard M. Myers, Igor Nenadić, Caroline M. Nievergelt, Markus M. Nöthen, John Nurnberger, Michael O. ’Donovan, Claire O. ’Donovan, Roel A. Ophoff, Michael J. Owen, Christos Pantelis, Carlos Pato, Michele T. Pato, George P. Patrinos, Joanna M. Pawlak, Roy H. Perlis, Evgenia Porichi, Danielle Posthuma, Josep Antoni Ramos-Quiroga, Andreas Reif, Eva Z. Reininghaus, Marta Ribasés, Marcella Rietschel, Ulrich Schall, Peter R. Schofield, Thomas G. Schulze, Laura Scott, Rodney J. Scott, Alessandro Serretti, Jordan W. Smoller, Beata Świątkowska, Maria Soler Artigas, Dan J. Stein, Fabian Streit, Claudio Toma, Paul Tooney, Marquis P. Vawter, Eduard Vieta, John B. Vincent, Irwin D. Waldman, Cynthia Shannon Weickert, Thomas Weickert, Stephanie H. Witt, Kyung Sue Hong, Masashi Ikeda, Nakao Iwata, Hong-Hee Won, Howard J. Edenberg, Stephan Ripke, Towfique Raj, Jonathan R.I. Coleman & Niamh Mullins
Description
Summary: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.
Item Description:Gesehen am 09.09.2025
Physical Description:Online Resource
ISSN:1546-1726
DOI:10.1038/s41593-025-01998-z

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