Fine-mapping genomic loci refines bipolar disorder risk genes

Koromina, Maria, Ravi, Ashvin, Panagiotaropoulou, Georgia, Schilder, Brian, Humphrey, Jack, Braun, Alice, Bidgeli, Tim, Chatzinakos, Chris, Coombes, Brandon, Kim, Jaeyoung, Liu, Xiaoxi, Terao, Chikashi, O'Connell, Kevin, Adams, Mark, Adolfsson, Rolf, Alda, Martin, Alfredsson, Lars, Andlauer, Till, Andreassen, Ole, Antoniou, Anastasia, Baune, Bernhard, Bengesser, Susanne, Biernacka, Joanna, Boehnke, Michael, Bosch, Rosa, Cairns, Murray, Carr, Vaughan, Casas, Miquel, Catts, Stanley, Cichon, Sven, Corvin, Aiden, Craddock, Nicholas, Dafnas, Konstantinos, Dalkner, Nina, Dannlowski, Udo, Degenhardt, Franziska, Di Florio, Arianna ORCID: https://orcid.org/0000-0003-0338-2748, Dikeos, Dimitris, Tabea Fellendorf, Frederlike, Ferentinos, Panagiotis, Forstner, Andreas, Forty, Liz, Frye, Mark, Fullerton, Janice, Gawlik, Micha, Gizer, Ian, Gordon-Smith, Katherine, Green, Melissa, Grigoroiu-Serbanescu, Maria, Guzman-Parra, Jose, Hahn, Tim, Henskens, Frans, Hillert, Jan, Jablensky, Assen, Jones, Ian ORCID: https://orcid.org/0000-0001-5821-5889, Jonsson, Lina, Kelsoe, John, Kircher, Tilo, Kirov, George ORCID: https://orcid.org/0000-0002-3427-3950, Kittel-Schneider, Sarah, Kogevinas, Manolis, Landen, Mikael, Leboyer, Marion, Lenger, Melanie, Lissowska, Jolanta, Lochner, Christine, Loughland, Carmel, MacIntyre, Donald, Martin, Nicholas, Maratou, Eirini, Mathews, Carol, Mayoral, Fermin, McElroy, Susan, McGregor, Nathaniel, McIntosh, Andrew, McQuillin, Andrew, Michie, Patricia, Mitchell, Philip, Moutsatsou, Paraskevi, Mowry, Bryan, Muller-Myhsok, Bertram, Myers, Richard, Nenadic, Igor, Nievergelt, Caroline, Nothen, Markus, Nurnberger, John, O'Donovan, Michael ORCID: https://orcid.org/0000-0001-7073-2379, O'Donovan, Claire, Ophoff, Roel, Owen, Michael ORCID: https://orcid.org/0000-0003-4798-0862, Pantelis, Christos, Pato, Carlos, Pato, Michele, Patrinos, George, Pawlak, Joanna, Perlis, Roy, Porichi, Evgenia, Posthuma, Danielle, Antoni Ramos-Quiroga, Josep, Reif, Andreas, Reininghaus, Eva, Ribases, Marta, Rietschel, Marcella, Schall, Ulrich, Schofield, Peter, Schulze, Thomas, Scott, Laura, Scott, Rodney, Serretti, Alessandro, Shannon Weickert, Cynthia, Smoller, Jordan, Soler Artigas, Maria, Stein, Dan, Streit, Fabian, Toma, Claudio, Tooney, Paul, Vawter, Marquis, Vieta, Eduard, Vincent, John, Waldman, Irwin, Weickert, Thomas, Witt, Stephanie, Sue Hong, Kyung, Ikeda, Masashi, Iwata, Nakao, Świątkowska, Beata, Won, Hong-Hee, Edenberg, Howard, Ripke, Stephan, Raj, Towfique, Coleman, Jonathan and Mullins, Niamh 2024. Fine-mapping genomic loci refines bipolar disorder risk genes. [Online]. medRxiv: OpenRxiv. Available at: https://doi.org/10.1101/2024.02.12.24302716

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Abstract

Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD 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 BD. 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 BD. Convergent lines of evidence supported the roles of genes involved in neurotransmission and neurodevelopment including SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, CRTC3, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, DPH1, GSDMB, MED24 and THRA in BD. 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 BD polygenic risk scores across diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).

Item Type:	Website Content
Date Type:	Published Online
Status:	Submitted
Schools:	Schools > Medicine Research Institutes & Centres > MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher:	OpenRxiv
Date of Acceptance:	7 May 2025
Last Modified:	09 Jun 2025 11:17
URI:	https://orca.cardiff.ac.uk/id/eprint/178275

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