Details der Publikation - Fine-mapping genomic loci refines bipolar disorder risk genes

Fine-mapping genomic loci refines bipolar disorder risk genes

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 22 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 ofSCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2in 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 and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://github.com/mkoromina/SAFFARI">https://github.com/mkoromina/SAFFARI</jats:ext-link>)..

Medienart:	Preprint

Erscheinungsjahr:	2024
Erschienen:	2024

Enthalten in:	bioRxiv.org - (2024) vom: 16. Feb. Zur Gesamtaufnahme - year:2024

Sprache:	Englisch

Beteiligte Personen:	Koromina, Maria [VerfasserIn] Ravi, Ashvin [VerfasserIn] Panagiotaropoulou, Georgia [VerfasserIn] Schilder, Brian M. [VerfasserIn] Humphrey, Jack [VerfasserIn] Braun, Alice [VerfasserIn] Bidgeli, Tim [VerfasserIn] Chatzinakos, Chris [VerfasserIn] Coombes, Brandon [VerfasserIn] Kim, Jaeyoung [VerfasserIn] Liu, Xiaoxi [VerfasserIn] Terao, Chikashi [VerfasserIn] O.’Connell, Kevin S. [VerfasserIn] Adams, Mark [VerfasserIn] Adolfsson, Rolf [VerfasserIn] Alda, Martin [VerfasserIn] Alfredsson, Lars [VerfasserIn] Andlauer, Till F. M. [VerfasserIn] Andreassen, Ole A. [VerfasserIn] Antoniou, Anastasia [VerfasserIn] Baune, Bernhard T. [VerfasserIn] Bengesser, Susanne [VerfasserIn] Biernacka, Joanna [VerfasserIn] Boehnke, Michael [VerfasserIn] Bosch, Rosa [VerfasserIn] Cairns, Murray [VerfasserIn] Carr, Vaughan J. [VerfasserIn] Casas, Miquel [VerfasserIn] Catts, Stanley [VerfasserIn] Cichon, Sven [VerfasserIn] Corvin, Aiden [VerfasserIn] Craddock, Nicholas [VerfasserIn] Dafnas, Konstantinos [VerfasserIn] Dalkner, Nina [VerfasserIn] Dannlowski, Udo [VerfasserIn] Degenhardt, Franziska [VerfasserIn] Florio, Arianna Di [VerfasserIn] Dikeos, Dimitris [VerfasserIn] Fellendorf, Frederike Tabea [VerfasserIn] Ferentinos, Panagiotis [VerfasserIn] Forstner, Andreas J. [VerfasserIn] Forty, Liz [VerfasserIn] Frye, Mark [VerfasserIn] Fullerton, Janice M. [VerfasserIn] Gawlik, Micha [VerfasserIn] Gizer, Ian R. [VerfasserIn] Gordon-Smith, Katherine [VerfasserIn] Green, Melissa J. [VerfasserIn] Grigoroiu-Serbanescu, Maria [VerfasserIn] Guzman-Parra, José [VerfasserIn] Hahn, Tim [VerfasserIn] Henskens, Frans [VerfasserIn] Hillert, Jan [VerfasserIn] Jablensky, Assen V. [VerfasserIn] Jones, Lisa [VerfasserIn] Jones, Ian [VerfasserIn] Jonsson, Lina [VerfasserIn] Kelsoe, John R. [VerfasserIn] Kircher, Tilo [VerfasserIn] Kirov, George [VerfasserIn] Kittel-Schneider, Sarah [VerfasserIn] Kogevinas, Manolis [VerfasserIn] Landén, Mikael [VerfasserIn] Leboyer, Marion [VerfasserIn] Lenger, Melanie [VerfasserIn] Lissowska, Jolanta [VerfasserIn] Lochner, Christine [VerfasserIn] Loughland, Carmel [VerfasserIn] MacIntyre, Donald [VerfasserIn] Martin, Nicholas G. [VerfasserIn] Maratou, Eirini [VerfasserIn] Mathews, Carol A. [VerfasserIn] Mayoral, Fermin [VerfasserIn] McElroy, Susan L. [VerfasserIn] McGregor, Nathaniel W. [VerfasserIn] McIntosh, Andrew [VerfasserIn] McQuillin, Andrew [VerfasserIn] Michie, Patricia [VerfasserIn] Milanova, Vihra [VerfasserIn] Mitchell, Philip B. [VerfasserIn] Moutsatsou, Paraskevi [VerfasserIn] Mowry, Bryan [VerfasserIn] Müller-Myhsok, Bertram [VerfasserIn] Myers, Richard [VerfasserIn] Nenadić, Igor [VerfasserIn] Nöthen, Markus M. [VerfasserIn] O’Donovan, Claire [VerfasserIn] O’Donovan, Michael [VerfasserIn] Ophoff, Roel A. [VerfasserIn] Owen, Michael J [VerfasserIn] Pantelis, Chris [VerfasserIn] Pato, Carlos [VerfasserIn] Pato, Michele T. [VerfasserIn] Patrinos, George P. [VerfasserIn] Pawlak, Joanna M. [VerfasserIn] Perlis, Roy H. [VerfasserIn] Porichi, Evgenia [VerfasserIn] Posthuma, Danielle [VerfasserIn] Ramos-Quiroga, Josep Antoni [VerfasserIn] Reif, Andreas [VerfasserIn] Reininghaus, Eva Z. [VerfasserIn] Ribasés, Marta [VerfasserIn] Rietschel, Marcella [VerfasserIn] Schall, Ulrich [VerfasserIn] Schulze, Thomas G. [VerfasserIn] Scott, Laura [VerfasserIn] Scott, Rodney J. [VerfasserIn] Serretti, Alessandro [VerfasserIn] Weickert, Cynthia Shannon [VerfasserIn] Smoller, Jordan W. [VerfasserIn] Artigas, Maria Soler [VerfasserIn] Stein, Dan J. [VerfasserIn] Streit, Fabian [VerfasserIn] Toma, Claudio [VerfasserIn] Tooney, Paul [VerfasserIn] Vieta, Eduard [VerfasserIn] Vincent, John B. [VerfasserIn] Waldman, Irwin D. [VerfasserIn] Weickert, Thomas [VerfasserIn] Witt, Stephanie H. [VerfasserIn] Hong, Kyung Sue [VerfasserIn] Ikeda, Masashi [VerfasserIn] Iwata, Nakao [VerfasserIn] Świątkowska, Beata [VerfasserIn] Won, Hong-Hee [VerfasserIn] Edenberg, Howard J. [VerfasserIn] Ripke, Stephan [VerfasserIn] Raj, Towfique [VerfasserIn] Coleman, Jonathan R. I. [VerfasserIn] Mullins, Niamh [VerfasserIn]

Links:	Volltext [kostenfrei]

Themen:	570 Biology

doi:	10.1101/2024.02.12.24302716

funding:
Förderinstitution / Projekttitel:

PPN (Katalog-ID):	XBI042491002

Internformat


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520			\|a 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 22 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 ofSCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2in 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 and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://github.com/mkoromina/SAFFARI">https://github.com/mkoromina/SAFFARI</jats:ext-link>).
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773	1	8	\|g year:2024 \|g day:16 \|g month:02
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Fine-mapping genomic loci refines bipolar disorder risk genes

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