Fine-mapping genomic loci refines bipolar disorder risk genes
Authors: Koromina Maria , Ravi Ashvin , Panagiotaropoulou Georgia , Schilder Brian M. , Humphrey Jack , Braun Alice , Bidgeli Tim , Chatzinakos Chris , Coombes Brandon , Kim Jaeyoung , Liu Xiaoxi , Terao Chikashi , O.’Connell Kevin S. , Adams Mark , 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 , 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 , Nöthen Markus M. , Nurnberger John , O.’Donovan Michael , O’Donovan Claire , 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 , Shannon Weickert Cynthia , Smoller Jordan W. , Soler Artigas Maria , Stein Dan J. , Streit Fabian , Toma Claudio , Tooney Paul , Vawter Marquis P. , Vieta Eduard , Vincent John B. , Waldman Irwin D. , Weickert Thomas , Witt Stephanie H. , Hong Kyung Sue , Ikeda Masashi , Iwata Nakao , Świątkowska Beata , Won Hong-Hee , Edenberg Howard J. , Ripke Stephan , Raj Towfique , Coleman Jonathan R. I. , Mullins Niamh 
Published: February 2024

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 includingSCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, CRTC3, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, DPH1, GSDMB, MED24andTHRAin 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).