Fine-mapping genomic loci refines bipolar disorder risk genes

Author:

Koromina MariaORCID,Ravi AshvinORCID,Panagiotaropoulou GeorgiaORCID,Schilder Brian M.ORCID,Humphrey JackORCID,Braun AliceORCID,Bidgeli Tim,Chatzinakos Chris,Coombes BrandonORCID,Kim Jaeyoung,Liu Xiaoxi,Terao Chikashi,O.’Connell Kevin S.ORCID,Adams Mark,Adolfsson RolfORCID,Alda MartinORCID,Alfredsson LarsORCID,Andlauer Till F. M.ORCID,Andreassen Ole A.ORCID,Antoniou AnastasiaORCID,Baune Bernhard T.ORCID,Bengesser SusanneORCID,Biernacka JoannaORCID,Boehnke MichaelORCID,Bosch RosaORCID,Cairns MurrayORCID,Carr Vaughan J.ORCID,Casas Miquel,Catts Stanley,Cichon SvenORCID,Corvin AidenORCID,Craddock NicholasORCID,Dafnas KonstantinosORCID,Dalkner NinaORCID,Dannlowski UdoORCID,Degenhardt FranziskaORCID,Florio Arianna DiORCID,Dikeos DimitrisORCID,Fellendorf Frederike TabeaORCID,Ferentinos PanagiotisORCID,Forstner Andreas J.ORCID,Forty LizORCID,Frye MarkORCID,Fullerton Janice M.ORCID,Gawlik MichaORCID,Gizer Ian R.ORCID,Gordon-Smith KatherineORCID,Green Melissa J.,Grigoroiu-Serbanescu MariaORCID,Guzman-Parra JoséORCID,Hahn Tim,Henskens FransORCID,Hillert Jan,Jablensky Assen V.,Jones Lisa,Jones IanORCID,Jonsson LinaORCID,Kelsoe John R.ORCID,Kircher TiloORCID,Kirov GeorgeORCID,Kittel-Schneider SarahORCID,Kogevinas ManolisORCID,Landén MikaelORCID,Leboyer MarionORCID,Lenger Melanie,Lissowska JolantaORCID,Lochner ChristineORCID,Loughland Carmel,MacIntyre Donald,Martin Nicholas G.,Maratou EiriniORCID,Mathews Carol A.ORCID,Mayoral FerminORCID,McElroy Susan L.ORCID,McGregor Nathaniel W.ORCID,McIntosh AndrewORCID,McQuillin AndrewORCID,Michie Patricia,Milanova Vihra,Mitchell Philip B.,Moutsatsou ParaskeviORCID,Mowry Bryan,Müller-Myhsok Bertram,Myers RichardORCID,Nenadić Igor,Nöthen Markus M.ORCID,O’Donovan ClaireORCID,O’Donovan Michael,Ophoff Roel A.ORCID,Owen Michael JORCID,Pantelis ChrisORCID,Pato Carlos,Pato Michele T.ORCID,Patrinos George P.ORCID,Pawlak Joanna M.ORCID,Perlis Roy H.ORCID,Porichi Evgenia,Posthuma DanielleORCID,Ramos-Quiroga Josep Antoni,Reif AndreasORCID,Reininghaus Eva Z.ORCID,Ribasés MartaORCID,Rietschel MarcellaORCID,Schall Ulrich,Schulze Thomas G.ORCID,Scott Laura,Scott Rodney J.ORCID,Serretti AlessandroORCID,Weickert Cynthia Shannon,Smoller Jordan W.ORCID,Artigas Maria SolerORCID,Stein Dan J.ORCID,Streit FabianORCID,Toma Claudio,Tooney Paul,Vieta EduardORCID,Vincent John B.ORCID,Waldman Irwin D.ORCID,Weickert Thomas,Witt Stephanie H.ORCID,Hong Kyung SueORCID,Ikeda MasashiORCID,Iwata Nakao,Świątkowska Beata,Won Hong-HeeORCID,Edenberg Howard J.ORCID,Ripke StephanORCID,Raj TowfiqueORCID,Coleman Jonathan R. I.ORCID,Mullins NiamhORCID

Abstract

AbstractBipolar 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 (https://github.com/mkoromina/SAFFARI).

Publisher

Cold Spring Harbor Laboratory

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