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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 of SCN2A, 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 KCNQ2 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 and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).

SUBMITTER: Koromina M

PROVIDER: S-EPMC10889003 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Fine-mapping genomic loci refines bipolar disorder risk genes.

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

medRxiv : the preprint server for health sciences 20240917

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 ...[more]

PMID: 38405768

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Project description:Heritable diseases often manifest in a highly tissue-specific manner, with different disease loci mediated by genes in distinct tissues or cell types. We propose Tissue-Gene Fine-Mapping (TGFM), a fine-mapping method that infers the posterior probability (PIP) for each gene-tissue pair to mediate a disease locus by analyzing GWAS summary statistics (and in-sample LD) and leveraging eQTL data from diverse tissues to build cis-predicted expression models; TGFM also assigns PIPs to causal variants that are not mediated by gene expression in assayed genes and tissues. TGFM accounts for both co-regulation across genes and tissues and LD between SNPs (generalizing existing fine-mapping methods), and incorporates genome-wide estimates of each tissue's contribution to disease as tissue-level priors. TGFM was well-calibrated and moderately well-powered in simulations; unlike previous methods, TGFM was able to attain correct calibration by modeling uncertainty in cis-predicted expression models. We applied TGFM to 45 UK Biobank diseases/traits (average N=316K) using eQTL data from 38 GTEx tissues. TGFM identified an average of 147 PIP > 0.5 causal genetic elements per disease/trait, of which 11% were gene-tissue pairs. Implicated gene-tissue pairs were concentrated in known disease-critical tissues, and causal genes were strongly enriched in disease-relevant gene sets. Causal gene-tissue pairs identified by TGFM recapitulated known biology (e.g., TPO-thyroid for Hypothyroidism), but also included biologically plausible novel findings (e.g., SLC20A2-artery aorta for Diastolic blood pressure). Further application of TGFM to single-cell eQTL data from 9 cell types in peripheral blood mononuclear cells (PBMC), analyzed jointly with GTEx tissues, identified 30 additional causal gene-PBMC cell type pairs at PIP > 0.5-primarily for autoimmune disease and blood cell traits, including the well-established role of CTLA4 in CD8+ T cells for All autoimmune disease. In conclusion, TGFM is a robust and powerful method for fine-mapping causal tissues and genes at disease-associated loci.

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Fine-mapping genomic loci refines bipolar disorder risk genes.

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Fine-mapping genomic loci refines bipolar disorder risk genes.

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