Fine-mapping genomic loci refines bipolar disorder risk genes

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dc.contributor.authorKoromina, M.
dc.contributor.authorRavi, A.
dc.contributor.authorPanagiotaropoulou, G.
dc.contributor.authorSchilder, B.M.
dc.contributor.authorHumphrey, J.
dc.contributor.authorBraun, A.
dc.contributor.authorBidgeli, T.
dc.contributor.authorChatzinakos, C.
dc.contributor.authorCoombes, B.J.
dc.contributor.authorKim, J.
dc.contributor.authorLiu, X.
dc.contributor.authorTerao, C.
dc.contributor.authorO’Connell, K.S.
dc.contributor.authorAdams, M.J.
dc.contributor.authorAdolfsson, R.
dc.contributor.authorAlda, M.
dc.contributor.authorAlfredsson, L.
dc.contributor.authorAndlauer, T.F.M.
dc.contributor.authorAndreassen, O.A.
dc.contributor.authorAntoniou, A.
dc.contributor.authoret al.
dc.date.issued2025
dc.description.abstractBipolar disorder is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 bipolar disorder 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 bipolar disorder. 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 bipolar disorder. Convergent lines of evidence supported the roles of genes involved in neurotransmission and neurodevelopment, including SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, FKBP2, RASGRP1, FURIN, FES, MED24 and THRA among others in bipolar disorder. 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 bipolar disorder polygenic risk scores across diverse populations and present a high-throughput fine-mapping pipeline.
dc.description.statementofresponsibilityMaria Koromina ... Bernhard T. Baune ... et al.
dc.identifier.citationNature Neuroscience, 2025; 28(7):1393-1403
dc.identifier.doi10.1038/s41593-025-01998-z
dc.identifier.issn1097-6256
dc.identifier.issn1546-1726
dc.identifier.orcidBaune, B.T. [0000-0001-6548-426X]
dc.identifier.urihttps://hdl.handle.net/2440/147729
dc.language.isoen
dc.publisherSpringer Nature
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1177991
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1176716
dc.rights© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
dc.source.urihttps://doi.org/10.1038/s41593-025-01998-z
dc.subjectBipolar disorder; Genome-wide association studies; Genomics
dc.subject.meshHumans
dc.subject.meshGenetic Predisposition to Disease
dc.subject.meshChromosome Mapping
dc.subject.meshBipolar Disorder
dc.subject.meshMultifactorial Inheritance
dc.subject.meshPolymorphism, Single Nucleotide
dc.subject.meshQuantitative Trait Loci
dc.subject.meshGenome-Wide Association Study
dc.titleFine-mapping genomic loci refines bipolar disorder risk genes
dc.typeJournal article
pubs.publication-statusPublished

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