Stochastic search and joint fine-mapping increases accuracy and identifies previously unreported associations in immune-mediated diseases.
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Asimit, J., Rainbow, D. B., Fortune, M., Grinberg, N., Wicker, L. S., & Wallace, C. (2019). Stochastic search and joint fine-mapping increases accuracy and identifies previously unreported associations in immune-mediated diseases.. Nature communications, 10 (1), 3216. https://doi.org/10.1038/s41467-019-11271-0
Thousands of genetic variants are associated with human disease risk, but linkage disequilibrium (LD) hinders fine-mapping the causal variants. Both lack of power, and joint tagging of two or more distinct causal variants by a single non-causal SNP, lead to inaccuracies in fine-mapping, with stochastic search more robust than stepwise. We develop a computationally efficient multinomial fine-mapping (MFM) approach that borrows information between diseases in a Bayesian framework. We show that MFM has greater accuracy than single disease analysis when shared causal variants exist, and negligible loss of precision otherwise. MFM analysis of six immune mediated diseases reveals causal variants undetected in individual disease analysis, including in IL2RA where we confirm functional effects of multiple causal variants using allele-specific expression in sorted CD4+ T cells from genotype-selected individuals. MFM has the potential to increase fine-mapping resolution in related diseases enabling the identification of associated cellular and molecular phenotypes.
CD4-Positive T-Lymphocytes, Humans, Genetic Predisposition to Disease, Bayes Theorem, Chromosome Mapping, Autoimmunity, Gene Expression Regulation, Genotype, Linkage Disequilibrium, Phenotype, Polymorphism, Single Nucleotide, Alleles, Models, Genetic, Interleukin-2 Receptor alpha Subunit, Genome-Wide Association Study, Genetic Association Studies, CTLA-4 Antigen
This work was supported by the MRC (MC UU 00002/4, MR/R021368/1), the Wellcome Trust (096388, 099772, 107212, 107881), the JDRF (9-2011-253 and 5-SRA-2015-130-A-N), the National Institute for Health Research Cambridge Biomedical Research Centre (BRC), and Dementia Platforms UK.
WELLCOME TRUST (107881/Z/15/Z)
WELLCOME TRUST (107212/Z/15/Z)
Juvenile Diabetes Research Foundation Ltd (JDRF) (5-SRA-2015-130-A-N)
Wellcome Trust (099772/Z/12/Z)
Wellcome Trust (096388/Z/11/Z)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (U01DK062418)
Medical Research Council (MC_UU_00002/4)
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External DOI: https://doi.org/10.1038/s41467-019-11271-0
This record's URL: https://www.repository.cam.ac.uk/handle/1810/294722
All rights reserved, Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/