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Eliciting priors and relaxing the single causal variant assumption in colocalisation analyses
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Abstract
Horizontal integration of summary statistics from different GWAS traits can be used to evaluate evidence for their shared genetic causality. One popular method to do this is a Bayesian method, coloc, which is attractive in requiring only GWAS summary statistics and no linkage disequilibrium estimates and is now being used routinely to perform thousands of comparisons between traits. Here we show that while most users do not adjust default software values, misspecification of prior parameters can substantially alter posterior inference. We suggest data driven methods to derive sensible prior values, and demonstrate how sensitivity analysis can be used to assess robustness of posterior inference. The flexibility of coloc comes at the expense of an unrealistic assumption of a single causal variant per trait. This assumption can be relaxed by stepwise conditioning, but this requires external software and an LD matrix aligned to study alleles. We have now implemented conditioning within coloc, and propose a new alternative method, masking, that does not require LD and approximates conditioning when causal variants are independent. Importantly, masking can be used in combination with conditioning where allelically aligned LD estimates are available for only a single trait. We have implemented these developments in a new version of coloc which we hope will enable more informed choice of priors and overcome the restriction of the single causal variant assumptions in coloc analysis.
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“Alternatively, Bayesian frameworks for colocalization analysis consider GWAS summary statistics for both traits across multiple SNPs in the region around the IV and assess either the evidence that each variant is jointly causal115 or consider shared causal variants as one of five competing hypotheses.116”
From Mendelian randomization (2022) · cites this paper as [116]
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Metadata
- Authors
- Wallace, C.
- Affiliations
- University of Cambridge (GB)
- Corresponding author
- Wallace, Chris
- ORCID
- Wallace, Chris
- Venue
- PLOS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2020-04-20
- Volume
- 16
- Issue
- 4
- Pages
- e1008720
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC7192519
- OpenAlex
- W3016489931
- Cited by
- 441
- References
- 59
- Citations by year
- 2026: 75 · 2025: 98 · 2024: 123 · 2023: 47 · 2022: 39 · 2021: 43 · 2020: 15
- FWCI
- 21.26
- Type
- journal article
- Language
- en
- Update notices
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- Wellcome Trust (WT107881)
- Medical Research Council (MC UU 00002/4)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
- Keywords
- COLOC, prior specification, prior distributions, sensitivity analysis, masking, linkage disequilibrium, GWAS summary statistics
- MeSH terms
- Humans, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome-Wide Association Study
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