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Eliciting priors and relaxing the single causal variant assumption in colocalisation analyses.

Published version
Peer-reviewed

Type

Article

Change log

Authors

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.

Description

Keywords

Genome-Wide Association Study, Humans, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Quantitative Trait Loci

Journal Title

PLoS Genetics

Conference Name

Journal ISSN

1553-7390
1553-7404

Volume Title

16

Publisher

Public Library of Science (PLoS)
Sponsorship
Wellcome Trust (107881/Z/15/Z)
Medical Research Council (MC_UU_00002/4)
Wellcome Trust https://wellcome.ac.uk/ (WT107881) and the MRC https://mrc.ukri.org/ (MC UU 00002/4)