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


Autoři: Chris Wallace aff001
Působiště autorů: Cambridge Institute for Therapeutic Immunology & Infectious Disease, and MRC Biostatistics Unit, University of Cambridge, Cambridge, United Kingdom aff001
Vyšlo v časopise: Eliciting priors and relaxing the single causal variant assumption in colocalisation analyses. PLoS Genet 16(4): e32767. doi:10.1371/journal.pgen.1008720
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008720

Souhrn

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.

Klíčová slova:

Bayesian method – Gene expression – Genetic epidemiology – Genetics of disease – Genome-wide association studies – Genomic signal processing – Molecular genetics – Quantitative traits


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