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Genetic colocalisation is an important tool to test for shared genetic aetiology and is commonly used to strengthen causal inference in genetic studies of molecular traits and drug targets. However, the single causal variant assumption of the original colocalization method is a considerable limitation in genomic regions with multiple causal effects.

We integrated conditional analyses (GCTA-COJO) and colocalisation analyses (coloc), into a novel analysis tool called Pair-Wise Conditional Colocalization (PWCoCo). PWCoCo performs conditional analyses to identify independent signals for the two tested traits in a genomic region and then conducts colocalisation of each pair of conditionally independent signals for the two traits using summary-level data. This allows for the stringent single-variant assumption to hold for each pair of colocalisation analysis.

We found that the computational efficiency of PWCoCo is on average better than colocalisation with Sum of Single Effects Regression using Summary Stats (SuSiE-RSS), with greater gains in efficiency for high-throughput analysis. In a case study using GWAS data for multiple sclerosis and brain cortex-derived eQTLs (MetaBrain), we recapitulated all previously identified genes, which showcased the robustness of the method. We further found colocalisation evidence for secondary signals in nine additional loci, which was not identifiable in conventional GWAS and/or colocalisation.

PWCoCo offers key improvements over existing methods, including: (1) robust colocalisation when the single variant assumption is violated; (2) independent colocalisation of secondary signals, which enables identification …