Genealogy-based trait association with LOCATER boosts power at loci with allelic heterogeneity.

A key methodological challenge for genome-wide association studies is how to leverage haplotype diversity and allelic heterogeneity to improve trait association power, especially in noncoding regions where it is difficult to predict variant impacts and define functional units for variant aggregation. Genealogy-based association methods have the potential to bridge this gap by testing combinations of common and rare haplotypes based purely on their ancestral relationships. In parallel work, we have developed an efficient local ancestry inference engine and a novel statistical method (LOCATER) for combining signals present on different branches of a locus-specific haplotype tree. Here, we develop a genome-wide LOCATER analysis pipeline and apply it to a genome sequencing study of 6795 Finnish individuals with 101 cardiometabolic traits and 18.9 million autosomal variants. We identify 351 significant trait associations at 47 distinct genomic loci and find that LOCATER boosts the single marker test (SMT) association signal at five loci by combining independent signals from distinct alleles. LOCATER successfully recovers known quantitative trait loci not found by SMT, including