Biobank-scale inference of ancestral recombination graphs enables genealogy-based mixed model association of complex traits

Accurate inference of gene genealogies from genetic data has the potential to facilitate a wide range of analyses. We introduce a method for accurately inferring biobank-scale genome-wide genealogies from sequencing or genotyping array data, as well as strategies to utilize genealogies within linear mixed models to perform association and other complex trait analyses. We use these new methods to build genome-wide genealogies using genotyping data for 337,464 UK Biobank individuals and to detect associations in 7 complex traits. Genealogy-based association detects more rare and ultra-rare signals (N = 133, frequency range 0.0004% - 0.1%) than genotype imputation from [~]65,000 sequenced haplotypes (N = 65). In a subset of 138,039 exome sequencing samples, these associations strongly tag (average r = 0.72) underlying sequencing variants, which are enriched for missense (2.3x) and loss-of-function (4.5x) variation. Inferred genealogies also capture additional association signals in higher frequency variants. These results demonstrate that large-scale inference of gene genealogies may be leveraged in the analysis of complex traits, complementing approaches that require the availability of large, population-specific sequencing panels.