Tree-based QTL mapping with expected local genetic relatedness matrices

Abstract

Understanding the genetic basis of complex phenotypes is a central pursuit of genetics. Genome-wide association studies (GWASs) are a powerful way to find genetic loci associated with phenotypes. GWASs are widely and successfully used, but they face challenges related to the fact that variants are tested for association with a phenotype independently, whereas in reality variants at different sites are correlated because of their shared evolutionary history. One way to model this shared history is through the ancestral recombination graph (ARG), which encodes a series of local coalescent trees. Recent computational and methodological breakthroughs have made it feasible to estimate approximate ARGs from large-scale samples. Here, we explore the potential of an ARG-based approach to quantitative-trait locus (QTL) mapping, echoing existing variance-components approaches. We propose a framework that relies on the conditional expectation of a local genetic relatedness matrix (local eGRM) given the ARG. Simulations show that our method is especially beneficial for finding QTLs in the presence of allelic heterogeneity. By framing QTL mapping in terms of the estimated ARG, we can also facilitate the detection of QTLs in understudied populations. We use local eGRM to analyze two chromosomes containing known body size loci in a sample of Native Hawaiians. Our investigations can provide intuition about the benefits of using estimated ARGs in population- and statistical-genetic methods in general.