Two-way mixed-effects methods for joint association analysis using both host and pathogen genomes

Infectious diseases are often affected by specific pairings of hosts and pathogens and therefore by both of their genomes. The integration of a pair of genomes into genome-wide association mapping can provide an exquisitely detailed view of the genetic landscape of complex traits. We present a statistical method, ATOMM (Analysis with a Two-Organism Mixed Model), that maps a trait of interest to a pair of genomes simultaneously; this method makes use of whole-genome sequence data for both host and pathogen organisms. ATOMM uses a two-way mixed-effect model to test for genetic associations and cross-species genetic interactions while accounting for sample structure including interactions between the genetic backgrounds of the two organisms. We demonstrate the applicability of ATOMM to a joint association study of quantitative disease resistance (QDR) in the Arabidopsis thaliana-Xanthomonas arboricola pathosystem. Our method uncovers a clear host-strain specificity in QDR and provides a powerful approach to identify genetic variants on both genomes that contribute to phenotypic variation.