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Bacteria pose unique challenges for genome-wide association studies (GWAS)because of strong structuring into distinct strains and substantial linkagedisequilibrium across the genome. While methods developed for human studies cancorrect for strain structure, this risks considerable loss- of-power becausegenetic differences between strains often contribute substantial phenotypicvariability. Here we propose a new method that captures lineage-levelassociations even when locus-specific associations cannot be fine-mapped. Wedemonstrate its ability to detect genes and genetic variants underlyingresistance to 17 antimicrobials in 3144 isolates from four taxonomicallydiverse clonal and recombining bacteria: Mycobacterium tuberculosis,Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae. Strongselection, recombination and penetrance confer high power to recover knownantimicrobial resistance mechanisms, and reveal a candidate association betweenthe outer membrane porin nmpC and cefazolin resistance in E. coli. Hence ourmethod pinpoints locus-specific effects where possible, and boosts power bydetecting lineage-level differences when fine-mapping is intractable.

Identifying lineage effects when controlling for population structure improves power in bacterial association studies