Prioritizing autoimmunity risk variants for functional analyses by fine-mapping mutations under natural selection

Pathogen-driven selection shaped adaptive mutations in immunity genes, including those contributing to inflammatory disorders. Functional characterization of such adaptive variants can shed light on disease biology and past adaptations. This popular idea, however, was difficult to test due to challenges in pinpointing adaptive mutations in selection footprints. In this study, using a local-tree-based approach, we show that 28% of risk loci (153/535) in 21 inflammatory disorders bear footprints of moderate and weak selection, and part of them are population specific. Weak selection footprints allow partial fine-mapping, and we show that in 19% (29/153) of the risk loci under selection, candidate disease variants are hitchhikers, and only in 39% of cases they are likely selection targets. We predict function for a subset of these selected SNPs and highlight examples of antagonistic pleiotropy. We conclude by offering disease variants under selection that can be tested functionally using infectious agents and other stressors to decipher the poorly understood link between environmental stressors and genetic risk in inflammatory conditions.