Genome-wide association and HLA region fine-mapping studies identify susceptibility loci for multiple common infections

We performed 23 genome-wide association studies for common infections, including chickenpox, shingles, cold sores, mononucleosis, mumps, hepatitis B, plantar warts, positive tuberculosis test results, strep throat, scarlet fever, pneumonia, bacterial meningitis, yeast infections, urinary tract infections, tonsillectomy, childhood ear infections, myringotomy, measles, hepatitis A, rheumatic fever, common colds, rubella and chronic sinus infection, in more than 200,000 individuals of European ancestry. For the first time, genome-wide significant associations (P < 5 x 10-8) were identified for many common infections. The associations were mapped to genes with key roles in acquired and innate immunity (HLA, IFNA21, FUT2, ST3GAL4, ABO, IFNL4, LCE3E, DSG1, LTBR, MTMR3, TNFRSF13B, TNFSF13B, NFKB1, CD40) and in regulation of embryonic developmental process (TBX1, FGF, FOXA1 and FOXN1). Several missense mutations were also identified (in LCE5A, DSG1, FUT2, TBX1, CDHR3, PLG, TNFRSF13B, FOXA1, SH2B3, ST5 and FOXN1). Missense mutations in FUT2 and TBX1 were implicated in multiple infections. We applied fine-mapping analysis to dissect associations in the human leukocyte antigen region, which suggested important roles of specific amino acid polymorphisms in the antigen-binding clefts. Our findings provide an important step toward dissecting the host genetic architecture of response to common infections.