Abstract
Infectious diseases have a profound impact on our health and many studies suggest that host genetics play a major role in the pathogenesis of most of them. We perform 23 genome-wide association studies for common infections and infection-associated procedures, 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 over 200,000 individuals of European ancestry. We detect 59 genome-wide significant (P < 5 × 10−8) associations in genes with key roles in immunity and embryonic development. We apply fine-mapping analysis to dissect associations in the human leukocyte antigen region, which suggests 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.
Highlights
Infectious diseases have a profound impact on our health and many studies suggest that host genetics play a major role in the pathogenesis of most of them
HLA human leukocyte antigen, SNP single-nucleotide polymorphism, TB tuberculosis, urinary tract infections (UTIs) urinary tract infection aThe alleles for each SNP are represented as high-risk allele/low-risk allele bStrep throat, plantar warts and UTI frequency are quantitative traits, for which we reported the effect size instead of the odds ratio
‘HLA-A Val95’ means amino acid Val at position 95 of the HLA-A protein bThe alleles for each SNP are represented as risk allele/non-risk allele; the allele for the HLA classical allele is recorded as ‘NA’, which means it either has or does not have the tested allele; the alleles for HLA amino acid polymorphisms are all the possible amino acids at that position cStrep throat, plantar warts and UTI frequency are quantitative traits, for which we reported the effect size instead of the odds ratio dThe ‘Cond. P value’ column contains conditional P values generated after iterative conditional regression within each category of variants (SNP, HLA alleles and HLA amino acid polymorphisms)
Summary
Infectious diseases have a profound impact on our health and many studies suggest that host genetics play a major role in the pathogenesis of most of them. We apply fine-mapping analysis to dissect associations in the human leukocyte antigen region, which suggests important roles of specific amino acid polymorphisms in the antigen-binding clefts. We detected 59 genome-wide significant (GWS) associations and in some instances our findings replicated previous GWASes. We further imputed and tested the HLA classical alleles and amino acid polymorphisms to dissect independent HLA signals for multiple common infections. Our fine-mapping studies identify novel HLA associations in European population and suggest important roles of specific amino acid polymorphisms in the antigen-binding clefts. By studying multiple infections together, we find that virus-induced infectious diseases are mainly associated with class I molecules and the bacteria-induced infectious diseases are mainly associated with class II molecules, while with notable exceptions, as discussed below
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