Genetic Determinants of Infectious Diseases in the Qatari Population

Background and Objectives: Human populations show striking phenotypic disparities in traits and diseases, including responses to infectious diseases (IDs). The impact of host genetic diversity on infection susceptibility and outcomes is increasingly recognized, yet remains largely unknown in Qatar. Here, we explored the distribution of infection-related host genetic variants in Qatar. Materials and Methods: Infection-related genetic variants from the GWAS Catalog were analyzed in 6047 Qatari whole genomes from the Qatar Genome Program (QGP) and compared with populations from the 1000 Genomes Project (1000G). Results: Out of 272,610 GWAS Catalog associations, 1086 were related to ID susceptibility, resistance, severity, progression, clearance, response to treatment, or vaccination, and hence included in the subsequent analysis. A significant heterogeneity in the allelic frequencies (AFs) between Qatari (n = 6047) and the 1000G populations (n = 2504) was observed. The QGP cohort carries significantly lower AFs of most risk variants associated with susceptibility to tuberculosis, malaria, hepatitis, diarrheal disease, and shingles (up to 222-fold, p < 0.0001). Contrarily, an enrichment in the AFs of variants that increase the risk of chickenpox, plantar warts, pneumonia, urinary tract infections (UTIs), and leprosy was observed among Qatari individuals, yet with much smaller-fold differences (≤5-fold, p < 0.0001). In addition, most severity/chronicity-related variants were considerably less prevalent in the Qatari population (up to 20.5-fold). Analysis of variants associated with antibody response revealed a distinct genetic distribution, especially in Epstein–Barr virus (EBV) and Chlamydia pneumoniae infections (27.8- and 3-fold, respectively). Moreover, a variable inter-population allelic distribution was observed in SNPs related to measles, mumps, and rubella (MMR), smallpox, and hepatitis B virus (HBV) vaccine response, as well as variants linked to viral clearance, viral load, virus-induced progression to cancer, and response to treatment. Conclusions: These findings reveal substantial differences in pathogen-associated host variants in a diverse Qatari cohort and highlight the need for follow-up validation and future GWAS discovery efforts.