Genetic Susceptibility to Infectious Diseases in the Qatari Population

Humans and pathogens have been in a perpetual battle for supremacy since existence. This continuous and dynamic interaction exerted a strong pressure on both, pathogens and hosts, and contributed to the variability in clinical outcomes of infectious diseases (IDs). The astonishing phenotypic disparity among human populations in response to pathogens constantly points up host genetic components. Despite being increasingly acknowledged, the role of host genetics in the susceptibility and clinical outcomes of IDs remains largely understudied in Qatar and the Middle Eastern region. In this work, we explored the genetic architecture of the Qatari population [n=6,128, Qatar Genome Project (QGP) participants] in the context of IDs using diverse statistical, computational, and laboratory experimental tools. Overall, we observed a significant heterogeneity between the Qatari and other world populations in the allelic frequencies (AF) of 1,086 known host variants related to IDs’ susceptibility, resistance, severity, progression, clearance, response to treatment, or vaccination (reaching 222-fold change).

Moreover, we found several mutations in the two key SARS-CoV-2 host entry genes (ACE2 and TMPRSS2), exclusively present in the Qatari genomes, two of which showed an enhanced binding affinity to SARS-CoV-2 spike protein and augmented SARS-CoV-2 pseudovirus entry. Additionally, by conducting the first GWAS on hepatitis E seropositivity, we identified a locus at 12p11.1 (lead SNP: rs559856097-A) significantly associated with anti-HEV antibodies level (p=2.3x10^-10), as well as several suggestive loci, many of which mapped to genes involved in immune regulation including IFNs (alpha/beta) and interleukin 21 (IL-21) signaling pathways.

These findings represent the first description of host genetic factors of IDs in Qatar, an ancestrally diverse Arabian population. This also emphasizes the necessity of functional validation as well as additional discovery and replication GWASs in Qatar and the region.