Frontiers in Genetics (Sep 2022)
Diverse selection pressures shaping the genetic architecture of behçet disease susceptibility
Abstract
Behçet disease (BD) is a polygenic, multifactorial, multisystem inflammatory condition with unknown etiology. Global distribution of BD is geographically structured, highest prevalence observed among East Asian, Middle Eastern, and Mediterranean populations. Although adaptive selection on a few BD susceptibility loci is speculated, a thorough evolutionary analysis on the genetic architecture of BD is lacking. We aimed to understand whether increased BD risk in the human populations with high prevalence is due to past selection on BD associated genes. We performed population genetics analyses with East Asian (high BD prevalence), European (low/very low BD prevalence), and African (very low/no BD prevalence) populations. Comparison of ancestral and derived alleles’ frequencies versus their reported susceptible or protective effect on BD showed both derived and ancestral alleles are associated with increased BD risk. Variants showing higher risk to and more significant association with BD had smaller allele frequency differences, and showed less population differentiation compared to variants that showed smaller risk and less significant association with BD. Results suggest BD alleles are not unique to East Asians but are also found in other world populations at appreciable frequencies, and argue against selection favoring these variants only in populations with high BD prevalence. BD associated gene analyses showed similar evolutionary histories driven by neutral processes for many genes or balancing selection for HLA (Human Leukocyte Antigen) genes in all three populations studied. However, nucleotide diversity in several HLA region genes was much higher in East Asians suggesting selection for high nucleotide and haplotype diversity in East Asians. Recent selective sweep for genes involved in antigen recognition, peptide processing, immune and cellular differentiation regulation was observed only in East Asians. We conclude that the evolutionary processes shaping the genetic diversity in BD risk genes are diverse, and elucidating the underlying specific selection mechanisms is complex. Several of the genes examined in this study are risk factors (such as ERAP1, IL23R, HLA-G) for other inflammatory diseases. Thus, our conclusions are not only limited to BD but may have broader implications for other inflammatory diseases.
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