Age Estimate of GJB2-p.(Arg143Trp) Founder Variant in Hearing Impairment in Ghana, Suggests Multiple Independent Origins across Populations

SIMPLE SUMMARY: The incidence of the GJB2-p.(Arg143Trp) founder mutation in numerous populations of different ethnolinguistic and geographical backgrounds has generated interest on the provenance and age of the variant, which is predominantly associated with non-syndromic hearing impairment in Ghana. To interrogate the multiple possible independent origins of the GJB2-p.(Arg143Trp) variant, we estimated the age of the variant in Ghana by Bayesian inference, using linked makers in whole-exome sequencing data from hearing-impaired unrelated individuals who are homozygous for the GJB2-p.(Arg143Trp) variant, and nonaffected controls from the same population. We estimated the age of the variant as approximately 9625 years, from a common indigenous Ghanaian ancestor. Haplotype backgrounds in Ghanaian hearing-impaired individuals were apparently different from those of their Japanese counterparts. We observed low haplotype diversity in the GJB2-p.(Arg143Trp) genomic region for homozygous individuals compared to the normal hearing Ghanaian controls, although the recombination rate is relatively high in the region. The GJB2-p.(Arg143Trp)-positive individuals shared no common haplotype with the Ghanaian GJB2-p.(Arg143Trp)-negative controls, and as well as no common haplotype with data extracted from populations in 1000 Genomes, further supporting the multiple independent origins of GJB2-p.(Arg143Trp) in the global population. ABSTRACT: Gap junction protein beta 2 (GJB2) (connexin 26) variants are commonly implicated in non-syndromic hearing impairment (NSHI). In Ghana, the GJB2 variant p.(Arg143Trp) is the largest contributor to NSHI and has a reported prevalence of 25.9% in affected multiplex families. To date, in the African continent, GJB2-p.(Arg143Trp) has only been reported in Ghana. Using whole-exome sequencing data from 32 individuals from 16 families segregating NSHI, and 38 unrelated hearing controls with the same ethnolinguistic background, we investigated the date and origin of p.(Arg143Trp) in Ghana using linked markers. With a Bayesian linkage disequilibrium gene mapping method, we estimated GJB2-p.(Arg143Trp) to have originated about 9625 years (385 generations) ago in Ghana. A haplotype analysis comparing data extracted from Ghanaians and those from the 1000 Genomes project revealed that GJB2-p.(Arg143Trp) is carried on different haplotype backgrounds in Ghanaian and Japanese populations, as well as among populations of European ancestry, lending further support to the multiple independent origins of the variant. In addition, we found substantial haplotype conservation in the genetic background of Ghanaian individuals with biallelic GJB2-p.(Arg143Trp) compared to the GJB2-p.(Arg143Trp)-negative group with normal hearing from Ghana, suggesting a strong evolutionary constraint in this genomic region in Ghanaian populations that are homozygous for GJB2-p.(Arg143Trp). The present study evaluates the age of GJB2-p.(Arg143Trp) at 9625 years and supports the multiple independent origins of this variant in the global population.