Assessment of coding region variants in Kuwaiti population: implications for medical genetics and population genomics

Sumi Elsa John,Osama Alsmadi,Sriraman Devarajan,Muthukrishnan Eaaswarkhanth,Thangavel Alphonse Thanaraj,Prashantha Hebbar,Arshad Mohamed Channanath,Jaakko Tuomilehto,Fahd Al-Mulla,Dinu Antony,Daisy Thomas

doi:10.1038/s41598-018-34815-8

Abstract

Consanguineous populations of the Arabian Peninsula have been underrepresented in global efforts that catalogue human exome variability. We sequenced 291 whole exomes of unrelated, healthy native Arab individuals from Kuwait to a median coverage of 45X and characterised 170,508 single-nucleotide variants (SNVs), of which 21.7% were ‘personal’. Up to 12% of the SNVs were novel and 36% were population-specific. Half of the SNVs were rare and 54% were missense variants. The study complemented the Greater Middle East Variome by way of reporting many additional Arabian exome variants. The study corroborated Kuwaiti population genetic substructures previously derived using genome-wide genotype data and illustrated the genetic relatedness among Kuwaiti population subgroups, Middle Eastern, European and Ashkenazi Jewish populations. The study mapped 112 rare and frequent functional variants relating to pharmacogenomics and disorders (recessive and common) to the phenotypic characteristics of Arab population. Comparative allele frequency data and carrier distributions of known Arab mutations for 23 disorders seen among Arabs, of putative OMIM-listed causal mutations for 12 disorders observed among Arabs but not yet characterized for genetic basis in Arabs, and of 17 additional putative mutations for disorders characterized for genetic basis in Arab populations are presented for testing in future Arab studies.

Highlights

Consanguineous populations of the Arabian Peninsula have been underrepresented in global efforts that catalogue human exome variability
Three variants significantly distinguished KWP from KWB: rs2289043_A > G (UNC5C), mostly prevalent in admixed Americans (75%) and Europeans (71%); rs3739310_T > G (KIAA1456), frequently found in East Asians (78%) and Europeans (77%); and rs764374986_G > A (AKAP12), a rare variant occurring mostly in Africans (0.01%) from Genome Aggregation Database (gnomAD) data set
Going by the practice that “pathogenic” variants are related to Mendelian disorders, we considered the variants associated with common disorders as risk factors. (i) rs1800435_G > C (MAF_KWT:12.41%; MAF_1KGP:6.4%) associated with “Aminolevulinate dehydratase, alad*1/alad*2 polymorphism susceptibility to lead poisoning ALAD porphyria”

Summary

Introduction

Consanguineous populations of the Arabian Peninsula have been underrepresented in global efforts that catalogue human exome variability. Though estimated to encompass only approximately 1–2% of the genome, harbour the most functional variation and contain almost 85% of the known disease-causing pathogenic variants[6,7]; several global whole-exome sequencing studies have been undertaken[8,9,10] Such large-scale global projects have revealed that human populations harbour a large amount of rare variations which exhibit little homology between diverged populations[3,9,10,11,12,13,14,15,16,17], Mendelian and rare genetic disorders are often associated with rare coding variants. The Greater Middle Eastern Variome study[26] detected several ancient founder populations and continental & sub-regional admixture in the extended region of Greater Middle East (comprising the Gulf region, North Africa and Central Asia); the study further stated that the ancestral Arab population from Arabian Peninsula could be observed in most of the GME regions possibly as a result of the Arab conquests in the seventh century

Methods

Results

Conclusion