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Despite the extreme and varying environmental conditions prevalent in the Arabian Peninsula, it has experienced several waves of human migrations following the out-of-Africa diaspora. Eventually, the inhabitants of the peninsula region adapted to the hot and dry environment. The adaptation and natural selection that shaped the extant human populations of the Arabian Peninsula region have been scarcely studied. In an attempt to explore natural selection in the region, we analyzed 662,750 variants in 583 Kuwaiti individuals. We searched for regions in the genome that display signatures of positive selection in the Kuwaiti population using an integrative approach in a conservative manner. We highlight a haplotype overlapping TNKS that showed strong signals of positive selection based on the results of the multiple selection tests conducted (integrated Haplotype Score, Cross Population Extended Haplotype Homozygosity, Population Branch Statistics, and log-likelihood ratio scores). Notably, the TNKS haplotype under selection potentially conferred a fitness advantage to the Kuwaiti ancestors for surviving in the harsh environment while posing a major health risk to present-day Kuwaitis. [ABSTRACT FROM AUTHOR]

The Arabian Peninsula, located at the nexus of Africa, Europe, and Asia, was implicated in early human migration. The Arab population is characterized by consanguinity and endogamy leading to inbreeding. Global genome-wide association (GWA) studies on metabolic traits under-represent the Arab population. Replicability of GWA-identified association signals in the Arab population has not been satisfactorily explored. It is important to assess how well GWA-identified findings generalize if their clinical interpretations are to benefit the target population. Our recent study from Kuwait, which performed genome-wide imputation and meta-analysis, observed 304 (from 151 genes) of the 4746 GWA-identified metabolic risk variants replicable in the Arab population. A recent large GWA study from Qatar found replication of 30 GWA-identified lipid risk variants. These complementing studies from the Peninsula increase the confidence in generalizing metabolic risk loci to the Arab population. However, both the studies reported a low extent of transferability. In this review, we examine the observed low transferability in the context of differences in environment, genetic correlations (allele frequencies, linkage disequilibrium, effect sizes, and heritability), and phenotype variance. We emphasize the need for large-scale GWA studies on deeply phenotyped cohorts of at least 20,000 Arab individuals. The review further presents GWA-identified metabolic risk variants generalizable to the Arab population. [ABSTRACT FROM AUTHOR]