Generalizability of GWA-Identified Genetic Risk Variants for Metabolic Traits to Populations from the Arabian Peninsula

Abstract

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.

Caveolin-1 rs1997623 variant and adult metabolic syndrome—Assessing the association in three ethnic cohorts of Arabs, South Asians and South East Asians

“…A combination of inherent genetic predispositions and rapid lifestyle changes in the rich post-oil era has shaped the observed high prevalence of metabolic disorders in the region. Generalizing metabolic risk loci established in global populations to the Arab population and vice versa is an open topic and has been discussed, in our previous study (Hebbar et al, 2021), in the context of differences in allele frequencies, linkage disequilibrium, effect sizes, and heritability), and phenotype variance.…”

Ethnic Variations in the Levels of Bone Biomarkers (Osteoprostegerin, Receptor Activator of Nuclear Factor Kappa-Β Ligand and Glycoprotein Non-Metastatic Melanoma Protein B) in People with Type 2 Diabetes

“…This high prevalence could be linked to a diet that is high in carbohydrates and simple sugars, accompanied by a sedentary lifestyle leading to a high prevalence of obesity [1]. In addition, family history and genetic background could also contribute to the increased rates of T2D in this region [2][3][4].…”