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.
Highlights
Over the past few years, a multitude of global genome-wide association (GWA) studies have identified genetic risk variants associated with metabolic traits and related disorders
Our recent examination of GWAS Catalog [3] against 313 search terms relating to four classes of metabolic traits found 7668 genetic variants from ~4000 genes associated with metabolic traits [4]; association signals involving 4746 (i.e., 62%) of the 7668 variants were at genome-wide significance (p-values of ≤5.0 × 10−8)
Such inbreeding communities are expected to have increased homozygosity at-risk variants for both monogenic and polygenic diseases as well as an accumulation of deleterious recessive alleles in the gene pool; our previous GWA study under a genetic model based on the recessive mode of inheritance pinpointed 16 novel risk variants associated with plasma TG levels in Arab individuals from Kuwait [15,16]
Summary
Over the past few years, a multitude of global genome-wide association (GWA) studies have identified genetic risk variants associated with metabolic traits and related disorders. The Arab population is characterized by unique features such as large families, consanguinity, endogamy, and first-cousin marriages, which have resulted in creation of inbreeding communities Such inbreeding communities are expected to have increased homozygosity at-risk variants for both monogenic and polygenic diseases as well as an accumulation of deleterious recessive alleles in the gene pool; our previous GWA study under a genetic model based on the recessive mode of inheritance pinpointed 16 novel risk variants associated with plasma TG levels in Arab individuals from Kuwait [15,16]. It is important to assess how well the GWA-identified risk loci generalizes, if a target population is to benefit from clinical interpretation of global GWA findings
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