Qatar genome: Insights on genomics from the Middle East

Mbarek, Hamdi; Gandhi, Geethanjali Devadoss; Selvaraj, Senthil; Al‐Muftah, Wadha; Badji, Radja; Al-Sarraj, Yasser; Saad, Chadi; Darwish, Dima; Alvi, Muhammad Arshad; Fadl, Tasnim; Yasin, Heba; Alkuwari, Fatima; Razali, Rozaimi Mohamad; Aamer, Waleed; Abbaszadeh, Fatemeh; Ahmed, Ikhlak; Mokrab, Younes; Suhre, Karsten; Fakhro, Khalid; Badii, Ramin; Ismail, Said I.; Althani, Asma

doi:10.1002/humu.24336

Cited by 45 publications

(50 citation statements)

References 53 publications

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“…Qatar Biobank (QBB) is a population study that includes adult Qatari nationals and long-term residents (≥15 years living in Qatar) [34,35]. QBB samples and data have been used in multiple genetic studies [19,[36][37][38].…”

Section: Study Populationmentioning

confidence: 99%

Ratios of Acetaminophen Metabolites Identify New Loci of Pharmacogenetic Relevance in a Genome-Wide Association Study

et al. 2022

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Genome-wide association studies (GWAS) with non-targeted metabolomics have identified many genetic loci of biomedical interest. However, metabolites with a high degree of missingness, such as drug metabolites and xenobiotics, are often excluded from such studies due to a lack of statistical power and higher uncertainty in their quantification. Here we propose ratios between related drug metabolites as GWAS phenotypes that can drastically increase power to detect genetic associations between pairs of biochemically related molecules. As a proof-of-concept we conducted a GWAS with 520 individuals from the Qatar Biobank for who at least five of the nine available acetaminophen metabolites have been detected. We identified compelling evidence for genetic variance in acetaminophen glucuronidation and methylation by UGT2A15 and COMT, respectively. Based on the metabolite ratio association profiles of these two loci we hypothesized the chemical structure of one of their products or substrates as being 3-methoxyacetaminophen, which we then confirmed experimentally. Taken together, our study suggests a novel approach to analyze metabolites with a high degree of missingness in a GWAS setting with ratios, and it also demonstrates how pharmacological pathways can be mapped out using non-targeted metabolomics measurements in large population-based studies.

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Section: Study Populationmentioning

confidence: 99%

Ratios of Acetaminophen Metabolites Identify New Loci of Pharmacogenetic Relevance in a Genome-Wide Association Study

et al. 2022

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“…As we described previously [ 25 ], the novel MYO6 variant is predicted to be pathogenic and is located near the ATP binding site in the motor domain of the MYO6 protein ( Table 1 and Figure 1 B,C). To assess the prevalence of the novel variant p.E60Q within the Qatari population, we used the genomic sequence of the participants from the Qatar Genome Program (QGP) dataset [ 28 ]. The QGP is a population-level genome project that aims to sequence all Qatari nationals, with the goal of developing personalized medicine for the prevention, diagnosis, and treatment of diseases.…”

Section: Resultsmentioning

confidence: 99%

Functional Characterization of the MYO6 Variant p.E60Q in Non-Syndromic Hearing Loss Patients

Alkowari

Guarch

Da’as

et al. 2022

IJMS

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Hereditary hearing loss (HHL) is a common genetic disorder accounting for at least 60% of pre-lingual deafness in children, of which 70% is inherited in an autosomal recessive pattern. The long tradition of consanguinity among the Qatari population has increased the prevalence of HHL, which negatively impacts the quality of life. Here, we functionally validated the pathogenicity of the c.178G>C, p.E60Q mutation in the MYO6 gene, which was detected previously in a Qatari HHL family, using cellular and animal models. In vitro analysis was conducted in HeLa cells transiently transfected with plasmids carrying MYO6WT or MYO6p.E60Q, and a zebrafish model was generated to characterize the in vivo phenotype. Cells transfected with MYO6WT showed higher expression of MYO6 in the plasma membrane and increased ATPase activity. Modeling the human MYO6 variants in zebrafish resulted in severe otic defects. At 72 h post-injection, MYO6p.E60Q embryos demonstrated alterations in the sizes of the saccule and utricle. Additionally, zebrafish with MYO6p.E60Q displayed super-coiled and bent hair bundles in otic hair cells when compared to control and MYO6WT embryos. In conclusion, our cellular and animal models add support to the in silico prediction that the p.E60Q missense variant is pathogenic and damaging to the protein. Since the c.178G>C MYO6 variant has a 0.5% allele frequency in the Qatari population, about 400 times higher than in other populations, it could contribute to explaining the high prevalence of hearing impairment in Qatar.

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“…Previously published works [5,9,[34][35][36] described the different ancestral components in the Qatari population.…”

Section: Discussionmentioning

confidence: 99%

Ancestry-related distribution of Runs of homozygosity and functional variants in Qatari population

et al. 2022

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Background Describing how genetic history shapes the pattern of medically relevant variants could improve the understanding of how specific loci interact with each other and affect diseases and traits prevalence. The Qatari population is characterized by a complex history of admixture and substructure, and the study of its population genomic features would provide valuable insights into the genetic landscape of functional variants. Here, we analyzed the genomic variation of 186 newly-genotyped healthy individuals from the Qatari peninsula. Results We discovered an intricate genetic structure using ancestry related analyses. In particular, the presence of three different clusters, Cluster 1, Cluster 2 and Cluster 3 (with Near Eastern, South Asian and African ancestry, respectively), was detected with an additional fourth one (Cluster 4) with East Asian ancestry. These subpopulations show differences in the distribution of runs of homozygosity (ROH) and admixture events in the past, ranging from 40 to 5 generations ago. This complex genetic history led to a peculiar pattern of functional markers under positive selection, differentiated in shared signals and private signals. Interestingly we found several signatures of shared selection on SNPs in the FADS2 gene, hinting at a possible common evolutionary link to dietary intake. Among the private signals, we found enrichment for markers associated with HDL and LDL for Cluster 1(Near Eastern ancestry) and Cluster 3 (South Asian ancestry) and height and blood traits for Cluster 2 (African ancestry). The differences in genetic history among these populations also resulted in the different frequency distribution of putative loss of function variants. For example, homozygous carriers for rs2884737, a variant linked to an anticoagulant drug (warfarin) response, are mainly represented by individuals with predominant Bedouin ancestry (risk allele frequency G at 0.48). Conclusions We provided a detailed catalogue of the different ancestral pattern in the Qatari population highlighting differences and similarities in the distribution of selected variants and putative loss of functions. Finally, these results would provide useful guidance for assessing genetic risk factors linked to consanguinity and genetic ancestry.

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Qatar genome: Insights on genomics from the Middle East

Cited by 45 publications

References 53 publications

Ratios of Acetaminophen Metabolites Identify New Loci of Pharmacogenetic Relevance in a Genome-Wide Association Study

Ratios of Acetaminophen Metabolites Identify New Loci of Pharmacogenetic Relevance in a Genome-Wide Association Study

Functional Characterization of the MYO6 Variant p.E60Q in Non-Syndromic Hearing Loss Patients

Ancestry-related distribution of Runs of homozygosity and functional variants in Qatari population

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