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Characterization of Greater Middle Eastern genetic variation for enhanced disease gene discovery.

ABSTRACT: The Greater Middle East (GME) has been a central hub of human migration and population admixture. The tradition of consanguinity, variably practiced in the Persian Gulf region, North Africa, and Central Asia, has resulted in an elevated burden of recessive disease. Here we generated a whole-exome GME variome from 1,111 unrelated subjects. We detected substantial diversity and admixture in continental and subregional populations, corresponding to several ancient founder populations with little evidence of bottlenecks. Measured consanguinity rates were an order of magnitude above those in other sampled populations, and the GME population exhibited an increased burden of runs of homozygosity (ROHs) but showed no evidence for reduced burden of deleterious variation due to classically theorized 'genetic purging'. Applying this database to unsolved recessive conditions in the GME population reduced the number of potential disease-causing variants by four- to sevenfold. These results show variegated genetic architecture in GME populations and support future human genetic discoveries in Mendelian and population genetics.

SUBMITTER: Scott EM

PROVIDER: S-EPMC5019950 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Characterization of Greater Middle Eastern genetic variation for enhanced disease gene discovery.

Scott Eric M EM Halees Anason A Itan Yuval Y Spencer Emily G EG He Yupeng Y Azab Mostafa Abdellateef MA Gabriel Stacey B SB Belkadi Aziz A Boisson Bertrand B Abel Laurent L Clark Andrew G AG Alkuraya Fowzan S FS Casanova Jean-Laurent JL Gleeson Joseph G JG

Nature genetics 20160718 9

The Greater Middle East (GME) has been a central hub of human migration and population admixture. The tradition of consanguinity, variably practiced in the Persian Gulf region, North Africa, and Central Asia, has resulted in an elevated burden of recessive disease. Here we generated a whole-exome GME variome from 1,111 unrelated subjects. We detected substantial diversity and admixture in continental and subregional populations, corresponding to several ancient founder populations with little ev ...[more]

PMID: 27428751

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Project description:BackgroundThe genetic architecture underlying Familial Hypercholesterolemia (FH) in Middle Eastern Arabs is yet to be fully described, and approaches to assess this from population-wide biobanks are important for public health planning and personalized medicine.MethodsWe evaluate the pilot phase cohort (n = 6,140 adults) of the Qatar Biobank (QBB) for FH using the Dutch Lipid Clinic Network (DLCN) criteria, followed by an in-depth characterization of all genetic alleles in known dominant (LDLR, APOB, and PCSK9) and recessive (LDLRAP1, ABCG5, ABCG8, and LIPA) FH-causing genes derived from whole-genome sequencing (WGS). We also investigate the utility of a globally established 12-SNP polygenic risk score to predict FH individuals in this cohort with Arab ancestry.ResultsUsing DLCN criteria, we identify eight (0.1%) 'definite', 41 (0.7%) 'probable' and 334 (5.4%) 'possible' FH individuals, estimating a prevalence of 'definite or probable' FH in the Qatari cohort of ~ 1:125. We identify ten previously known pathogenic single-nucleotide variants (SNVs) and 14 putatively novel SNVs, as well as one novel copy number variant in PCSK9. Further, despite the modest sample size, we identify one homozygote for a known pathogenic variant (ABCG8, p. Gly574Arg, global MAF = 4.49E-05) associated with Sitosterolemia 2. Finally, calculation of polygenic risk scores found that individuals with 'definite or probable' FH have a significantly higher LDL-C SNP score than 'unlikely' individuals (p = 0.0003), demonstrating its utility in Arab populations.ConclusionWe design and implement a standardized approach to phenotyping a population biobank for FH risk followed by systematically identifying known variants and assessing putative novel variants contributing to FH burden in Qatar. Our results motivate similar studies in population-level biobanks - especially those with globally under-represented ancestries - and highlight the importance of genetic screening programs for early detection and management of individuals with high FH risk in health systems.

Dataset Information

Characterization of Greater Middle Eastern genetic variation for enhanced disease gene discovery.

Publications

Characterization of Greater Middle Eastern genetic variation for enhanced disease gene discovery.

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