Characterization of greater middle eastern genetic variation for enhanced disease gene discovery

Greater Middle East Variome Consortium

Research output: Contribution to journalLetterpeer-review

129 Scopus citations

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 Asia1-3, has resulted in an elevated burden of recessive disease4. 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.

Original languageEnglish (US)
Pages (from-to)1071-1079
Number of pages9
JournalNature Genetics
Volume48
Issue number9
DOIs
StatePublished - Sep 1 2016

Bibliographical note

Funding Information:
The authors thank S. Sunyaev and D. Reich for help with PolyPhen-2 and DAF corrections, M. Turchin for help with purging analysis, J. Pickrell for help with TreeMix, and V. Bafna, N. Schork, and S. Bonissone for suggestions. Work was supported by grants from the US National Institutes of Health (P01HD070494 and R01NS048453), the Qatari National Research Foundation (NPRP6-1463), the Simons Foundation Autism Research Initiative (175303 and 275275) to J.G.G., the Yale Center for Mendelian Disorders (U54HG006504), the Broad Institute (U54HG003067), the Rockefeller University CTSA (5UL1RR024143-04), the Howard Hughes Medical Institute (to J.G.G. and J.-L.C.), INSERM, the St. Giles Foundation, and the Candidoser Association and by grants R01AI088364, R37AI095983, P01AI061093, U01AI109697 (to J.-L.C.), U01AI088685 (to J.-L.C. and L.A.), R21AI107508 (to E. Jouanguy), the DHFMR Collaborative Research Grant, and KACST 13-BIO1113-20 (to F.S.A.).

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