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

Greater Middle East Variome Consortium

doi:10.1038/ng.3592

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

Greater Middle East Variome Consortium

Pediatrics - Genetics and Metabolism

Research output: Contribution to journal › Letter › peer-review

120 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 Asia^1-3, 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 language	English (US)
Pages (from-to)	1071-1079
Number of pages	9
Journal	Nature Genetics
Volume	48
Issue number	9
DOIs	https://doi.org/10.1038/ng.3592
State	Published - 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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@article{bbc22a152736453580219a313c42d3d4,

title = "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 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 {\textquoteleft}genetic purging{\textquoteright}. 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.",

author = "{Greater Middle East Variome Consortium} and Scott, {Eric M.} and Anason Halees and Yuval Itan and Spencer, {Emily G.} and Yupeng He and Azab, {Mostafa Abdellateef} and Gabriel, {Stacey B.} and Aziz Belkadi and Bertrand Boisson and Laurent Abel and Clark, {Andrew G.} and Rahim, {Sohair Abdel} and Alkuraya, {Fowzan S.} and Casanova, {Jean Laurent} and Gleeson, {Joseph G.} and Mohammed Abdou and Avinash Abhytankar and Parisa Adimi and Jamil Ahmad and Mustafa Akcakus and Guside Aksu and {Al Hajjar}, Sami and {Al Juamaah}, Suliman and {Al Muhsen}, Saleh and {Al Sannaa}, Nouriya and {Al Tameni}, Salem and Jumana Al-Aama and Nasir Al-Allawi and Raidah Al-Baradie and Lihadh Al-Gazali and Amal Al-Hashem and Waleed Al-Herz and Deema Al-Jeaid and Asma Al-Tawari and Abdullah Alangari and Alexandre Alcais and AlFawaz, {Tariq S.} and Zobaida Alsum and Aomar Ammar-Khodja and Sepideh Amouian and Cigdem Arikan and Omid Aryani and Ayca Aslanger and Cigdem Aydogmus and Caner Aytekin and Matloob Azam and Boglarka Bansagi and Barbouche, {Mohamed Rhida} and Laila Bastaki and William Dobyns",

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.).",

year = "2016",

month = sep,

day = "1",

doi = "10.1038/ng.3592",

language = "English (US)",

volume = "48",

pages = "1071--1079",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "9",

}

TY - JOUR

T1 - Characterization of greater middle eastern genetic variation for enhanced disease gene discovery

AU - Greater Middle East Variome Consortium

AU - Scott, Eric M.

AU - Halees, Anason

AU - Itan, Yuval

AU - Spencer, Emily G.

AU - He, Yupeng

AU - Azab, Mostafa Abdellateef

AU - Gabriel, Stacey B.

AU - Belkadi, Aziz

AU - Boisson, Bertrand

AU - Abel, Laurent

AU - Clark, Andrew G.

AU - Rahim, Sohair Abdel

AU - Alkuraya, Fowzan S.

AU - Casanova, Jean Laurent

AU - Gleeson, Joseph G.

AU - Abdou, Mohammed

AU - Abhytankar, Avinash

AU - Adimi, Parisa

AU - Ahmad, Jamil

AU - Akcakus, Mustafa

AU - Aksu, Guside

AU - Al Hajjar, Sami

AU - Al Juamaah, Suliman

AU - Al Muhsen, Saleh

AU - Al Sannaa, Nouriya

AU - Al Tameni, Salem

AU - Al-Aama, Jumana

AU - Al-Allawi, Nasir

AU - Al-Baradie, Raidah

AU - Al-Gazali, Lihadh

AU - Al-Hashem, Amal

AU - Al-Herz, Waleed

AU - Al-Jeaid, Deema

AU - Al-Tawari, Asma

AU - Alangari, Abdullah

AU - Alcais, Alexandre

AU - AlFawaz, Tariq S.

AU - Alsum, Zobaida

AU - Ammar-Khodja, Aomar

AU - Amouian, Sepideh

AU - Arikan, Cigdem

AU - Aryani, Omid

AU - Aslanger, Ayca

AU - Aydogmus, Cigdem

AU - Aytekin, Caner

AU - Azam, Matloob

AU - Bansagi, Boglarka

AU - Barbouche, Mohamed Rhida

AU - Bastaki, Laila

AU - Dobyns, William

N1 - 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.).

PY - 2016/9/1

Y1 - 2016/9/1

N2 - 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.

AB - 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.

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DO - 10.1038/ng.3592

M3 - Letter

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JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 9

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