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

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

294 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
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 - 1 Sep 2016

Funding

Funders	Funder number
Candidoser Association	U01AI109697, R01AI088364, R37AI095983, U01AI088685, P01AI061093, KACST 13-BIO1113-20, R21AI107508
Qatari National Research Foundation	NPRP6-1463
Yale Center for Mendelian Disorders	U54HG006504
National Institutes of Health	R01NS048453
Howard Hughes Medical Institute
National Institute of Child Health and Human Development	P01HD070494
St. Giles Foundation
Rockefeller University	5UL1RR024143-04
Broad Institute	U54HG003067
Simons Foundation Autism Research Initiative	275275, 175303
Institut national de la santé et de la recherche médicale

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10.1038/ng.3592

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@article{a72a3c49779d4dbbbeb56dd49ed4ce5d,

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 Annick Raas-Rothschild and Vared Shkalim",

year = "2016",

month = sep,

day = "1",

doi = "10.1038/ng.3592",

language = "אנגלית",

volume = "48",

pages = "1071--1079",

journal = "Nature Genetics",

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number = "9",

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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 - Raas-Rothschild, Annick

AU - Shkalim, Vared

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

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