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PMID: 27428751 Published · ppublish English Journal Article

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

Nature genetics ·Vol. 48 ·No. 9 ·2016-00-00 ·Pages 1071-6

Scott EM, Halees A, Itan Y, Spencer EG, He Y, Azab MA, Gabriel SB, Belkadi A, Boisson B, Abel L, Clark AG, Greater Middle East Variome Consortium, Alkuraya FS, Casanova JL, Gleeson JG

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.

MeSH Terms
Asians/genetics Cohort Studies Consanguinity Disease/genetics Exome/genetics Genes, Recessive Genetic Markers/genetics Genetic Variation/genetics Genetics, Population Genome, Human Genome-Wide Association Study Homozygote Human Migration Humans Middle East Whites/genetics
Chemicals
Genetic Markers
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Scott Eric M
Howard Hughes Medical Institute, Rockefeller University, New York, New York, USA. | Rady Children's Institute for Genomic Medicine, Department of Neurosciences, University of California, San Diego, La Jolla, California, USA. | Laboratory for Pediatric Brain Disease, Rockefeller University, New York, New York, USA.
Halees Anason
Department of Biostatistics, Epidemiology and Scientific Computing, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Itan Yuval
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University, New York, New York, USA.
Spencer Emily G
Howard Hughes Medical Institute, Rockefeller University, New York, New York, USA. | Rady Children's Institute for Genomic Medicine, Department of Neurosciences, University of California, San Diego, La Jolla, California, USA. | Laboratory for Pediatric Brain Disease, Rockefeller University, New York, New York, USA.
He Yupeng
Howard Hughes Medical Institute, Rockefeller University, New York, New York, USA. | Rady Children's Institute for Genomic Medicine, Department of Neurosciences, University of California, San Diego, La Jolla, California, USA. | Laboratory for Pediatric Brain Disease, Rockefeller University, New York, New York, USA.
Azab Mostafa Abdellateef
Howard Hughes Medical Institute, Rockefeller University, New York, New York, USA. | Rady Children's Institute for Genomic Medicine, Department of Neurosciences, University of California, San Diego, La Jolla, California, USA. | Laboratory for Pediatric Brain Disease, Rockefeller University, New York, New York, USA.
Gabriel Stacey B
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Belkadi Aziz
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, INSERM, Paris, France. | Paris Descartes University, Imagine Institute, Paris, France.
Boisson Bertrand
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University, New York, New York, USA. | Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, INSERM, Paris, France. | Paris Descartes University, Imagine Institute, Paris, France.
Abel Laurent
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University, New York, New York, USA. | Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, INSERM, Paris, France. | Paris Descartes University, Imagine Institute, Paris, France.
Clark Andrew G
Department of Molecular Biology and Genetics, Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, USA.
Greater Middle East Variome Consortium
Alkuraya Fowzan S
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. | Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
Casanova Jean-Laurent
Howard Hughes Medical Institute, Rockefeller University, New York, New York, USA. | St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University, New York, New York, USA. | Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, INSERM, Paris, France. | Paris Descartes University, Imagine Institute, Paris, France. | Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, Paris, France.
Gleeson Joseph G
Howard Hughes Medical Institute, Rockefeller University, New York, New York, USA. | Rady Children's Institute for Genomic Medicine, Department of Neurosciences, University of California, San Diego, La Jolla, California, USA. | Laboratory for Pediatric Brain Disease, Rockefeller University, New York, New York, USA.
Investigators
170 investigators, click to expand
Rahim Sohair Abdel
Abdel-Hadi Sawsan
Abdel-Salam Ghada
Abdel-Salam Ekram
Abdou Mohammed
Abhytankar Avinash
Adimi Parisa
Ahmad Jamil
Akcakus Mustafa
Aksu Guside
Hajjar Sami Al
Juamaah Suliman Al
Muhsen Saleh Al
Sannaa Nouriya Al
Tameni Salem Al
Al-Aama Jumana
Al-Allawi Nasir
Al-Baradie Raidah
Al-Gazali Lihadh
Al-Hashem Amal
Al-Herz Waleed
Al-Jeaid Deema
Al-Tawari Asma
Alangari Abdullah
Alcais Alexandre
S AlFawaz Tariq
Alsum Zobaida
Ammar-Khodja Aomar
Amouian Sepideh
Arikan Cigdem
Aryani Omid
Aslanger Ayca
Aydogmus Cigdem
Aytekin Caner
Azam Matloob
Bansagi Boglarka
Barbouche Mohamed-Rhida
Bastaki Laila
Ben-Omran Tawfeg
Bindu Parayil Sankaran
Blancas Lizbeth
Boisson-Dupuis Stéphanie
Bonnet Damien
Stambouli Omar Boudghene
Bousfiha Aziz
Boussafara Lobna
Boutros Jeannette
Bustamante Jacinta
Caksen Huseyin
Camcioglu Yildiz
Catherinot Emilie
Celik Fatma C
Ciancanelli Michael
Cipe Funda E
Clark Gary
Cobat Aurélie
Comu Sinan
Condie Angela
Condino-Neto Antonio
Desai Mukesh
Dobyns William
Dogu Figen
Domaia Mohamed
Dorum Meltem
Egritas Odul
Azbaoui Safa El
Baghdadi Jamila El
Ruby Mona El
El-Harouni Ashraf
Elfeky Reem A
Elghazali Gehad
Faqeih Eissa
Fenerci Elif
Fieschi Claire
Funda Cipe
Gamal Iman
Gelik Umit
Genel Fetah
Gezdirici Alper
M Girisha Katta
Goldstein Amy
Grattan-Smith Padraic
Gupta Neerja
Hahn Jin
Hatipoglu Nevin
Hennekam Raoul
Houshmand Massoud
Ichai Philippe
Ikinciogullari Aydan
Ismail Samira
Jalas Chaim
Jouanguy Emmanuelle
Kabra Madhulika
Kalkan Göknur
Kara Majdi
Karaca Neslihan
Karaer Kadri
Kariminejad Ariana
Kayserili Hulya
Keser-Emiroglu Melike
Kilic Sara S
Kissani Najib
Kokron Cristina
Koul Roshan
Kutukculer Necil
Lanternier Fanny
Mahdaviani Alireza
Mahlaoui Nizar
Mansour Lobna
Mansouri Davood
Margari Lucia
Valente Enza Maria
Marzouki Naima
Masri Amira
Megahed Amina
Megahed Hisham
Mekki Najla
Mesdaghi Mehrnaz
Mikati Mohd
Mojahedi Faezeh
Mulley John
Nampoothiri Sheela
Navarrete Carmen
Omar Tarek
Oraby Azza
Pandaluz Ayse
Parvaneh Nima
Patiroglu Turkan
Koc Zeynep Peker
Pellier Isabelle
Picard Capucine
Puel Anne
Raas-Rothschild Annick
Rajab Anna
Raoult Didier
Reisli Ismail
Rezaei Nima
Sabri Ayoub
Sahin Yasin
Saleem Laila
Salem Fadia
AlSediq Najla Sameer
Sanal Ozden
Sanger Terry
Shakankiry Hanan
Shang Lei
Shehata Nabil
Shembesh Nuri
Shkalim Vared
Softah Ameen
Sogaty Sameera
Soliman Neveen
Sonmez-Aunaci Fatma
Sztriha Laszlo
Taibi-Berrah Lynda
Temtamy Samia
Tonekaboni Hasan
Trauner Doris
Tuysuz Beyhan
Tuysuz Beyhan
Varan Ali
Vogt Guillaume
Walsh Christopher
Woods Geoffrey
Yesil Gozde
Yildiran Alisan
Yildiz Basak
Yuksel Adnan
Zaki Maha
Zhang Shen-Ying
Conflict of Interest

The authors declare no competing financial interests

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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.3592
Published
2016-00-00
Epub
2016-00-18
Pages
1071-6
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC5019950
Subset
IM
Grants
NCATS NIH HHS · UL1 TR000043 · United States
NHGRI NIH HHS · U54 HG003067 · United States
NIAID NIH HHS · U01 AI088685 · United States
NINDS NIH HHS · P30 NS047101 · United States
NCATS NIH HHS · UL1 TR001866 · United States
NINDS NIH HHS · R01 NS048453 · United States
NHGRI NIH HHS · U54 HG006504 · United States
NCRR NIH HHS · UL1 RR024143 · United States
Howard Hughes Medical Institute · United States
NIAID NIH HHS · R37 AI095983 · United States
NICHD NIH HHS · P01 HD070494 · United States
NIAID NIH HHS · R01 AI088364 · United States
NIAID NIH HHS · P01 AI061093 · United States
NIAID NIH HHS · U01 AI109697 · United States
NIAID NIH HHS · R21 AI107508 · United States
Corrections
CommentIn
PMID: 27573686
External Links
PubMed source DOI: 10.1038/ng.3592 PMC Full Text View journal details
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