title: Association Studies and Direct DNA Sequencing Implicate Genetic Susceptibility Loci in the Etiology of Nonsyndromic Orofacial Clefts in Sub-Saharan African Populations.
abstract: Orofacial clefts (OFCs) are congenital dysmorphologies of the human face and oral cavity, with a global incidence of 1 per 700 live births. These anomalies exhibit a multifactorial pattern of inheritance, with genetic and environmental factors both playing crucial roles. Many loci have been implicated in the etiology of nonsyndromic cleft lip with or without cleft palate (NSCL/P) in populations of Asian and European ancestries, through genome-wide association studies and candidate gene studies. However, few populations of African descent have been studied to date. Here, the authors show evidence of an association of some loci with NSCL/P and nonsyndromic cleft palate only (NSCPO) in cohorts from Africa (Ghana, Ethiopia, and Nigeria). The authors genotyped 48 single-nucleotide polymorphisms that were selected from previous genome-wide association studies and candidate gene studies. These markers were successfully genotyped on 701 NSCL/P and 163 NSCPO cases, 1,070 unaffected relatives, and 1,078 unrelated controls. The authors also directly sequenced 7 genes in 184 nonsyndromic OFC (NSOFC) cases and 96 controls from Ghana. Population-specific associations were observed in the case-control analyses of the subpopulations, with West African subpopulations (Ghana and Nigeria) showing a similar pattern of associations. In meta-analyses of the case-control cohort, PAX7 (rs742071, P = 5.10 × 10(-3)), 8q24 (rs987525, P = 1.22 × 10(-3)), and VAX1 (rs7078160, P = 0.04) were nominally associated with NSCL/P, and MSX1 (rs115200552, P = 0.01), TULP4 (rs651333, P = 0.04), CRISPLD2 (rs4783099, P = 0.02), and NOG1 (rs17760296, P = 0.04) were nominally associated with NSCPO. Moreover, 7 loci exhibited evidence of threshold overtransmission in NSOFC cases through the transmission disequilibrium test and through analyses of the family-based association for disease traits. Through DNA sequencing, the authors also identified 2 novel, rare, potentially pathogenic variants (p.Asn323Asp and p.Lys426IlefsTer6) in ARHGAP29 In conclusion, the authors have shown evidence for the association of many loci with NSCL/P and NSCPO. To the best of this knowledge, this study is the first to demonstrate any of these association signals in any African population.
authors.affiliation: Department of Biochemistry and Biotechnology, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana Cleft Clinic, Komfo Anokye Teaching Hospital, Kumasi, Ghana Department of Pediatrics, University of Iowa, Iowa City, IA, USA Department of Oral Pathology, Radiology and Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: L J J
authors.initials: LJ
authors.lastname: Gowans
authors.affiliation: College of Medicine, University of Lagos, Lagos, Nigeria.
authors.forename: W L
authors.initials: WL
authors.lastname: Adeyemo
authors.affiliation: Addis Ababa University, Addis Ababa, Ethiopia.
authors.forename: M
authors.initials: M
authors.lastname: Eshete
authors.affiliation: Department of Orthodontics, University of Dundee, Dundee, Scotland.
authors.forename: P A
authors.initials: PA
authors.lastname: Mossey
authors.affiliation: Department of Oral Pathology, Radiology and Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Busch
authors.affiliation: Obafemi Awolowo University Teaching Hospital, Ile-Ife, Nigeria.
authors.forename: B
authors.initials: B
authors.lastname: Aregbesola
authors.affiliation: Cleft Clinic, Komfo Anokye Teaching Hospital, Kumasi, Ghana Department of Surgery, School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.
authors.forename: P
authors.initials: P
authors.lastname: Donkor
authors.affiliation: Department of Biochemistry and Biotechnology, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.
authors.forename: F K N
authors.initials: FK
authors.lastname: Arthur
authors.affiliation: Department of Oral and Maxillofacial Surgery, State House Hospital, Abuja, Nigeria.
authors.forename: S A
authors.initials: SA
authors.lastname: Bello
authors.affiliation: Department of Oral Pathology, Radiology and Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Martinez
authors.affiliation: Department of Oral Pathology, Radiology and Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Oral Pathology, Radiology and Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Augustine-Akpan
authors.affiliation: Addis Ababa University, Addis Ababa, Ethiopia.
authors.forename: W
authors.initials: W
authors.lastname: Deressa
authors.affiliation: Department of Biochemistry and Biotechnology, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.
authors.forename: P
authors.initials: P
authors.lastname: Twumasi
authors.affiliation: College of Medicine, University of Lagos, Lagos, Nigeria.
authors.forename: J
authors.initials: J
authors.lastname: Olutayo
authors.affiliation: Addis Ababa University, Addis Ababa, Ethiopia.
authors.forename: M
authors.initials: M
authors.lastname: Deribew
authors.affiliation: Cleft Clinic, Komfo Anokye Teaching Hospital, Kumasi, Ghana Department of Surgery, School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.
authors.forename: P
authors.initials: P
authors.lastname: Agbenorku
authors.affiliation: Cleft Clinic, Komfo Anokye Teaching Hospital, Kumasi, Ghana Department of Surgery, School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.
authors.forename: A A
authors.initials: AA
authors.lastname: Oti
authors.affiliation: Obafemi Awolowo University Teaching Hospital, Ile-Ife, Nigeria.
authors.forename: R
authors.initials: R
authors.lastname: Braimah
authors.affiliation: Cleft Clinic, Komfo Anokye Teaching Hospital, Kumasi, Ghana.
authors.forename: G
authors.initials: G
authors.lastname: Plange-Rhule
authors.affiliation: Yekatit 12 Hospital Medical College, Addis Ababa, Ethiopia.
authors.forename: M
authors.initials: M
authors.lastname: Gesses
authors.affiliation: Cleft Clinic, Komfo Anokye Teaching Hospital, Kumasi, Ghana Department of Surgery, School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.
authors.forename: S
authors.initials: S
authors.lastname: Obiri-Yeboah
authors.affiliation: Department of Burns and Plastic Surgery, Ladoke Akintola University of Technology Teaching Hospital, Osogbo, Nigeria.
authors.forename: G O
authors.initials: GO
authors.lastname: Oseni
authors.affiliation: Department of Burns and Plastic Surgery, Ladoke Akintola University of Technology Teaching Hospital, Osogbo, Nigeria.
authors.forename: P B
authors.initials: PB
authors.lastname: Olaitan
authors.affiliation: Division of Pediatric Surgery, Department of Surgery, University of Ilorin, Ilorin, Nigeria.
authors.forename: L
authors.initials: L
authors.lastname: Abdur-Rahman
authors.affiliation: Yekatit 12 Hospital Medical College, Addis Ababa, Ethiopia.
authors.forename: F
authors.initials: F
authors.lastname: Abate
authors.affiliation: Yekatit 12 Hospital Medical College, Addis Ababa, Ethiopia.
authors.forename: T
authors.initials: T
authors.lastname: Hailu
authors.affiliation: Haukeland University Hospital Bergen, Bergen, Norway.
authors.forename: P
authors.initials: P
authors.lastname: Gravem
authors.affiliation: Department of Burns and Plastic Surgery, Ladoke Akintola University of Technology Teaching Hospital, Osogbo, Nigeria.
authors.forename: M O
authors.initials: MO
authors.lastname: Ogunlewe
authors.affiliation: School of Dental Medicine, University of Puerto Rico Medical Science Campus, San Juan, Puerto Rico.
authors.forename: C J
authors.initials: CJ
authors.lastname: Buxó
authors.affiliation: Department of Oral Biology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Marazita
authors.affiliation: Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Adeyemo
authors.affiliation: Department of Pediatrics, University of Iowa, Iowa City, IA, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Murray
authors.affiliation: Department of Oral Pathology, Radiology and Medicine, University of Iowa, Iowa City, IA, USA azeez-butali@uiowa.edu.
authors.forename: A
authors.initials: A
authors.lastname: Butali
mesh_terms: D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D005002:Ethiopia / Q000453:epidemiology; D005260:Female; D056426:Genetic Loci / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005869:Ghana / Q000453:epidemiology; D006801:Humans; D008297:Male; D009549:Nigeria / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: D005819:Genetic Markers
keywords: candidate genes; craniofacial genetics; genetic heterogeneity; genome-wide association studies (GWAS); population genetics; rare variants