Association studies and direct DNA sequencing implicate some known genetic susceptibility loci in the etiology of nonsyndromic orofacial clefts in sub-Saharan African populations

Jephthah Joojo Gowans, Wasiu L. Adeyemo, Mekonen A. Eshete, Peter Mossey, Tamara Busch, Babatunde Aregbesola, Peter Donkor, Fareed K N Arthur, Seidu A Bello, Andres Martinez, Mary Li, Eno-Abasi Augustine-Akpan, Wakgari Deressa, Peter Twumasi, Olutayo James, Deribew M, Pius Agbenorku, Alex Acheampong Oti, Rahman Braimah, Gyikua Plange-Rhule & 14 others Gesses M, Solomon Obiri-Yeboah, Ganiyu O Oseni, Peter B Olaitan, Lukman Abdur-Rahman, Abate F, Hailu T, Gravem P, Mobolanle O. Ogunlewe, Carmen J. Buxó, Mary L. Marazita, Adebowale Adeyemo, Jeffery C Murray, Azeez Butali

Research output: Contribution to journalArticle

16 Citations (Scopus)
123 Downloads (Pure)

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 multifactorial pattern of inheritance, with both genetic and environmental factors playing crucial roles. Many loci have been implicated in the aetiology of nonsyndromic cleft lip with or without cleft palate (NSCL/P) in populations of Asian and European ancestries through genome-wide association studies (GWAS) and candidate gene studies. However, few populations of African descent have been studied to date. Here, we show evidence of association of some loci with NSCL/P and nonsyndromic cleft palate only (NSCPO) in cohorts from Africa (Ghana, Ethiopia and Nigeria). We genotyped 48 SNPs that were selected from previous GWAS and candidate gene studies. These markers were successfully genotyped on 701 NSCL/P and 163 NSCPO cases, 1070 unaffected relatives and 1078 unrelated controls. We 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 sub-populations, with West African subpopulations (Ghana and Nigeria) showing similar pattern of associations. In meta-analyses of the case-control cohort, PAX7 (rs742071, p=5.10×10-03), 8q24 (rs987525, p=1.22×10-03) and VAX1 (rs7078160, p=0.04) were nominally associated with NSCL/P; 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 over-transmission in NSOFC cases in both transmission disequilibrium test (TDT) and family-based association for disease traits (DFAM) analyses. Through DNA sequencing, we also identified two novel, rare, potentially pathogenic variants (p.Asn323Asp and p.Lys426IlefsTer6) in ARHGAP29. In conclusion, we have shown evidence of association of many loci with NSCL/P and NSCPO. To the best of our knowledge, our study is the first to demonstrate any of these association signals in any African population.
Original languageEnglish
Pages (from-to)1245-1256
Number of pages12
JournalJournal of Dental Research
Volume95
Issue number11
Early online date1 Jul 2016
DOIs
Publication statusPublished - Oct 2016

Fingerprint

Genetic Loci
Cleft Palate
Genetic Predisposition to Disease
DNA Sequence Analysis
Ghana
Population
Genome-Wide Association Study
Nigeria
Multifactorial Inheritance
Genes
Ethiopia
Cleft Lip
Live Birth
Single Nucleotide Polymorphism
Mouth
Meta-Analysis
Incidence

Keywords

  • Carniofacial anomalies
  • Craniofacial biology/genetics
  • Genetics
  • Genomics
  • Orofacial cleft(s)
  • Population genetics

Cite this

Gowans, Jephthah Joojo ; Adeyemo, Wasiu L. ; Eshete, Mekonen A. ; Mossey, Peter ; Busch, Tamara ; Aregbesola, Babatunde ; Donkor, Peter ; Arthur, Fareed K N ; Bello, Seidu A ; Martinez, Andres ; Li, Mary ; Augustine-Akpan, Eno-Abasi ; Deressa, Wakgari ; Twumasi, Peter ; James, Olutayo ; M, Deribew ; Agbenorku, Pius ; Oti, Alex Acheampong ; Braimah, Rahman ; Plange-Rhule, Gyikua ; M, Gesses ; Obiri-Yeboah, Solomon ; Oseni, Ganiyu O ; Olaitan, Peter B ; Abdur-Rahman, Lukman ; F, Abate ; T, Hailu ; P, Gravem ; Ogunlewe, Mobolanle O. ; Buxó, Carmen J. ; Marazita, Mary L. ; Adeyemo, Adebowale ; Murray, Jeffery C ; Butali, Azeez. / Association studies and direct DNA sequencing implicate some known genetic susceptibility loci in the etiology of nonsyndromic orofacial clefts in sub-Saharan African populations. In: Journal of Dental Research. 2016 ; Vol. 95, No. 11. pp. 1245-1256.
@article{5129d399a9934b989bc75546a6771d8d,
title = "Association studies and direct DNA sequencing implicate some known 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 multifactorial pattern of inheritance, with both genetic and environmental factors playing crucial roles. Many loci have been implicated in the aetiology of nonsyndromic cleft lip with or without cleft palate (NSCL/P) in populations of Asian and European ancestries through genome-wide association studies (GWAS) and candidate gene studies. However, few populations of African descent have been studied to date. Here, we show evidence of association of some loci with NSCL/P and nonsyndromic cleft palate only (NSCPO) in cohorts from Africa (Ghana, Ethiopia and Nigeria). We genotyped 48 SNPs that were selected from previous GWAS and candidate gene studies. These markers were successfully genotyped on 701 NSCL/P and 163 NSCPO cases, 1070 unaffected relatives and 1078 unrelated controls. We 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 sub-populations, with West African subpopulations (Ghana and Nigeria) showing similar pattern of associations. In meta-analyses of the case-control cohort, PAX7 (rs742071, p=5.10×10-03), 8q24 (rs987525, p=1.22×10-03) and VAX1 (rs7078160, p=0.04) were nominally associated with NSCL/P; 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 over-transmission in NSOFC cases in both transmission disequilibrium test (TDT) and family-based association for disease traits (DFAM) analyses. Through DNA sequencing, we also identified two novel, rare, potentially pathogenic variants (p.Asn323Asp and p.Lys426IlefsTer6) in ARHGAP29. In conclusion, we have shown evidence of association of many loci with NSCL/P and NSCPO. To the best of our knowledge, our study is the first to demonstrate any of these association signals in any African population.",
keywords = "Carniofacial anomalies, Craniofacial biology/genetics, Genetics, Genomics, Orofacial cleft(s), Population genetics",
author = "Gowans, {Jephthah Joojo} and Adeyemo, {Wasiu L.} and Eshete, {Mekonen A.} and Peter Mossey and Tamara Busch and Babatunde Aregbesola and Peter Donkor and Arthur, {Fareed K N} and Bello, {Seidu A} and Andres Martinez and Mary Li and Eno-Abasi Augustine-Akpan and Wakgari Deressa and Peter Twumasi and Olutayo James and Deribew M and Pius Agbenorku and Oti, {Alex Acheampong} and Rahman Braimah and Gyikua Plange-Rhule and Gesses M and Solomon Obiri-Yeboah and Oseni, {Ganiyu O} and Olaitan, {Peter B} and Lukman Abdur-Rahman and Abate F and Hailu T and Gravem P and Ogunlewe, {Mobolanle O.} and Bux{\'o}, {Carmen J.} and Marazita, {Mary L.} and Adebowale Adeyemo and Murray, {Jeffery C} and Azeez Butali",
note = "This work was supported by the National Institute of Dental and Craniofacial Research (R00 DE022378) and the Robert Wood Johnson Foundation (72429; A.B.); the National Institutes of Health (R37 DE-08559 and DE-016148; J.C.M.); the Ghana Cleft Foundation (L.J.J.G.); the National Institute of Dental and Craniofacial Research (R01-DE009886 and R01 DE012472; M.L.M.); and the National Institute of Minority Health and Disparities (U54-MD007587, R25-MD007607; C.J.B.) and the National Institute of Dental and Craniofacial Research (K99-DE024571; C.J.B.).",
year = "2016",
month = "10",
doi = "10.1177/0022034516657003",
language = "English",
volume = "95",
pages = "1245--1256",
journal = "Journal of Dental Research",
issn = "0022-0345",
publisher = "SAGE Publications",
number = "11",

}

Gowans, JJ, Adeyemo, WL, Eshete, MA, Mossey, P, Busch, T, Aregbesola, B, Donkor, P, Arthur, FKN, Bello, SA, Martinez, A, Li, M, Augustine-Akpan, E-A, Deressa, W, Twumasi, P, James, O, M, D, Agbenorku, P, Oti, AA, Braimah, R, Plange-Rhule, G, M, G, Obiri-Yeboah, S, Oseni, GO, Olaitan, PB, Abdur-Rahman, L, F, A, T, H, P, G, Ogunlewe, MO, Buxó, CJ, Marazita, ML, Adeyemo, A, Murray, JC & Butali, A 2016, 'Association studies and direct DNA sequencing implicate some known genetic susceptibility loci in the etiology of nonsyndromic orofacial clefts in sub-Saharan African populations', Journal of Dental Research, vol. 95, no. 11, pp. 1245-1256. https://doi.org/10.1177/0022034516657003

Association studies and direct DNA sequencing implicate some known genetic susceptibility loci in the etiology of nonsyndromic orofacial clefts in sub-Saharan African populations. / Gowans, Jephthah Joojo; Adeyemo, Wasiu L.; Eshete, Mekonen A.; Mossey, Peter; Busch, Tamara; Aregbesola, Babatunde; Donkor, Peter; Arthur, Fareed K N; Bello, Seidu A; Martinez, Andres; Li, Mary; Augustine-Akpan, Eno-Abasi; Deressa, Wakgari; Twumasi, Peter; James, Olutayo ; M, Deribew; Agbenorku, Pius; Oti, Alex Acheampong ; Braimah, Rahman; Plange-Rhule, Gyikua; M, Gesses; Obiri-Yeboah, Solomon; Oseni, Ganiyu O; Olaitan, Peter B; Abdur-Rahman, Lukman; F, Abate; T, Hailu; P, Gravem; Ogunlewe, Mobolanle O.; Buxó, Carmen J.; Marazita, Mary L.; Adeyemo, Adebowale; Murray, Jeffery C; Butali, Azeez (Lead / Corresponding author).

In: Journal of Dental Research, Vol. 95, No. 11, 10.2016, p. 1245-1256.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Association studies and direct DNA sequencing implicate some known genetic susceptibility loci in the etiology of nonsyndromic orofacial clefts in sub-Saharan African populations

AU - Gowans, Jephthah Joojo

AU - Adeyemo, Wasiu L.

AU - Eshete, Mekonen A.

AU - Mossey, Peter

AU - Busch, Tamara

AU - Aregbesola, Babatunde

AU - Donkor, Peter

AU - Arthur, Fareed K N

AU - Bello, Seidu A

AU - Martinez, Andres

AU - Li, Mary

AU - Augustine-Akpan, Eno-Abasi

AU - Deressa, Wakgari

AU - Twumasi, Peter

AU - James, Olutayo

AU - M, Deribew

AU - Agbenorku, Pius

AU - Oti, Alex Acheampong

AU - Braimah, Rahman

AU - Plange-Rhule, Gyikua

AU - M, Gesses

AU - Obiri-Yeboah, Solomon

AU - Oseni, Ganiyu O

AU - Olaitan, Peter B

AU - Abdur-Rahman, Lukman

AU - F, Abate

AU - T, Hailu

AU - P, Gravem

AU - Ogunlewe, Mobolanle O.

AU - Buxó, Carmen J.

AU - Marazita, Mary L.

AU - Adeyemo, Adebowale

AU - Murray, Jeffery C

AU - Butali, Azeez

N1 - This work was supported by the National Institute of Dental and Craniofacial Research (R00 DE022378) and the Robert Wood Johnson Foundation (72429; A.B.); the National Institutes of Health (R37 DE-08559 and DE-016148; J.C.M.); the Ghana Cleft Foundation (L.J.J.G.); the National Institute of Dental and Craniofacial Research (R01-DE009886 and R01 DE012472; M.L.M.); and the National Institute of Minority Health and Disparities (U54-MD007587, R25-MD007607; C.J.B.) and the National Institute of Dental and Craniofacial Research (K99-DE024571; C.J.B.).

PY - 2016/10

Y1 - 2016/10

N2 - 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 multifactorial pattern of inheritance, with both genetic and environmental factors playing crucial roles. Many loci have been implicated in the aetiology of nonsyndromic cleft lip with or without cleft palate (NSCL/P) in populations of Asian and European ancestries through genome-wide association studies (GWAS) and candidate gene studies. However, few populations of African descent have been studied to date. Here, we show evidence of association of some loci with NSCL/P and nonsyndromic cleft palate only (NSCPO) in cohorts from Africa (Ghana, Ethiopia and Nigeria). We genotyped 48 SNPs that were selected from previous GWAS and candidate gene studies. These markers were successfully genotyped on 701 NSCL/P and 163 NSCPO cases, 1070 unaffected relatives and 1078 unrelated controls. We 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 sub-populations, with West African subpopulations (Ghana and Nigeria) showing similar pattern of associations. In meta-analyses of the case-control cohort, PAX7 (rs742071, p=5.10×10-03), 8q24 (rs987525, p=1.22×10-03) and VAX1 (rs7078160, p=0.04) were nominally associated with NSCL/P; 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 over-transmission in NSOFC cases in both transmission disequilibrium test (TDT) and family-based association for disease traits (DFAM) analyses. Through DNA sequencing, we also identified two novel, rare, potentially pathogenic variants (p.Asn323Asp and p.Lys426IlefsTer6) in ARHGAP29. In conclusion, we have shown evidence of association of many loci with NSCL/P and NSCPO. To the best of our knowledge, our study is the first to demonstrate any of these association signals in any African population.

AB - 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 multifactorial pattern of inheritance, with both genetic and environmental factors playing crucial roles. Many loci have been implicated in the aetiology of nonsyndromic cleft lip with or without cleft palate (NSCL/P) in populations of Asian and European ancestries through genome-wide association studies (GWAS) and candidate gene studies. However, few populations of African descent have been studied to date. Here, we show evidence of association of some loci with NSCL/P and nonsyndromic cleft palate only (NSCPO) in cohorts from Africa (Ghana, Ethiopia and Nigeria). We genotyped 48 SNPs that were selected from previous GWAS and candidate gene studies. These markers were successfully genotyped on 701 NSCL/P and 163 NSCPO cases, 1070 unaffected relatives and 1078 unrelated controls. We 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 sub-populations, with West African subpopulations (Ghana and Nigeria) showing similar pattern of associations. In meta-analyses of the case-control cohort, PAX7 (rs742071, p=5.10×10-03), 8q24 (rs987525, p=1.22×10-03) and VAX1 (rs7078160, p=0.04) were nominally associated with NSCL/P; 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 over-transmission in NSOFC cases in both transmission disequilibrium test (TDT) and family-based association for disease traits (DFAM) analyses. Through DNA sequencing, we also identified two novel, rare, potentially pathogenic variants (p.Asn323Asp and p.Lys426IlefsTer6) in ARHGAP29. In conclusion, we have shown evidence of association of many loci with NSCL/P and NSCPO. To the best of our knowledge, our study is the first to demonstrate any of these association signals in any African population.

KW - Carniofacial anomalies

KW - Craniofacial biology/genetics

KW - Genetics

KW - Genomics

KW - Orofacial cleft(s)

KW - Population genetics

UR - http://www.scopus.com/inward/record.url?scp=84988489513&partnerID=8YFLogxK

U2 - 10.1177/0022034516657003

DO - 10.1177/0022034516657003

M3 - Article

VL - 95

SP - 1245

EP - 1256

JO - Journal of Dental Research

JF - Journal of Dental Research

SN - 0022-0345

IS - 11

ER -