Shared genetic risk between major orofacial cleft phenotypes in an African population

Azeez Alade; Tabitha Peter; Tamara Busch; Waheed Awotoye; Deepti Anand; Oladayo Abimbola; Emmanuel Aladenika; Mojisola Olujitan; Oscar Rysavy; Phuong Fawng Nguyen; Thirona Naicker; Peter A Mossey; Lord J J Gowans; Mekonen A Eshete; Wasiu L Adeyemo; Erliang Zeng; Eric Van Otterloo; Michael O'Rorke; Adebowale Adeyemo; Jeffrey C Murray; Salil A Lachke; Paul A Romitti; Azeez Butali

doi:10.1002/gepi.22564

Shared genetic risk between major orofacial cleft phenotypes in an African population

Genet Epidemiol. 2024 Apr 18. doi: 10.1002/gepi.22564. Online ahead of print.

Authors

Azeez Alade^{1

2}, Tabitha Peter¹, Tamara Busch¹, Waheed Awotoye³, Deepti Anand⁴, Oladayo Abimbola¹, Emmanuel Aladenika¹, Mojisola Olujitan¹, Oscar Rysavy¹, Phuong Fawng Nguyen¹, Thirona Naicker⁵, Peter A Mossey⁶, Lord J J Gowans⁷, Mekonen A Eshete⁸, Wasiu L Adeyemo⁹, Erliang Zeng¹, Eric Van Otterloo^{1

10}, Michael O'Rorke², Adebowale Adeyemo¹¹, Jeffrey C Murray¹², Salil A Lachke^{4

13}, Paul A Romitti², Azeez Butali^{1

14}

Affiliations

¹ Iowa Institute of Oral Health Research, University of Iowa, Iowa City, Iowa, USA.
² Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa, USA.
³ Department of Orthodontics, College of Dentistry, University of Iowa, Iowa City, Iowa, USA.
⁴ Department of Biological Sciences, University of Delaware, Newark, Delaware, USA.
⁵ Department of Paediatrics, Clinical Genetics, University of KwaZulu-Natal and Inkosi Albert Luthuli Central Hospital, Durban, South Africa.
⁶ Department of Orthodontics, University of Dundee, Dundee, UK.
⁷ Komfo Anokye Teaching Hospital and Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.
⁸ Department of Surgery, Addis Ababa University, School of Medicine, Addis Ababa, Ethiopia.
⁹ Department of Oral and Maxillofacial Surgery, University of Lagos, Lagos, Nigeria.
¹⁰ Department of Periodontics, College of Dentistry, University of Iowa, Iowa City, Iowa, USA.
¹¹ National Human Genomic Research Institute, Bethesda, Maryland, USA.
¹² Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA.
¹³ Center for Bioinformatics and Computational Biology, University of Delaware, Newark, Delaware, USA.
¹⁴ Department of Oral Pathology, Radiology and Medicine, College of Dentistry, University of Iowa, Iowa City, Iowa, USA.

PMID: 38634654
DOI: 10.1002/gepi.22564

Abstract

Nonsyndromic orofacial clefts (NSOFCs) represent a large proportion (70%-80%) of all OFCs. They can be broadly categorized into nonsyndromic cleft lip with or without cleft palate (NSCL/P) and nonsyndromic cleft palate only (NSCPO). Although NSCL/P and NSCPO are considered etiologically distinct, recent evidence suggests the presence of shared genetic risks. Thus, we investigated the genetic overlap between NSCL/P and NSCPO using African genome-wide association study (GWAS) data on NSOFCs. These data consist of 814 NSCL/P, 205 NSCPO cases, and 2159 unrelated controls. We generated common single-nucleotide variants (SNVs) association summary statistics separately for each phenotype (NSCL/P and NSCPO) under an additive genetic model. Subsequently, we employed the pleiotropic analysis under the composite null (PLACO) method to test for genetic overlap. Our analysis identified two loci with genome-wide significance (rs181737795 [p = 2.58E-08] and rs2221169 [p = 4.5E-08]) and one locus with marginal significance (rs187523265 [p = 5.22E-08]). Using mouse transcriptomics data and information from genetic phenotype databases, we identified MDN1, MAP3k7, KMT2A, ARCN1, and VADC2 as top candidate genes for the associated SNVs. These findings enhance our understanding of genetic variants associated with NSOFCs and identify potential candidate genes for further exploration.

Keywords: craniofacial; genetics; nonsyndromic; orofacial clefts; pleiotropy; single‐nucleotide variations; transcriptomics.

Grants and funding

DE/NIDCR NIH HHS/United States