Rare Variants Analyses Suggest Novel Cleft Genes in the African Population

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

doi:10.21203/rs.3.rs-3921355/v1

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Rare Variants Analyses Suggest Novel Cleft Genes in the African Population

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Rare Variants Analyses Suggest Novel Cleft Genes in the African Population

Azeez Alade, Peter Mossey, Waheed Awotoye, Tamara Busch, Abimbola Oladayo, Emmanuel Aladenika, Mojisola Olujitan, J J Lord Gowans, Mekonen A Eshete, Wasiu L Adeyemo, …

Research square

02/27/2024

DOI: 10.21203/rs.3.rs-3921355/v1

PMCID: PMC10925394

PMID: 38464065

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https://doi.org/10.21203/rs.3.rs-3921355/v1View

Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

Non-syndromic orofacial clefts (NSOFCs) are common birth defects with a complex etiology. While over 60 common risk loci have been identified, they explain only a small proportion of the heritability for NSOFC. Rare variants have been implicated in the missing heritability. Thus, our study aimed to identify genes enriched with nonsynonymous rare coding variants associated with NSOFCs. Our sample included 814 non-syndromic cleft lip with or without palate (NSCL/P), 205 non-syndromic cleft palate only (NSCPO), and 2150 unrelated control children from Nigeria, Ghana, and Ethiopia. We conducted a gene-based analysis separately for each phenotype using three rare-variants collapsing models: (1) protein-altering (PA), (2) missense variants only (MO); and (3) loss of function variants only (LOFO). Subsequently, we utilized relevant transcriptomics data to evaluate associated gene expression and examined their mutation constraint using the gnomeAD database. In total, 13 genes showed suggestive associations (p = E-04). Among them, eight genes (ABCB1, ALKBH8, CENPF, CSAD, EXPH5, PDZD8, SLC16A9, and TTC28) were consistently expressed in relevant mouse and human craniofacial tissues during the formation of the face, and three genes (ABCB1, TTC28, and PDZD8) showed statistically significant mutation constraint. These findings underscore the role of rare variants in identifying candidate genes for NSOFCs.

Genetics

Nonsyndromic

Craniofacial

Orofacial clefts

Transcriptomics

Rare variants

Details

Title: Subtitle: Rare Variants Analyses Suggest Novel Cleft Genes in the African Population
Creators: Azeez Alade - University of Iowa
Peter Mossey - University of Dundee
Waheed Awotoye - University of Iowa
Tamara Busch - University of Iowa
Abimbola Oladayo - University of Iowa
Emmanuel Aladenika - University of Iowa
Mojisola Olujitan - University of Iowa
J J Lord Gowans - Komfo Anokye Teaching Hospital
Mekonen A Eshete - Addis Ababa University
Wasiu L Adeyemo - University of Lagos
Erliang Zeng - University of Iowa
Eric Otterloo - University of Iowa
Michael O'Rorke - University of Iowa
Adebowale Adeyemo - National Human Genome Research Institute
Jeffrey C Murray - University of Iowa
Justin Cotney - University of Connecticut
Salil A Lachke - University of Delaware
Paul Romitti - University of Iowa
Azeez Butali - University of Iowa
Emma Wentworth - University of Connecticut
Deepti Anand - University of Delaware
Thirona Naicker - University of KwaZulu-Natal
Resource Type: Preprint
Publication Details: Research square
DOI: 10.21203/rs.3.rs-3921355/v1
PMID: 38464065
PMCID: PMC10925394
Grant note: R01 DE028300 / NIDCR NIH HHS K99 DE022378 / NIDCR NIH HHS R03 DE024776 / NIDCR NIH HHS R00 DE022378 / NIDCR NIH HHS
Language: English
Date posted: 02/27/2024
Academic Unit: Preventive and Community Dentistry; Oral Pathology, Radiology and Medicine; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Pathology; Iowa Neuroscience Institute; Biostatistics; Pediatric Dentistry; Craniofacial Anomalies Research Center; Dental Research; Periodontics
Record Identifier: 9984572381002771

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