Shared genetic risk between major orofacial cleft phenotypes in an African population
Date
2024-04-18
Journal Title
Journal ISSN
Volume Title
Publisher
Genetic Epidemiology
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.
Description
This article was originally published in Genetic Epidemiology. The version of record is available at: https://doi.org/10.1002/gepi.22564. © 2024 The Authors. Genetic Epidemiology published by Wiley Periodicals LLC. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Keywords
craniofacial, genetics, nonsyndromic, orofacial clefts, pleiotropy, single-nucleotide variations, transcriptomics
Citation
Alade, A., Peter, T., Busch, T., Awotoye, W., Anand, D., Abimbola, O., Aladenika, E., Olujitan, M., Rysavy, O., Nguyen, P. F., Naicker, T., Mossey, P. A., Gowans, L. J. J., Eshete, M. A., Adeyemo, W. L., Zeng, E., Van Otterloo, E., O'Rorke, M., Adeyemo, A., … Butali, A. (2024). Shared genetic risk between major orofacial cleft phenotypes in an African population. Genetic Epidemiology, 1–12. https://doi.org/10.1002/gepi.22564