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

Azeez Alade (Lead / Corresponding author), 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. MurraySalil A. Lachke, Paul A. Romitti, Azeez Butali

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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.

Original languageEnglish
Pages (from-to)1-12
Number of pages12
JournalGenetic Epidemiology
Early online date18 Apr 2024
DOIs
Publication statusE-pub ahead of print - 18 Apr 2024

Keywords

  • craniofacial
  • genetics
  • nonsyndromic
  • orofacial clefts
  • pleiotropy
  • single-nucleotide variations
  • transcriptomics

ASJC Scopus subject areas

  • Epidemiology
  • Genetics(clinical)

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