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

Area of Science:

• Genetics
• Human Genomics
• Congenital Anomalies

Background:

• Nonsyndromic orofacial clefts (NSOFCs) are common birth defects, comprising 70%-80% of all orofacial clefts (OFCs).
• NSOFCs are typically classified as nonsyndromic cleft lip with or without cleft palate (NSCL/P) and nonsyndromic cleft palate only (NSCPO), often considered etiologically distinct.
• Emerging evidence suggests potential shared genetic underpinnings between NSCL/P and NSCPO.

Purpose of the Study:

• To investigate the genetic overlap between NSCL/P and NSCPO.
• To identify shared genetic risk loci for NSOFCs using African genome-wide association study (GWAS) data.
• To pinpoint candidate genes associated with NSOFCs.

Main Methods:

• Utilized GWAS data from 814 NSCL/P cases, 205 NSCPO cases, and 2159 controls of African ancestry.
• Generated single-nucleotide variant (SNV) association summary statistics for each phenotype.
• Employed the Pleiotropic Analysis under the Composite Null (PLACO) method to assess genetic overlap.

Main Results:

• Identified two genome-wide significant loci (rs181737795, rs2221169) and one marginally significant locus (rs187523265) for NSOFCs.
• Associated SNVs implicated potential candidate genes including MDN1, MAP3k7, KMT2A, ARCN1, and VADC2, supported by mouse transcriptomics and genetic databases.
• Demonstrated significant genetic overlap between NSCL/P and NSCPO.

Conclusions:

• The study provides evidence for shared genetic risks contributing to different forms of NSOFCs.
• Identified specific genetic loci and candidate genes that warrant further investigation in NSOFC etiology.
• Enhances the understanding of the genetic architecture of nonsyndromic orofacial clefts.