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Trio-based GWAS identifies novel associations and subtype-specific risk factors for cleft palate

Kelsey Robinson¹, Trenell J Mosley¹, Kenneth S Rivera-González²

¹Department of Human Genetics, Emory University, Atlanta, GA 30322, USA.

|September 18, 2023

Insights

Genetic analysis reveals new risk factors for cleft palate (CP), a common birth defect. This study identified specific genetic associations for cleft hard palate (CHP) and broader risks for CP, improving our understanding of its complex genetic basis.

Area of Science:

Genetics
Craniofacial Biology
Birth Defects Research

Background:

Cleft palate (CP) is a frequent craniofacial birth defect with high heritability but few identified genetic risk factors.
CP presents as a spectrum of defects, historically studied as a single entity, potentially masking subtype-specific genetic influences.

Purpose of the Study:

To identify genetic risk factors for cleft palate (CP) by analyzing broad CP risks and subtype-specific risks (cleft soft palate [CSP] and cleft hard palate [CHP]).
To evaluate genetic associations in the context of CP subtypes and investigate potential replication of previously identified orofacial cleft SNPs.

Main Methods:

Genome-wide association study (GWAS) utilizing transmission disequilibrium tests (TDT) on 435 case-parent trios.
Analysis included broad CP risk (n=435), CSP risk (n=259), and CHP risk (n=125).
Investigated 20 loci reaching suggestive significance and tested for nominal replication of 22 previously associated SNPs.

Main Results:

A genome-wide significant locus at 9q33.3 (rs7035976) was associated with cleft hard palate (CHP), implicating the ANGPTL2 gene.
Nineteen additional loci showed suggestive significance, with limited overlap between broad CP, CSP, and CHP analyses.
Observed similarities in odds ratios across groups for broad CP-associated SNPs, but distinct patterns for subtype-specific SNPs.

Conclusions:

This study provides newly identified genetic associations for broad cleft palate (CP) risk and evidence for subtype-specific genetic risks.
The findings highlight the importance of considering CP subtypes in genetic research to uncover distinct etiological pathways.
The identified locus and gene (ANGPTL2) offer new avenues for understanding the molecular mechanisms underlying craniofacial development and CP.

Read full analysis

Abstract:

Cleft palate (CP) is one of the most common craniofacial birth defects; however, there are relatively few established genetic risk factors associated with its occurrence despite high heritability. Historically, CP has been studied as a single phenotype, although it manifests across a spectrum of defects involving the hard and/or soft palate. We performed a genome-wide association study using transmission disequilibrium tests of 435 case-parent trios to evaluate broad risks for any cleft palate (ACP) (n = 435), and subtype-specific risks for any cleft soft palate (CSP), (n = 259) and any cleft hard palate (CHP) (n = 125). We identified a single genome-wide significant locus at 9q33.3 (lead SNP rs7035976, p = 4.24 × 10^-8) associated with CHP. One gene at this locus, angiopoietin-like 2 (ANGPTL2), plays a role in osteoblast differentiation. It is expressed both in craniofacial tissue of human embryos and developing mouse palatal shelves. We found 19 additional loci reaching suggestive significance (p < 5 × 10^-6), of which only one overlapped between groups (chromosome 17q24.2, ACP and CSP). Odds ratios for the 20 loci were most similar across all 3 groups for SNPs associated with the ACP group, but more distinct when comparing SNPs associated with either subtype. We also found nominal evidence of replication (p < 0.05) for 22 SNPs previously associated with orofacial clefts. Our study to evaluate CP risks in the context of its subtypes and we provide newly reported associations affecting the broad risk for CP as well as evidence of subtype-specific risks.

Keywords:

GWAS genome sequencing hard palate osteogenesis palate palatogenesis phenotypic heterogeneity soft palate subtype

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