Genetic associations and parent-of-origin effects of PVRL1 in non-syndromic cleft lip with or without cleft palate across multiple ethnic populations

Abstract

Objectives: This study investigated the associations of PVRL1 gene variants with non-syndromic cleft lip with or without cleft palate (NSCL/P) by evaluating transmission distortion and parent-of-origin (POO) effects in multiple ethnic populations.

Methods: We conducted allelic and genotypic transmission disequilibrium tests (TDT) on 10 single-nucleotide variants (SNVs) in PVRL1 using data from 142 Korean families with an affected child. POO effects were analyzed using the POO likelihood ratio test, comparing transmission rates of maternally and paternally inherited alleles. To assess generalizability and ethnic heterogeneity, we compared results from Korean families with data from the Center for Craniofacial and Dental Genetics, which included 2,226 individuals from 497 European and 245 Asian trios.

Results: TDT analysis identified significant over-transmission of the rs7940667 (G361V) C allele in Korean families (p=0.007), a finding replicated in both Asian (p=6.5×10-7) and European families (p=1.6×10-10). Eight SNVs showed strong TDT evidence in larger Asian and European datasets after multiple comparison corrections (p<0.0073). Of these, 4 SNVs (rs7940667, rs7103685, rs7129848, and rs4409845) showed particularly robust association (p<5×10-8). POO analysis revealed significant maternal over-transmission of the rs10790330-A allele in Korean families (p=0.044). This finding was replicated in European families (p=9.0×10-4). Additionally, 3 other SNVs, rs7129848 (p=0.001) and the linked SNVs rs3935406 and rs10892434 (p=0.025), exhibited maternal over-transmission in the validation datasets.

Conclusions: Our findings provide robust evidence supporting the associations of PVRL1 variants with NSCL/P susceptibility. Further research is necessary to explore the potential clinical applications of these findings.

Keywords: Case-parent trio design; Human poliovirus receptor related 1; Nonsyndromic cleft lip with or without cleft palate; Parent-of-origin effect; Transmission disequilibrium test.

Figure 1.

Flowchart depicting the study design and sample selection process for the Korean family trios of non-syndromic cleft lip with or without cleft palate. n, number of families; OC, oral cleft; TDT, transmission disequilibrium test.

Figure 2.

Evidence for the association of PVRL1 with non-syndromic cleft lip with or without cleft palate in families of multiple ethnicities. (A) Transmission disequilibrium test (TDT) results. Each displayed p-value corresponds to the model (allelic or genotypic) that provided the best fit to the data for that single-nucleotide polymorphism (SNP). The red dashed line represents the genome-wide significance threshold (p<5×10^-8), while the grey solid line indicates the Bonferroni-corrected significance threshold (p<0.01). (B) Parent-of-origin (POO) effect analysis. The red dashed line represents the Bonferroni-corrected significance threshold (p<0.01), and the grey solid line indicates the nominal significance threshold (p<0.05); p-values were derived from the POO likelihood ratio test.