Investigation of parental transmission of GABBR2 Single Nucleotide Polymorphisms and its association with nonsyndromic cleft lip with or without cleft palate

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Ronald Munger


Background and Objectives: Genetic factors and maternal smoking status have been suggested to be a strong cause in the risk of cleft. GABBR2 has been found to be associated with plasma vitamin B12 (Hazra, 2009). Expression of GABBR2 may be regulated by nicotine. We investigated the association between 189 SNPs of GABBR2 and non-syndromic cleft lip with or without cleft palate in 165 Utah case-parent trios. Methods: Minor allele and chi-square test for Hardy-Weinberg equilibrium at each SNP were computed between parents. Pairwise linkage disequilibrium was computed as D' and r2 for all SNPs. Both allelic and genotypic transmission disequilibrium tests (TDTs) were performed for individual SNPs using package TRIO in R. The results were confirmed in PLINK. Sliding windows of haplotypes consisting of two SNPs were tested. Haplotype analysis was performed using PBAT. Results: The family-based genotypic and allelic TDT showed significant evidence of linkage and association at rs375828 at a nominal value of p<0.05. This SNP remained significant after maxT permutation allelic TDT test with p-value = 0.02. All haplotypes including rs375828 also showed nominally significant p values, possibly reflecting effects of this single SNP. No significant genotype-environment interaction was found. Conclusions: These findings suggest the possible involvement of GABBR2-rs375828 in the etiology of CL/P in Utah cleft-parent trios without excess parental transmission.

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