Journal Article

Genome-wide meta-analyses of nonsyndromic orofacial clefts identify novel associations between FOXE1 and all orofacial clefts, and TP63 and cleft lip with or without cleft palate

Orioli, Ieda M., Carlson, Jenna C., Vieira, Alexandre R., Feingold, Eleanor, Moreno, Lina, Shaffer, John R., Castilla, Eduardo E., Christensen, Kaare, Hecht, Jacqueline T., Padilla, Carmencita, Butali, Azeez, Leslie, Elizabeth J., Weinberg, Seth M., Deleyiannis, Fred W. B., Murray, Jeffrey C., Beaty, Terri H., Buxó, Carmen J., Leigh Field, L., Marazita, Mary L., Wehby, George L.

2017

Overview

Nonsyndromic orofacial clefts (OFCs) are a heterogeneous group of common craniofacial birth defects with complex etiologies that include genetic and environmental risk factors. OFCs are commonly categorized as cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP), which have historically been analyzed as distinct entities. Genes for both CL/P and CP have been identified via multiple genome-wide linkage and association studies (GWAS); however, altogether, known variants account for a minority of the estimated heritability in risk to these craniofacial birth defects. We performed genome-wide meta-analyses of CL/P, CP, and all OFCs across two large, multiethnic studies. We then performed population-specific meta-analyses in sub-samples of Asian and European ancestry. In addition to observing associations with known variants, we identified a novel genome-wide significant association between SNPs located in an intronic TP63 enhancer and CL/P ( p  = 1.16 × 10 −8 ). Several novel loci with compelling candidate genes approached genome-wide significance on 4q21.1 ( SHROOM3 ), 12q13.13 ( KRT18 ), and 8p21 ( NRG1 ). In the analysis of all OFCs combined, SNPs near FOXE1 reached genome-wide significance ( p  = 1.33 × 10 −9 ). Our results support the highly heterogeneous nature of OFCs and illustrate the utility of meta-analysis for discovering new genetic risk factors.

• Publisher: Springer Berlin Heidelberg,Springer,Springer Nature B.V
• Subject: Analysis / Biomedical and Life Sciences / Biomedicine / Birth defects / Chromosome Mapping / Cleft lip / Cleft Lip - genetics / Cleft palate / Cleft Palate - genetics / Dentistry / Epidemiology / Forkhead Transcription Factors - genetics / Gene Function / Gene loci / Genetic aspects / Genetic research / Genetics / Genome-Wide Association Study / Genomes / Genomics / Human Genetics / Humans / Medicine / Meta-analysis / Metabolic Diseases / Molecular Medicine / Original Investigation / Polymorphism, Single Nucleotide / Public health / Risk factors / Transcription Factors - genetics / Tumor Suppressor Proteins - genetics