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

CARLSON, JENNA C.; BUXÓ, CARMEN J.; DELEYIANNIS, FRED W. B.; MORENO, LINA; VIEIRA, ALEXANDRE R.; WEINBERG, SETH M.; MARAZITA, MARY L.; LESLIE, ELIZABETH J.; SHAFFER, JOHN R.; BUTALI, AZEEZ; CASTILLA, EDUARDO E.; CHRISTENSEN, KAARE; LEIGH FIELD, L.; HECHT, JACQUELINE T.; ORIOLI, IEDA M.; PADILLA, CARMENCITA; WEHBY, GEORGE L.; FEINGOLD, ELEANOR; MURRAY, JEFFREY C.; BEATY, TERRI H.

HUMAN GENETICS.

SPRINGER

Año: 2017 vol. 136 p. 275 - 286

0340-6717

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.