A multi-ethnic genome-wide association study identifies novel loci for nonsyndromic cleft lip with or without cleft palate on 2p24.2, 17q23 and 19q31.
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Date
2016-07-01
Authors
Leslie, E.J.
Carlson, J.C.
Shaffer, J.R.
Feingold, E.
Wehby, G.
Laurie, C.A.
Jain, D.
Laurie, C.C.
Doheny, K.F.
McHenry, T.
Journal Title
Journal ISSN
Volume Title
Publisher
Oxford Academic
Abstract
Orofacial clefts (OFCs), which include non-syndromic cleft lip with or without cleft palate (CL/P), are among the most common birth defects in humans, affecting approximately 1 in 700 newborns. CL/P is phenotypically heterogeneous and has a complex etiology caused by genetic and environmental factors. Previous genome-wide association studies (GWASs) have identified at least 15 risk loci for CL/P. As these loci do not account for all of the genetic variance of CL/P, we hypothesized the existence of additional risk loci. We conducted a multiethnic GWAS in 6480 participants (823 unrelated cases, 1700 unrelated controls and 1319 case-parent trios) with European, Asian, African and Central and South American ancestry. Our GWAS revealed novel associations on 2p24 near FAM49A, a gene of unknown function (P = 4.22 × 10-8), and 19q13 near RHPN2, a gene involved in organizing the actin cytoskeleton (P = 4.17 × 10-8). Other regions reaching genome-wide significance were 1p36 (PAX7), 1p22 (ARHGAP29), 1q32 (IRF6), 8q24 and 17p13 (NTN1), all reported in previous GWASs. Stratification by ancestry group revealed a novel association with a region on 17q23 (P = 2.92 × 10-8) among individuals with European ancestry. This region included several promising candidates including TANC2, an oncogene required for development, and DCAF7, a scaffolding protein required for craniofacial development. In the Central and South American ancestry group, significant associations with loci previously identified in Asian or European ancestry groups reflected their admixed ancestry. In summary, we have identified novel CL/P risk loci and suggest new genes involved in craniofacial development, confirming the highly heterogeneous etiology of OFCs.
Description
Staff publications
Keywords
Genome-wide association study , Multi-ethnic , Orofacial clefts , Cleft lip and palate , Chromosome , Research Subject Categories::ODONTOLOGY
Citation
Leslie EJ, Carlson JC, Shaffer JR, Feingold E, Wehby G, Laurie CA, Jain D, Laurie CC, Doheny KF, McHenry T, Resick J, Sanchez C, Jacobs J, Emanuele B, Vieira AR, Neiswanger K, Lidral AC, Valencia-Ramirez LC, Lopez-Palacio AM, Rivera Valencia D, Arcos-Burgos M, Czeizel AE, Field LL, Padilla CD, Cutiongco-de la Paz EM, Deleyiannis F, Christensen K, Munger RG, Lie RT, Wilcox A, Romitti PA, Castilla EE, Mereb JC, Poletta FA, Orioli IM, Carvalho FM, Hecht JT, Blanton SH, Buxó CJ, Butali A, Mossey PA, Adeyemo WL, James O, Braimah RO, Aregbesola BS, Eshete MA, Abate F, Koruyucu M, Seymen F, Ma L, Enríquez de Salamanca J, Weinberg S, Moreno L, Murray JC, Marazita ML. A multi-ethnic genome-wide association study identifies novel loci for nonsyndromic cleft lip with or without cleft palate on 2p24.2, 17q23 and 19q31. Hum Mol Genet 2016; 25:2862-2872.