TY - JOUR
T1 - A multi-ethnic genome-wide association study identifies novel loci for non-syndromic cleft lip with or without cleft palate on 2p 24.2, 17q23 and 19q13
AU - Leslie, Elizabeth J.
AU - Carlson, Jenna C.
AU - Shaffer, John R.
AU - Feingold, Eleanor
AU - Wehby, George
AU - Laurie, Cecelia A.
AU - Jain, Deepti
AU - Laurie, Cathy C.
AU - Doheny, Kimberly F.
AU - McHenry, Toby
AU - Resick, Judith
AU - Sanchez, Carla
AU - Jacobs, Jennifer
AU - Emanuele, Beth
AU - Vieira, Alexandre R.
AU - Neiswanger, Katherine
AU - Lidral, Andrew C.
AU - Valencia-Ramirez, Luz Consuelo
AU - Lopez-Palacio, Ana Maria
AU - Valencia, Dora Rivera
AU - Arcos-Burgos, Mauricio
AU - Czeizel, Andrew E.
AU - Field, L. Leigh
AU - Padilla, Carmencita D.
AU - Maria, Eva
AU - Cutiongco-de la Paz, C.
AU - Deleyiannis, Frederic
AU - Christensen, Kaare
AU - Munger, Ronald G.
AU - Lie, Rolv T.
AU - Wilcox, Allen
AU - Romitti, Paul A.
AU - Castilla, Eduardo E.
AU - Mereb, Juan C.
AU - Poletta, Fernando A.
AU - Orioli, Iêda M.
AU - Carvalho, Flavia M.
AU - Hecht, Jacqueline T.
AU - Blanton, Susan H.
AU - Buxó, Carmen J.
AU - Butali, Azeez
AU - Mossey, Peter A.
AU - Adeyemo, Wasiu L.
AU - James, Olutayo
AU - Braimah, Ramat O.
AU - Aregbesola, Babatunde S.
AU - Eshete, Mekonen A.
AU - Abate, Fikre
AU - Koruyucu, Mine
AU - Seymen, Figen
AU - Ma, Lian
AU - de Salamanca, Javier Enríquez
AU - Weinberg, Seth M.
AU - Moreno, Lina
AU - Murray, Jeffrey C.
AU - Marazita, Mary L.
N1 - Publisher Copyright:
© The Author 2016. Published by Oxford University Press.
PY - 2016
Y1 - 2016
N2 - Orofacial clefts (OFCs), which include non-syndromic cleft lip with or without cleft palate (CL/P), are among themost 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 amultiethnic 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.
AB - Orofacial clefts (OFCs), which include non-syndromic cleft lip with or without cleft palate (CL/P), are among themost 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 amultiethnic 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.
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U2 - 10.1093/hmg/ddw104
DO - 10.1093/hmg/ddw104
M3 - Article
C2 - 27033726
AN - SCOPUS:85016059513
SN - 0964-6906
VL - 25
SP - 2862
EP - 2872
JO - Human molecular genetics
JF - Human molecular genetics
IS - 13
ER -