TY - JOUR
T1 - A multi-ethnic genome-wide association study identifies novel loci for non-syndromic cleft lip with or without cleft palate on 2p24.2, 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 - Cutiongco-de la Paz, Eva Maria 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 - National Institutes of Health (X01-HG007485 to MLM, R01-DE016148 to M.L.M., U01-DE024425 to M.L.M, R37-DE008559 to J.C.M. and MLM, R01-DE009886 to M.L.M., R21-DE016930 to M.L.M., R01-DE014667 to A.C.L. and L.M.M., R21-DE016930 to M.L.M., R01-DE012472 to M.L.M., R01-DE011931 to J.T.H., R01-DE011948 to K.C., R01-DD000295 to G.L.W., U54-MD007587 to C.J.B., R25-MD007607 to C.J.B., K99-DE024571 to C.J.B., K99/R00-DE022378 to A.B., K99-DE025060 to E.J.L., and R01-DE020895 to
G.L.W.). Genotyping and data cleaning were provided via an National Institutes of Health contract HHSN268201200008I to the Johns Hopkins Center for Inherited Disease Research. Additional support provided by: the Robert Wood Johnson Foundation, AMFDP Grant (72429 to A.B.); an intramural grant from the Research Institute of the Children’s Hospital of Colorado (FWD); operating costs support in the Philippines was provided by the Institute of Human Genetics, National Institutes of Health, University of the Philippines, Manila (C.P.); grants through Fundac¸ao de Amparo ~ a Pesquisa do Estado do Rio de Janeiro, Brazil (I.M.O.): grant numbers (E-26/102.797/2012, E-26/110.140/2013); grants through CNPq, Brazil (I.M.O.): grant numbers: (481069/2012-7, 306396/2013-0, 400427/2013-3). Some replication samples were from the Utah Child and Family Health study (R01-DE016877 [R.G.M.]. Some replication samples were from the Danish National Birth Cohort (PIs Mads Melbye and Jørn Olsen) funded by a major grant from the Danish National Research Foundation and initiated by the Danish Epidemiology Science Centre. Additional support for the Danish National Birth Cohort was obtained from the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Augustinus Foundation, and the Health Foundation. Some replication samples were from the Norwegian Cleft Study and from the Norwegian MoBa Study, both supported by the National Institute of Environmental Health Sciences/National Institutes of Health Intramural Research Program and the Norwegian Research Council.
PY - 2016/7/1
Y1 - 2016/7/1
N2 - 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.
AB - 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.
U2 - 10.1093/hmg/ddw104
DO - 10.1093/hmg/ddw104
M3 - Article
C2 - 27033726
SN - 0964-6906
VL - 25
SP - 2862
EP - 2872
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 13
ER -