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

被引：163

作者：

Leslie, Elizabeth J. ^{[1
]}

Carlson, Jenna C. ^{[1
,2
]}

Shaffer, John R. ^{[1
,3
]}

Feingold, Eleanor ^{[1
,2
,3
]}

Wehby, George ^{[4
]}

Laurie, Cecelia A. ^{[5
]}

Jain, Deepti ^{[5
]}

Laurie, Cathy C. ^{[5
]}

Doheny, Kimberly F. ^{[6
]}

McHenry, Toby ^{[1
]}

Resick, Judith ^{[1
]}

Sanchez, Carla ^{[1
]}

Jacobs, Jennifer ^{[1
]}

Emanuele, Beth ^{[1
]}

Vieira, Alexandre R. ^{[1
,3
]}

Neiswanger, Katherine ^{[1
]}

Lidral, Andrew C. ^{[7
]}

Consuelo Valencia-Ramirez, Luz ^{[11
]}

Maria Lopez-Palacio, Ana ^{[12
]}

Rivera Valencia, Dora ^{[13
]}

Arcos-Burgos, Mauricio ^{[14
]}

Czeizel, Andrew E. ^{[15
]}

Field, L. Leigh ^{[16
]}

Padilla, Carmencita D. ^{[17
,18
,19
,20
]}

Maria, Eva

Cutiongco-de la Paz, C. ^{[17
,18
,19
,20
]}

Deleyiannis, Frederic ^{[21
]}

Christensen, Kaare ^{[22
]}

Munger, Ronald G. ^{[23
]}

Lie, Rolv T. ^{[24
]}

Wilcox, Allen ^{[25
]}

Romitti, Paul A. ^{[8
]}

Castilla, Eduardo E. ^{[26
,27
,28
]}

Mereb, Juan C. ^{[30
]}

Poletta, Fernando A. ^{[26
,27
,28
]}

Orioli, Ieda M. ^{[28
,29
]}

Carvalho, Flavia M. ^{[27
,28
]}

Hecht, Jacqueline T. ^{[31
]}

Blanton, Susan H. ^{[32
]}

Buxo, Carmen J. ^{[33
]}

Butali, Azeez ^{[9
]}

Mossey, Peter A. ^{[34
]}

Adeyemo, Wasiu L. ^{[35
]}

James, Olutayo ^{[35
]}

Braimah, Ramat O. ^{[36
]}

Aregbesola, Babatunde S. ^{[36
]}

Eshete, Mekonen A. ^{[37
]}

Abate, Fikre ^{[37
]}

Koruyucu, Mine ^{[38
]}

Seymen, Figen ^{[38
]}

机构：

[1] Univ Pittsburgh, Ctr Craniofacial & Dent Genet, Dept Oral Biol, Sch Dent Med, Pittsburgh, PA 15219 USA

[2] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA

[3] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA

[4] Univ Iowa, Coll Publ Hlth, Dept Hlth Management & Policy, Iowa City, IA 52246 USA

[5] Univ Washington, Dept Biostat, Genet Coordinating Ctr, Seattle, WA 98195 USA

[6] Johns Hopkins Univ, Ctr Inherited Dis Res, Baltimore, MD 21224 USA

[7] Univ Iowa, Dept Orthodont, Coll Publ Hlth, Iowa City, IA 52242 USA

[8] Univ Iowa, Dept Epidemiol, Coll Publ Hlth, Iowa City, IA 52242 USA

[9] Univ Iowa, Coll Dent, Dept Oral Pathol Radiol & Med, Dows Inst Dent Res, Iowa City, IA 52242 USA

[10] Univ Iowa, Dept Pediat, Carver Coll Med, Iowa City, IA 52242 USA

[11] Fdn Clin Noel, Medellin 050012, Colombia

[12] Univ Antioquia, Dept Basic Integrated Studies, Coll Dent, Medellin 050001, Colombia

[13] Univ Antioquia, Populat Genet & Mutacarcinogenesis Grp, Medellin 050001, Colombia

[14] Australian Natl Univ, ANU Coll Med Biol & Environm, John Curtin Sch Med Res, Genom & Predict Med,Genome Biol Dept, Canberra, ACT 0200, Australia

[15] Fdn Community Control Hereditary Dis, H-1051 Budapest, Hungary

[16] Univ British Columbia, Dept Med Genet, Vancouver, BC V6H 3N1, Canada

[17] Coll Med, Dept Pediat, Manila 1000, Philippines

[18] Natl Inst Hlth, Inst Human Genet, Manila 1000, Philippines

[19] Univ Philippines Manila, Manila 1000, Philippines

[20] Univ Philippines Syst, Philippine Genome Ctr, Manila 1101, Philippines

[21] Univ Colorado, Dept Surg Plast & Reconstruct Surg, Sch Med, Denver, CO 80045 USA

[22] Univ Southern Denmark, Dept Epidemiol, Inst Publ Hlth, DK-5230 Odense, Denmark

[23] Utah State Univ, Dept Nutr Dietet & Food Sci, Logan, UT 84322 USA

[24] Univ Bergen, Dept Global Publ Hlth & Primary Care, NO-5020 Bergen, Norway

[25] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA

[26] CEMIC Ctr Med Educ & Clin Res, RA-1431 Buenos Aires, DF, Argentina

[27] Fiocruz MS, Inst Oswaldo Cruz, Lab Congenital Malformat Epidemiol, BR-21040360 Rio De Janeiro, Brazil

[28] Univ Fed Rio de Janeiro, ECLAMC Latin Amer Collaborat Study Congenital Mal, INAGEMP Natl Inst Populat Med Genet, BR-21941617 Rio De Janeiro, Brazil

[29] Univ Fed Rio de Janeiro, Dept Genet, Inst Biol, BR-21941617 Rio De Janeiro, Brazil

[30] Hosp Area, ECLAMC Latin Amer Collaborat Study Congenital Mal, RA-8430 El Bolson, Argentina

[31] Univ Texas Hlth Sci Ctr Houston, Dept Pediat, Houston, TX 77030 USA

[32] Univ Miami, Hussman Inst Human Gen, Mailman Sch Med, Dr John T Macdonald Fdn,Dept Human Genet, Coral Gables, FL 33124 USA

[33] Univ Puerto Rico, Sch Dent Med, San Juan, PR 00936 USA

[34] Univ Dundee, Dept Orthodont, Dundee DD1 4HN, Scotland

[35] Univ Lagos, Coll Med, Dept Oral & Maxillofacial Surg, PMB 12003, Lagos, Nigeria

[36] Obafemi Awolowo Univ, Dept Oral & Maxillofacial Surg, PMB 13, Ife, Nigeria

[37] Univ Addis Ababa, Sch Med, Dept Surg, POB 26493, Addis Ababa, Ethiopia

[38] Istanbul Univ, Dept Pedodont, TR-34116 Istanbul, Turkey

[39] Peking Univ, Sch Stomatol, Beijing 100081, Peoples R China

[40] Hosp Infantil Univ Nino Jesus, Unidad Cirugia Plast, Madrid 28009, Spain

[41] Univ Pittsburgh, Sch Med, Clin & Translat Sci, Pittsburgh, PA 15213 USA

来源：

HUMAN MOLECULAR GENETICS | 2016年 / 25卷 / 13期

基金：

美国国家卫生研究院; 新加坡国家研究基金会;

关键词：

SUSCEPTIBILITY LOCUS; CAUSE VAN; GENE; RISK; POPULATION; EXPRESSION; MUTATIONS; VARIANTS; CANCER; ENDOTHELIN-1;

D O I：

10.1093/hmg/ddw104

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 am ultiethnic 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 x 10(-8)), and 19q13 near RHPN2, a gene involved in organizing the actin cytoskeleton (P = 4.17 x 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 x 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.

引用

页码：2862 / 2872

页数：11

共 53 条

[1] Confirming genes influencing risk to cleft lip with/without cleft palate in a case-parent trio study [J].

Beaty, T. H. ;

Taub, M. A. ;

Scott, A. F. ;

Murray, J. C. ;

Marazita, M. L. ;

Schwender, H. ;

Parker, M. M. ;

Hetmanski, J. B. ;

Balakrishnan, P. ;

Mansilla, M. A. ;

Mangold, E. ;

Ludwig, K. U. ;

Noethen, M. M. ;

Rubini, M. ;

Elcioglu, N. ;

Ruczinski, I. .

HUMAN GENETICS, 2013, 132 (07) :771-781

[2] A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4 [J].

Beaty, Terri H. ;

Murray, Jeffrey C. ;

Marazita, Mary L. ;

Munger, Ronald G. ;

Ruczinski, Ingo ;

Hetmanski, Jacqueline B. ;

Liang, Kung Yee ;

Wu, Tao ;

Murray, Tanda ;

Fallin, M. Daniele ;

Redett, Richard A. ;

Raymond, Gerald ;

Schwender, Holger ;

Jin, Sheng-Chih ;

Cooper, Margaret E. ;

Dunnwald, Martine ;

Mansilla, Maria A. ;

Leslie, Elizabeth ;

Bullard, Stephen ;

Lidral, Andrew C. ;

Moreno, Lina M. ;

Menezes, Renato ;

Vieira, Alexandre R. ;

Petrin, Aline ;

Wilcox, Allen J. ;

Lie, Rolv T. ;

Jabs, Ethylin W. ;

Wu-Chou, Yah Huei ;

Chen, Philip K. ;

Wang, Hong ;

Ye, Xiaoqian ;

Huang, Shangzhi ;

Yeow, Vincent ;

Chong, Samuel S. ;

Jee, Sun Ha ;

Shi, Bing ;

Christensen, Kaare ;

Melbye, Mads ;

Doheny, Kimberly F. ;

Pugh, Elizabeth W. ;

Ling, Hua ;

Castilla, Eduardo E. ;

Czeizel, Andrew E. ;

Ma, Lian ;

Field, L. Leigh ;

Brody, Lawrence ;

Pangilinan, Faith ;

Mills, James L. ;

Molloy, Anne M. ;

Kirke, Peadar N. .

NATURE GENETICS, 2010, 42 (06) :525-U76

[3] Interferon regulatory factor 6 regulates keratinocyte migration [J].

Biggs, Leah C. ;

Naridze, Rachelle L. ;

DeMali, Kris A. ;

Lusche, Daniel F. ;

Kuhl, Spencer ;

Soll, David R. ;

Schutte, Brian C. ;

Dunnwald, Martine .

JOURNAL OF CELL SCIENCE, 2014, 127 (13) :2840-2848

[4] Key susceptibility locus for nonsyndromic cleft lip with or without cleft palate on chromosome 8q24 [J].

Birnbaum, Stefanie ;

Ludwig, Kerstin U. ;

Reutter, Heiko ;

Herms, Stefan ;

Steffens, Michael ;

Rubini, Michele ;

Baluardo, Carlotta ;

Ferrian, Melissa ;

de Assis, Nilma Almeida ;

Alblas, Margrieta A. ;

Barth, Sandra ;

Freudenberg, Jan ;

Lauster, Carola ;

Schmidt, Guel ;

Scheer, Martin ;

Braumann, Bert ;

Berge, Stefaan J. ;

Reich, Rudolf H. ;

Schiefke, Franziska ;

Hemprich, Alexander ;

Poetzsch, Simone ;

Steegers-Theunissen, Regine P. ;

Poetzsch, Bernd ;

Moebus, Susanne ;

Horsthemke, Bernhard ;

Kramer, Franz-Josef ;

Wienker, Thomas F. ;

Mossey, Peter A. ;

Propping, Peter ;

Cichon, Sven ;

Hoffmann, Per ;

Knapp, Michael ;

Noethen, Markus M. ;

Mangold, Elisabeth .

NATURE GENETICS, 2009, 41 (04) :473-477

[5] Developmental factor IRF6 exhibits tumor suppressor activity in squamous cell carcinomas [J].

Botti, Elisabetta ;

Spallone, Giulia ;

Moretti, Francesca ;

Marinari, Barbara ;

Pinetti, Valentina ;

Galanti, Sergio ;

De Meo, Paolo D'Onorio ;

De Nicola, Francesca ;

Ganci, Federica ;

Castrignano, Tiziana ;

Pesole, Graziano ;

Chimenti, Sergio ;

Guerrini, Luisa ;

Fanciulli, Maurizio ;

Blandino, Giovanni ;

Karin, Michael ;

Costanzo, Antonio .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2011, 108 (33) :13710-13715

[6]

Bravo ML, 1996, GENE GEOGR, V10, P11

[7] Replication of Genome Wide Association Identified Candidate Genes Confirm the Role of Common and Rare Variants in PAX7 and VAX1 in the Etiology of Nonsyndromic CL(P) [J].

Butali, Azeez ;

Suzuki, Satoshi ;

Cooper, Margaret E. ;

Mansilla, Adela M. ;

Cuenco, Karen ;

Leslie, Elizabeth J. ;

Suzuki, Yasushi ;

Niimi, Teruyuki ;

Yamamoto, Masahiko ;

Ayanga, Gongorjav ;

Erkhembaatar, Tudevdorj ;

Furukawa, Hiroo ;

Fujiwawa, Kumiko ;

Imura, Hideto ;

Petrin, Aline L. ;

Natsume, Nagato ;

Beaty, Terri H. ;

Marazita, Mary L. ;

Murray, Jeffery C. .

AMERICAN JOURNAL OF MEDICAL GENETICS PART A, 2013, 161A (05) :965-972

[8] Epidermal Wound Repair Is Regulated by the Planar Cell Polarity Signaling Pathway [J].

Caddy, Jacinta ;

Wilanowski, Tomasz ;

Darido, Charbel ;

Dworkin, Sebastian ;

Ting, Stephen B. ;

Zhao, Quan ;

Rank, Gerhard ;

Auden, Alana ;

Srivastava, Seema ;

Papenfuss, Tony A. ;

Murdoch, Jennifer N. ;

Humbert, Patrick O. ;

Boulos, Nidal ;

Weber, Thomas ;

Zuo, Jian ;

Cunningham, John M. ;

Jane, Stephen M. .

DEVELOPMENTAL CELL, 2010, 19 (01) :138-147

[9] Strong Amerind/white sex bias and a possible sephardic contribution among the founders of a population in northwest Colombia [J].

Carvajal-Carmona, LG ;

Soto, ID ;

Pineda, N ;

Ortíz-Barrientos, D ;

Duque, C ;

Ospina-Duque, J ;

McCarthy, M ;

Montoya, P ;

Alvarez, VM ;

Bedoya, G ;

Ruiz-Linares, A .

AMERICAN JOURNAL OF HUMAN GENETICS, 2000, 67 (05) :1287-1295

[10] Improved whole-chromosome phasing for disease and population genetic studies [J].

Delaneau, Olivier ;

Zagury, Jean-Francois ;

Marchini, Jonathan .

NATURE METHODS, 2013, 10 (01) :5-6

← 1 2 3 4 5 6 →