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

Elizabeth J. Leslie, Jenna C. Carlson, John R. Shaffer, Eleanor Feingold, George Wehby, Cecelia A. Laurie, Deepti Jain, Cathy C. Laurie, Kimberly Doheny, Toby McHenry, Judith Resick, Carla Sanchez, Jennifer Jacobs, Beth Emanuele, Alexandre R. Vieira, Katherine Neiswanger, Andrew C. Lidral, Luz Consuelo Valencia-Ramirez, Ana Maria Lopez-Palacio, Dora Rivera ValenciaMauricio Arcos-Burgos, Andrew E. Czeizel, L. Leigh Field, Carmencita D. Padilla, Eva Maria, C. Cutiongco-de la Paz, Frederic Deleyiannis, Kaare Christensen, Ronald G. Munger, Rolv T. Lie, Allen Wilcox, Paul A. Romitti, Eduardo E. Castilla, Juan C. Mereb, Fernando A. Poletta, Iêda M. Orioli, Flavia M. Carvalho, Jacqueline T. Hecht, Susan H. Blanton, Carmen J. Buxó, Azeez Butali, Peter A. Mossey, Wasiu L. Adeyemo, Olutayo James, Ramat O. Braimah, Babatunde S. Aregbesola, Mekonen A. Eshete, Fikre Abate, Mine Koruyucu, Figen Seymen, Lian Ma, Javier Enríquez de Salamanca, Seth M. Weinberg, Lina Moreno, Jeffrey C. Murray, Mary L. Marazita

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2862-2872
Number of pages11
JournalHuman molecular genetics
Volume25
Issue number13
DOIs
StatePublished - Jan 1 2016

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Cleft Lip
Genome-Wide Association Study
Cleft Palate
Genes
Actin Cytoskeleton
Oncogenes
Genome
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

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. / Leslie, Elizabeth J.; Carlson, Jenna C.; Shaffer, John R.; Feingold, Eleanor; Wehby, George; Laurie, Cecelia A.; Jain, Deepti; Laurie, Cathy C.; Doheny, Kimberly; McHenry, Toby; Resick, Judith; Sanchez, Carla; Jacobs, Jennifer; Emanuele, Beth; Vieira, Alexandre R.; Neiswanger, Katherine; Lidral, Andrew C.; Valencia-Ramirez, Luz Consuelo; Lopez-Palacio, Ana Maria; Valencia, Dora Rivera; Arcos-Burgos, Mauricio; Czeizel, Andrew E.; Field, L. Leigh; Padilla, Carmencita D.; Maria, Eva; Cutiongco-de la Paz, C.; Deleyiannis, Frederic; Christensen, Kaare; Munger, Ronald G.; Lie, Rolv T.; Wilcox, Allen; Romitti, Paul A.; Castilla, Eduardo E.; Mereb, Juan C.; Poletta, Fernando A.; Orioli, Iêda M.; Carvalho, Flavia M.; Hecht, Jacqueline T.; Blanton, Susan H.; Buxó, Carmen J.; Butali, Azeez; Mossey, Peter A.; Adeyemo, Wasiu L.; James, Olutayo; Braimah, Ramat O.; Aregbesola, Babatunde S.; Eshete, Mekonen A.; Abate, Fikre; Koruyucu, Mine; Seymen, Figen; Ma, Lian; de Salamanca, Javier Enríquez; Weinberg, Seth M.; Moreno, Lina; Murray, Jeffrey C.; Marazita, Mary L.

In: Human molecular genetics, Vol. 25, No. 13, 01.01.2016, p. 2862-2872.

Research output: Contribution to journalArticle

Leslie, EJ, Carlson, JC, Shaffer, JR, Feingold, E, Wehby, G, Laurie, CA, Jain, D, Laurie, CC, Doheny, K, McHenry, T, Resick, J, Sanchez, C, Jacobs, J, Emanuele, B, Vieira, AR, Neiswanger, K, Lidral, AC, Valencia-Ramirez, LC, Lopez-Palacio, AM, Valencia, DR, Arcos-Burgos, M, Czeizel, AE, Field, LL, Padilla, CD, Maria, E, Cutiongco-de la Paz, C, 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, de Salamanca, JE, Weinberg, SM, Moreno, L, Murray, JC & Marazita, ML 2016, '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', Human molecular genetics, vol. 25, no. 13, pp. 2862-2872. https://doi.org/10.1093/hmg/ddw104
Leslie, Elizabeth J. ; Carlson, Jenna C. ; Shaffer, John R. ; Feingold, Eleanor ; Wehby, George ; Laurie, Cecelia A. ; Jain, Deepti ; Laurie, Cathy C. ; Doheny, Kimberly ; McHenry, Toby ; Resick, Judith ; Sanchez, Carla ; Jacobs, Jennifer ; Emanuele, Beth ; Vieira, Alexandre R. ; Neiswanger, Katherine ; Lidral, Andrew C. ; Valencia-Ramirez, Luz Consuelo ; Lopez-Palacio, Ana Maria ; Valencia, Dora Rivera ; Arcos-Burgos, Mauricio ; Czeizel, Andrew E. ; Field, L. Leigh ; Padilla, Carmencita D. ; Maria, Eva ; Cutiongco-de la Paz, C. ; Deleyiannis, Frederic ; Christensen, Kaare ; Munger, Ronald G. ; Lie, Rolv T. ; Wilcox, Allen ; Romitti, Paul A. ; Castilla, Eduardo E. ; Mereb, Juan C. ; Poletta, Fernando A. ; Orioli, Iêda M. ; Carvalho, Flavia M. ; Hecht, Jacqueline T. ; Blanton, Susan H. ; Buxó, Carmen J. ; Butali, Azeez ; Mossey, Peter A. ; Adeyemo, Wasiu L. ; James, Olutayo ; Braimah, Ramat O. ; Aregbesola, Babatunde S. ; Eshete, Mekonen A. ; Abate, Fikre ; Koruyucu, Mine ; Seymen, Figen ; Ma, Lian ; de Salamanca, Javier Enríquez ; Weinberg, Seth M. ; Moreno, Lina ; Murray, Jeffrey C. ; Marazita, Mary L. / 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. In: Human molecular genetics. 2016 ; Vol. 25, No. 13. pp. 2862-2872.
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title = "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",
abstract = "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.",
author = "Leslie, {Elizabeth J.} and Carlson, {Jenna C.} and Shaffer, {John R.} and Eleanor Feingold and George Wehby and Laurie, {Cecelia A.} and Deepti Jain and Laurie, {Cathy C.} and Kimberly Doheny and Toby McHenry and Judith Resick and Carla Sanchez and Jennifer Jacobs and Beth Emanuele and Vieira, {Alexandre R.} and Katherine Neiswanger and Lidral, {Andrew C.} and Valencia-Ramirez, {Luz Consuelo} and Lopez-Palacio, {Ana Maria} and Valencia, {Dora Rivera} and Mauricio Arcos-Burgos and Czeizel, {Andrew E.} and Field, {L. Leigh} and Padilla, {Carmencita D.} and Eva Maria and {Cutiongco-de la Paz}, C. and Frederic Deleyiannis and Kaare Christensen and Munger, {Ronald G.} and Lie, {Rolv T.} and Allen Wilcox and Romitti, {Paul A.} and Castilla, {Eduardo E.} and Mereb, {Juan C.} and Poletta, {Fernando A.} and Orioli, {I{\^e}da M.} and Carvalho, {Flavia M.} and Hecht, {Jacqueline T.} and Blanton, {Susan H.} and Bux{\'o}, {Carmen J.} and Azeez Butali and Mossey, {Peter A.} and Adeyemo, {Wasiu L.} and Olutayo James and Braimah, {Ramat O.} and Aregbesola, {Babatunde S.} and Eshete, {Mekonen A.} and Fikre Abate and Mine Koruyucu and Figen Seymen and Lian Ma and {de Salamanca}, {Javier Enr{\'i}quez} and Weinberg, {Seth M.} and Lina Moreno and Murray, {Jeffrey C.} and Marazita, {Mary L.}",
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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

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.

PY - 2016/1/1

Y1 - 2016/1/1

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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