Genome-wide meta-analyses of nonsyndromic orofacial clefts identify novel associations between FOXE1 and all orofacial clefts, and TP63 and cleft lip with or without cleft palate

Elizabeth J. Leslie; Jenna C. Carlson; John R. Shaffer; Azeez Butali; Carmen J. Buxó; Eduardo E. Castilla; Kaare Christensen; Fred W.B. Deleyiannis; L. Leigh Field; Jacqueline T. Hecht; Lina Moreno; Ieda M. Orioli; Carmencita Padilla; Alexandre R. Vieira; George L. Wehby; Eleanor Feingold; Seth M. Weinberg; Jeffrey C. Murray; Terri H. Beaty; Mary L. Marazita

doi:10.1007/s00439-016-1754-7

Genome-wide meta-analyses of nonsyndromic orofacial clefts identify novel associations between FOXE1 and all orofacial clefts, and TP63 and cleft lip with or without cleft palate

Elizabeth J. Leslie
, Jenna C. Carlson
, John R. Shaffer
, Azeez Butali
, Carmen J. Buxó
, Eduardo E. Castilla
, Kaare Christensen
, Fred W.B. Deleyiannis
, L. Leigh Field
, Jacqueline T. Hecht
, Lina Moreno
, Ieda M. Orioli
, Carmencita Padilla
, Alexandre R. Vieira
, George L. Wehby
, Eleanor Feingold
, Seth M. Weinberg
, Jeffrey C. Murray
, Terri H. Beaty
, Mary L. Marazita^*

^*Corresponding author for this work

Epidemiology, Biostatistics and Biodemography

University of Pittsburgh
The University of Iowa
University of Puerto Rico
University of Colorado
University of British Columbia (UBC)
McGovern Medical School and School of Dentistry UT Health at Houston
Federal University of Rio de Janeiro
University of the Philippines
Iowa State University
Johns Hopkins University
CEMIC: Center for Medical Education and Clinical Research
ECLAMC (Latin American Collaborative Study of Congenital Malformations) at Hospital de Area, El Bolson 8430, Argentina.
Oswaldo Cruz Foundation
National Institute of Population Medical Genetics

Research output: Contribution to journal › Journal article › Research › peer-review

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Abstract

Nonsyndromic orofacial clefts (OFCs) are a heterogeneous group of common craniofacial birth defects with complex etiologies that include genetic and environmental risk factors. OFCs are commonly categorized as cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP), which have historically been analyzed as distinct entities. Genes for both CL/P and CP have been identified via multiple genome-wide linkage and association studies (GWAS); however, altogether, known variants account for a minority of the estimated heritability in risk to these craniofacial birth defects. We performed genome-wide meta-analyses of CL/P, CP, and all OFCs across two large, multiethnic studies. We then performed population-specific meta-analyses in sub-samples of Asian and European ancestry. In addition to observing associations with known variants, we identified a novel genome-wide significant association between SNPs located in an intronic TP63 enhancer and CL/P (p = 1.16 × 10⁻⁸). Several novel loci with compelling candidate genes approached genome-wide significance on 4q21.1 (SHROOM3), 12q13.13 (KRT18), and 8p21 (NRG1). In the analysis of all OFCs combined, SNPs near FOXE1 reached genome-wide significance (p = 1.33 × 10⁻⁹). Our results support the highly heterogeneous nature of OFCs and illustrate the utility of meta-analysis for discovering new genetic risk factors.

Original language	English
Journal	Human Genetics
Volume	136
Issue number	3
Pages (from-to)	275-286
ISSN	0340-6717
DOIs	https://doi.org/10.1007/s00439-016-1754-7
Publication status	Published - 2017

Funding

Many thanks to the participating families world-wide who made this project possible. The tireless efforts by the dedicated field staff and collaborators were similarly essential to the success of this study. This work was supported by grants from the National Institutes of Health (NIH) including: K99-DE025060 [EJL], X01-HG007485 [MLM, EF], R01-DE016148 [MLM, SMW], U01-DE024425 [MLM], R37-DE008559 [JCM, MLM], R01-DE009886 [MLM], R21-DE016930 [MLM], R01-DE014667 [LMM], R01-DE012472 [MLM], R01-DE011931 [JTH], R01-DE011948 [KC], U01-DD000295 [GLW], K99 -DE024571 [CJB], R25-MD007607 [CJB], R01-DE014581 [TB], U01-DE018993??[TB]. Genotyping and data cleaning were provided via an NIH contract to the Johns Hopkins Center for Inherited Disease Research: HHSN268201200008I. Additional support provided by the Robert Wood Johnson Foundation, AMFDP Grant 72429 [AB]; 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 [CP]; grants through FAPERJ, Brazil [IMO]: grant numbers: E-26/102.797/2012, E-26/110.140/2013; grants through CNPq, Brazil [IMO]: grant numbers: 481069/2012-7, 306396/2013-0, 400427/2013-3.

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Genome-wide meta-analyses of nonsyndromic orofacial clefts identify novel associations between FOXE1 and all orofacial clefts, and TP63 and cleft lip with or without cleft palateAccepted manuscript, 518 KB

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Leslie, E. J., Carlson, J. C., Shaffer, J. R., Butali, A., Buxó, C. J., Castilla, E. E., Christensen, K., Deleyiannis, F. W. B., Leigh Field, L., Hecht, J. T., Moreno, L., Orioli, I. M., Padilla, C., Vieira, A. R., Wehby, G. L., Feingold, E., Weinberg, S. M., Murray, J. C., Beaty, T. H., & Marazita, M. L. (2017). Genome-wide meta-analyses of nonsyndromic orofacial clefts identify novel associations between FOXE1 and all orofacial clefts, and TP63 and cleft lip with or without cleft palate. Human Genetics, 136(3), 275-286. https://doi.org/10.1007/s00439-016-1754-7

@article{ab6f06fcc13a476e9d863ed7b7844b66,

title = "Genome-wide meta-analyses of nonsyndromic orofacial clefts identify novel associations between FOXE1 and all orofacial clefts, and TP63 and cleft lip with or without cleft palate",

abstract = "Nonsyndromic orofacial clefts (OFCs) are a heterogeneous group of common craniofacial birth defects with complex etiologies that include genetic and environmental risk factors. OFCs are commonly categorized as cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP), which have historically been analyzed as distinct entities. Genes for both CL/P and CP have been identified via multiple genome-wide linkage and association studies (GWAS); however, altogether, known variants account for a minority of the estimated heritability in risk to these craniofacial birth defects. We performed genome-wide meta-analyses of CL/P, CP, and all OFCs across two large, multiethnic studies. We then performed population-specific meta-analyses in sub-samples of Asian and European ancestry. In addition to observing associations with known variants, we identified a novel genome-wide significant association between SNPs located in an intronic TP63 enhancer and CL/P (p = 1.16 {\texttimes} 10−8). Several novel loci with compelling candidate genes approached genome-wide significance on 4q21.1 (SHROOM3), 12q13.13 (KRT18), and 8p21 (NRG1). In the analysis of all OFCs combined, SNPs near FOXE1 reached genome-wide significance (p = 1.33 {\texttimes} 10−9). Our results support the highly heterogeneous nature of OFCs and illustrate the utility of meta-analysis for discovering new genetic risk factors.",

author = "Leslie, \{Elizabeth J.\} and Carlson, \{Jenna C.\} and Shaffer, \{John R.\} and Azeez Butali and Bux{\'o}, \{Carmen J.\} and Castilla, \{Eduardo E.\} and Kaare Christensen and Deleyiannis, \{Fred W.B.\} and \{Leigh Field\}, L. and Hecht, \{Jacqueline T.\} and Lina Moreno and Orioli, \{Ieda M.\} and Carmencita Padilla and Vieira, \{Alexandre R.\} and Wehby, \{George L.\} and Eleanor Feingold and Weinberg, \{Seth M.\} and Murray, \{Jeffrey C.\} and Beaty, \{Terri H.\} and Marazita, \{Mary L.\}",

year = "2017",

doi = "10.1007/s00439-016-1754-7",

language = "English",

volume = "136",

pages = "275--286",

journal = "Human Genetics",

issn = "0340-6717",

publisher = "Springer Science+Business Media",

number = "3",

}

Leslie, EJ, Carlson, JC, Shaffer, JR, Butali, A, Buxó, CJ, Castilla, EE, Christensen, K, Deleyiannis, FWB, Leigh Field, L, Hecht, JT, Moreno, L, Orioli, IM, Padilla, C, Vieira, AR, Wehby, GL, Feingold, E, Weinberg, SM, Murray, JC, Beaty, TH & Marazita, ML 2017, 'Genome-wide meta-analyses of nonsyndromic orofacial clefts identify novel associations between FOXE1 and all orofacial clefts, and TP63 and cleft lip with or without cleft palate', Human Genetics, vol. 136, no. 3, pp. 275-286. https://doi.org/10.1007/s00439-016-1754-7

Genome-wide meta-analyses of nonsyndromic orofacial clefts identify novel associations between FOXE1 and all orofacial clefts, and TP63 and cleft lip with or without cleft palate. / Leslie, Elizabeth J.; Carlson, Jenna C.; Shaffer, John R. et al.
In: Human Genetics, Vol. 136, No. 3, 2017, p. 275-286.

Research output: Contribution to journal › Journal article › Research › peer-review

TY - JOUR

T1 - Genome-wide meta-analyses of nonsyndromic orofacial clefts identify novel associations between FOXE1 and all orofacial clefts, and TP63 and cleft lip with or without cleft palate

AU - Leslie, Elizabeth J.

AU - Carlson, Jenna C.

AU - Shaffer, John R.

AU - Butali, Azeez

AU - Buxó, Carmen J.

AU - Castilla, Eduardo E.

AU - Christensen, Kaare

AU - Deleyiannis, Fred W.B.

AU - Leigh Field, L.

AU - Hecht, Jacqueline T.

AU - Moreno, Lina

AU - Orioli, Ieda M.

AU - Padilla, Carmencita

AU - Vieira, Alexandre R.

AU - Wehby, George L.

AU - Feingold, Eleanor

AU - Weinberg, Seth M.

AU - Murray, Jeffrey C.

AU - Beaty, Terri H.

AU - Marazita, Mary L.

PY - 2017

Y1 - 2017

N2 - Nonsyndromic orofacial clefts (OFCs) are a heterogeneous group of common craniofacial birth defects with complex etiologies that include genetic and environmental risk factors. OFCs are commonly categorized as cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP), which have historically been analyzed as distinct entities. Genes for both CL/P and CP have been identified via multiple genome-wide linkage and association studies (GWAS); however, altogether, known variants account for a minority of the estimated heritability in risk to these craniofacial birth defects. We performed genome-wide meta-analyses of CL/P, CP, and all OFCs across two large, multiethnic studies. We then performed population-specific meta-analyses in sub-samples of Asian and European ancestry. In addition to observing associations with known variants, we identified a novel genome-wide significant association between SNPs located in an intronic TP63 enhancer and CL/P (p = 1.16 × 10−8). Several novel loci with compelling candidate genes approached genome-wide significance on 4q21.1 (SHROOM3), 12q13.13 (KRT18), and 8p21 (NRG1). In the analysis of all OFCs combined, SNPs near FOXE1 reached genome-wide significance (p = 1.33 × 10−9). Our results support the highly heterogeneous nature of OFCs and illustrate the utility of meta-analysis for discovering new genetic risk factors.

AB - Nonsyndromic orofacial clefts (OFCs) are a heterogeneous group of common craniofacial birth defects with complex etiologies that include genetic and environmental risk factors. OFCs are commonly categorized as cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP), which have historically been analyzed as distinct entities. Genes for both CL/P and CP have been identified via multiple genome-wide linkage and association studies (GWAS); however, altogether, known variants account for a minority of the estimated heritability in risk to these craniofacial birth defects. We performed genome-wide meta-analyses of CL/P, CP, and all OFCs across two large, multiethnic studies. We then performed population-specific meta-analyses in sub-samples of Asian and European ancestry. In addition to observing associations with known variants, we identified a novel genome-wide significant association between SNPs located in an intronic TP63 enhancer and CL/P (p = 1.16 × 10−8). Several novel loci with compelling candidate genes approached genome-wide significance on 4q21.1 (SHROOM3), 12q13.13 (KRT18), and 8p21 (NRG1). In the analysis of all OFCs combined, SNPs near FOXE1 reached genome-wide significance (p = 1.33 × 10−9). Our results support the highly heterogeneous nature of OFCs and illustrate the utility of meta-analysis for discovering new genetic risk factors.

U2 - 10.1007/s00439-016-1754-7

DO - 10.1007/s00439-016-1754-7

M3 - Journal article

C2 - 28054174

AN - SCOPUS:85008182706

SN - 0340-6717

VL - 136

SP - 275

EP - 286

JO - Human Genetics

JF - Human Genetics

IS - 3

ER -

Genome-wide meta-analyses of nonsyndromic orofacial clefts identify novel associations between FOXE1 and all orofacial clefts, and TP63 and cleft lip with or without cleft palate

Abstract

Funding

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