Identification of 16q21 as a modifier of nonsyndromic orofacial cleft phenotypes
- Autores
- Carlson, Jenna C.; Standley, Jennifer; Petrin, Aline; Shaffer, John R.; Butali, Azeez; Buxó, Carmen J.; Castilla, Eduardo Enrique; Christensen, Kaare; Deleyiannis, Frederic W.-D.; Hecht, Jacqueline T.; Field, L. Leigh; Garidkhuu, Ariuntuul; Moreno Uribe, Lina M.; Nagato, Natsume; Orioli, Ieda M.; Padilla, Carmencita; Poletta, Fernando Adrián; Suzuki, Satoshi; Vieira, Alexandre R.; Wehby, George; Weinberg, Seth M.; Beaty, Terri H.; Feingold, Eleanor; Murray, Jeffrey C.; Marazita, Mary L.; Leslie, Elizabeth J.
- Año de publicación
- 2017
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- Orofacial clefts (OFCs) are common, complex birth defects with extremely heterogeneous phenotypic presentations. Two common subtypes—cleft lip alone (CL) and CL plus cleft palate (CLP)—are typically grouped into a single phenotype for genetic analysis (i.e., CL with or without cleft palate, CL/P). However, mounting evidence suggests there may be unique underlying pathophysiology and/or genetic modifiers influencing expression of these two phenotypes. To this end, we performed a genome-wide scan for genetic modifiers by directly comparing 450 CL cases with 1,692 CLP cases from 18 recruitment sites across 13 countries from North America, Central or South America, Asia, Europe, and Africa. We identified a region on 16q21 that is strongly associated with different cleft type (P = 5.611 × 10−8). We also identified significant evidence of gene–gene interactions between this modifier locus and two recognized CL/P risk loci: 8q21 and 9q22 (FOXE1) (P = 0.012 and 0.023, respectively). Single nucleotide polymorphism (SNPs) in the 16q21 modifier locus demonstrated significant association with CL over CLP. The marker alleles on 16q21 that increased risk for CL were found at highest frequencies among individuals with a family history of CL (P = 0.003). Our results demonstrate the existence of modifiers for which type of OFC develops and suggest plausible elements responsible for phenotypic heterogeneity, further elucidating the complex genetic architecture of OFCs.
Fil: Carlson, Jenna C.. University of Pittsburgh; Estados Unidos
Fil: Standley, Jennifer. University of Iowa; Estados Unidos
Fil: Petrin, Aline. University of Iowa; Estados Unidos
Fil: Shaffer, John R.. University of Pittsburgh; Estados Unidos
Fil: Butali, Azeez. University of Iowa; Estados Unidos
Fil: Buxó, Carmen J.. Universidad de Puerto Rico; Puerto Rico
Fil: Castilla, Eduardo Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina
Fil: Christensen, Kaare. University of Southern Denmark; Dinamarca
Fil: Deleyiannis, Frederic W.-D.. State University of Colorado Boulder; Estados Unidos
Fil: Hecht, Jacqueline T.. University of Texas; Estados Unidos
Fil: Field, L. Leigh. University of British Columbia; Canadá
Fil: Garidkhuu, Ariuntuul. Tohoku University; Japón. Mongolian National University Of Medical Sciences; Mongolia
Fil: Moreno Uribe, Lina M.. University of Iowa; Estados Unidos
Fil: Nagato, Natsume. Aichi Gakuin University; Japón
Fil: Orioli, Ieda M.. Instituto Nacional de Genética Médica Populacional; Brasil. Universidade Federal do Rio de Janeiro; Brasil
Fil: Padilla, Carmencita. University Of The Philippines Manila; Filipinas
Fil: Poletta, Fernando Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina
Fil: Suzuki, Satoshi. Aichi Gakuin University; Japón
Fil: Vieira, Alexandre R.. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados Unidos
Fil: Wehby, George. University of Iowa; Estados Unidos
Fil: Weinberg, Seth M.. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados Unidos
Fil: Beaty, Terri H.. University Johns Hopkins; Estados Unidos
Fil: Feingold, Eleanor. University of Pittsburgh; Estados Unidos
Fil: Murray, Jeffrey C.. University of Iowa; Estados Unidos
Fil: Marazita, Mary L.. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados Unidos
Fil: Leslie, Elizabeth J.. University of Emory; Estados Unidos - Materia
-
Complex Trait
Genetic Modifier
Gene-Gene Interaction
Orofacial Cleft - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
.jpg)
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/45143
Ver los metadatos del registro completo
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Identification of 16q21 as a modifier of nonsyndromic orofacial cleft phenotypesCarlson, Jenna C.Standley, JenniferPetrin, AlineShaffer, John R.Butali, AzeezBuxó, Carmen J.Castilla, Eduardo EnriqueChristensen, KaareDeleyiannis, Frederic W.-D.Hecht, Jacqueline T.Field, L. LeighGaridkhuu, AriuntuulMoreno Uribe, Lina M.Nagato, NatsumeOrioli, Ieda M.Padilla, CarmencitaPoletta, Fernando AdriánSuzuki, SatoshiVieira, Alexandre R.Wehby, GeorgeWeinberg, Seth M.Beaty, Terri H.Feingold, EleanorMurray, Jeffrey C.Marazita, Mary L.Leslie, Elizabeth J.Complex TraitGenetic ModifierGene-Gene InteractionOrofacial Clefthttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Orofacial clefts (OFCs) are common, complex birth defects with extremely heterogeneous phenotypic presentations. Two common subtypes—cleft lip alone (CL) and CL plus cleft palate (CLP)—are typically grouped into a single phenotype for genetic analysis (i.e., CL with or without cleft palate, CL/P). However, mounting evidence suggests there may be unique underlying pathophysiology and/or genetic modifiers influencing expression of these two phenotypes. To this end, we performed a genome-wide scan for genetic modifiers by directly comparing 450 CL cases with 1,692 CLP cases from 18 recruitment sites across 13 countries from North America, Central or South America, Asia, Europe, and Africa. We identified a region on 16q21 that is strongly associated with different cleft type (P = 5.611 × 10−8). We also identified significant evidence of gene–gene interactions between this modifier locus and two recognized CL/P risk loci: 8q21 and 9q22 (FOXE1) (P = 0.012 and 0.023, respectively). Single nucleotide polymorphism (SNPs) in the 16q21 modifier locus demonstrated significant association with CL over CLP. The marker alleles on 16q21 that increased risk for CL were found at highest frequencies among individuals with a family history of CL (P = 0.003). Our results demonstrate the existence of modifiers for which type of OFC develops and suggest plausible elements responsible for phenotypic heterogeneity, further elucidating the complex genetic architecture of OFCs.Fil: Carlson, Jenna C.. University of Pittsburgh; Estados UnidosFil: Standley, Jennifer. University of Iowa; Estados UnidosFil: Petrin, Aline. University of Iowa; Estados UnidosFil: Shaffer, John R.. University of Pittsburgh; Estados UnidosFil: Butali, Azeez. University of Iowa; Estados UnidosFil: Buxó, Carmen J.. Universidad de Puerto Rico; Puerto RicoFil: Castilla, Eduardo Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; ArgentinaFil: Christensen, Kaare. University of Southern Denmark; DinamarcaFil: Deleyiannis, Frederic W.-D.. State University of Colorado Boulder; Estados UnidosFil: Hecht, Jacqueline T.. University of Texas; Estados UnidosFil: Field, L. Leigh. University of British Columbia; CanadáFil: Garidkhuu, Ariuntuul. Tohoku University; Japón. Mongolian National University Of Medical Sciences; MongoliaFil: Moreno Uribe, Lina M.. University of Iowa; Estados UnidosFil: Nagato, Natsume. Aichi Gakuin University; JapónFil: Orioli, Ieda M.. Instituto Nacional de Genética Médica Populacional; Brasil. Universidade Federal do Rio de Janeiro; BrasilFil: Padilla, Carmencita. University Of The Philippines Manila; FilipinasFil: Poletta, Fernando Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; ArgentinaFil: Suzuki, Satoshi. Aichi Gakuin University; JapónFil: Vieira, Alexandre R.. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados UnidosFil: Wehby, George. University of Iowa; Estados UnidosFil: Weinberg, Seth M.. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados UnidosFil: Beaty, Terri H.. University Johns Hopkins; Estados UnidosFil: Feingold, Eleanor. University of Pittsburgh; Estados UnidosFil: Murray, Jeffrey C.. University of Iowa; Estados UnidosFil: Marazita, Mary L.. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados UnidosFil: Leslie, Elizabeth J.. University of Emory; Estados UnidosWiley-liss, Div John Wiley & Sons Inc2017-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/45143Carlson, Jenna C.; Standley, Jennifer; Petrin, Aline; Shaffer, John R.; Butali, Azeez; et al.; Identification of 16q21 as a modifier of nonsyndromic orofacial cleft phenotypes; Wiley-liss, Div John Wiley & Sons Inc; Genetic Epidemiology; 41; 8; 12-2017; 887-8970741-0395CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1002/gepi.22090info:eu-repo/semantics/altIdentifier/url/https://onlinelibrary.wiley.com/doi/abs/10.1002/gepi.22090info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T14:29:01Zoai:ri.conicet.gov.ar:11336/45143instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 14:29:02.062CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
| dc.title.none.fl_str_mv |
Identification of 16q21 as a modifier of nonsyndromic orofacial cleft phenotypes |
| title |
Identification of 16q21 as a modifier of nonsyndromic orofacial cleft phenotypes |
| spellingShingle |
Identification of 16q21 as a modifier of nonsyndromic orofacial cleft phenotypes Carlson, Jenna C. Complex Trait Genetic Modifier Gene-Gene Interaction Orofacial Cleft |
| title_short |
Identification of 16q21 as a modifier of nonsyndromic orofacial cleft phenotypes |
| title_full |
Identification of 16q21 as a modifier of nonsyndromic orofacial cleft phenotypes |
| title_fullStr |
Identification of 16q21 as a modifier of nonsyndromic orofacial cleft phenotypes |
| title_full_unstemmed |
Identification of 16q21 as a modifier of nonsyndromic orofacial cleft phenotypes |
| title_sort |
Identification of 16q21 as a modifier of nonsyndromic orofacial cleft phenotypes |
| dc.creator.none.fl_str_mv |
Carlson, Jenna C. Standley, Jennifer Petrin, Aline Shaffer, John R. Butali, Azeez Buxó, Carmen J. Castilla, Eduardo Enrique Christensen, Kaare Deleyiannis, Frederic W.-D. Hecht, Jacqueline T. Field, L. Leigh Garidkhuu, Ariuntuul Moreno Uribe, Lina M. Nagato, Natsume Orioli, Ieda M. Padilla, Carmencita Poletta, Fernando Adrián Suzuki, Satoshi Vieira, Alexandre R. Wehby, George Weinberg, Seth M. Beaty, Terri H. Feingold, Eleanor Murray, Jeffrey C. Marazita, Mary L. Leslie, Elizabeth J. |
| author |
Carlson, Jenna C. |
| author_facet |
Carlson, Jenna C. Standley, Jennifer Petrin, Aline Shaffer, John R. Butali, Azeez Buxó, Carmen J. Castilla, Eduardo Enrique Christensen, Kaare Deleyiannis, Frederic W.-D. Hecht, Jacqueline T. Field, L. Leigh Garidkhuu, Ariuntuul Moreno Uribe, Lina M. Nagato, Natsume Orioli, Ieda M. Padilla, Carmencita Poletta, Fernando Adrián Suzuki, Satoshi Vieira, Alexandre R. Wehby, George Weinberg, Seth M. Beaty, Terri H. Feingold, Eleanor Murray, Jeffrey C. Marazita, Mary L. Leslie, Elizabeth J. |
| author_role |
author |
| author2 |
Standley, Jennifer Petrin, Aline Shaffer, John R. Butali, Azeez Buxó, Carmen J. Castilla, Eduardo Enrique Christensen, Kaare Deleyiannis, Frederic W.-D. Hecht, Jacqueline T. Field, L. Leigh Garidkhuu, Ariuntuul Moreno Uribe, Lina M. Nagato, Natsume Orioli, Ieda M. Padilla, Carmencita Poletta, Fernando Adrián Suzuki, Satoshi Vieira, Alexandre R. Wehby, George Weinberg, Seth M. Beaty, Terri H. Feingold, Eleanor Murray, Jeffrey C. Marazita, Mary L. Leslie, Elizabeth J. |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Complex Trait Genetic Modifier Gene-Gene Interaction Orofacial Cleft |
| topic |
Complex Trait Genetic Modifier Gene-Gene Interaction Orofacial Cleft |
| purl_subject.fl_str_mv |
https://purl.org/becyt/ford/3.1 https://purl.org/becyt/ford/3 |
| dc.description.none.fl_txt_mv |
Orofacial clefts (OFCs) are common, complex birth defects with extremely heterogeneous phenotypic presentations. Two common subtypes—cleft lip alone (CL) and CL plus cleft palate (CLP)—are typically grouped into a single phenotype for genetic analysis (i.e., CL with or without cleft palate, CL/P). However, mounting evidence suggests there may be unique underlying pathophysiology and/or genetic modifiers influencing expression of these two phenotypes. To this end, we performed a genome-wide scan for genetic modifiers by directly comparing 450 CL cases with 1,692 CLP cases from 18 recruitment sites across 13 countries from North America, Central or South America, Asia, Europe, and Africa. We identified a region on 16q21 that is strongly associated with different cleft type (P = 5.611 × 10−8). We also identified significant evidence of gene–gene interactions between this modifier locus and two recognized CL/P risk loci: 8q21 and 9q22 (FOXE1) (P = 0.012 and 0.023, respectively). Single nucleotide polymorphism (SNPs) in the 16q21 modifier locus demonstrated significant association with CL over CLP. The marker alleles on 16q21 that increased risk for CL were found at highest frequencies among individuals with a family history of CL (P = 0.003). Our results demonstrate the existence of modifiers for which type of OFC develops and suggest plausible elements responsible for phenotypic heterogeneity, further elucidating the complex genetic architecture of OFCs. Fil: Carlson, Jenna C.. University of Pittsburgh; Estados Unidos Fil: Standley, Jennifer. University of Iowa; Estados Unidos Fil: Petrin, Aline. University of Iowa; Estados Unidos Fil: Shaffer, John R.. University of Pittsburgh; Estados Unidos Fil: Butali, Azeez. University of Iowa; Estados Unidos Fil: Buxó, Carmen J.. Universidad de Puerto Rico; Puerto Rico Fil: Castilla, Eduardo Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina Fil: Christensen, Kaare. University of Southern Denmark; Dinamarca Fil: Deleyiannis, Frederic W.-D.. State University of Colorado Boulder; Estados Unidos Fil: Hecht, Jacqueline T.. University of Texas; Estados Unidos Fil: Field, L. Leigh. University of British Columbia; Canadá Fil: Garidkhuu, Ariuntuul. Tohoku University; Japón. Mongolian National University Of Medical Sciences; Mongolia Fil: Moreno Uribe, Lina M.. University of Iowa; Estados Unidos Fil: Nagato, Natsume. Aichi Gakuin University; Japón Fil: Orioli, Ieda M.. Instituto Nacional de Genética Médica Populacional; Brasil. Universidade Federal do Rio de Janeiro; Brasil Fil: Padilla, Carmencita. University Of The Philippines Manila; Filipinas Fil: Poletta, Fernando Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina Fil: Suzuki, Satoshi. Aichi Gakuin University; Japón Fil: Vieira, Alexandre R.. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados Unidos Fil: Wehby, George. University of Iowa; Estados Unidos Fil: Weinberg, Seth M.. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados Unidos Fil: Beaty, Terri H.. University Johns Hopkins; Estados Unidos Fil: Feingold, Eleanor. University of Pittsburgh; Estados Unidos Fil: Murray, Jeffrey C.. University of Iowa; Estados Unidos Fil: Marazita, Mary L.. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados Unidos Fil: Leslie, Elizabeth J.. University of Emory; Estados Unidos |
| description |
Orofacial clefts (OFCs) are common, complex birth defects with extremely heterogeneous phenotypic presentations. Two common subtypes—cleft lip alone (CL) and CL plus cleft palate (CLP)—are typically grouped into a single phenotype for genetic analysis (i.e., CL with or without cleft palate, CL/P). However, mounting evidence suggests there may be unique underlying pathophysiology and/or genetic modifiers influencing expression of these two phenotypes. To this end, we performed a genome-wide scan for genetic modifiers by directly comparing 450 CL cases with 1,692 CLP cases from 18 recruitment sites across 13 countries from North America, Central or South America, Asia, Europe, and Africa. We identified a region on 16q21 that is strongly associated with different cleft type (P = 5.611 × 10−8). We also identified significant evidence of gene–gene interactions between this modifier locus and two recognized CL/P risk loci: 8q21 and 9q22 (FOXE1) (P = 0.012 and 0.023, respectively). Single nucleotide polymorphism (SNPs) in the 16q21 modifier locus demonstrated significant association with CL over CLP. The marker alleles on 16q21 that increased risk for CL were found at highest frequencies among individuals with a family history of CL (P = 0.003). Our results demonstrate the existence of modifiers for which type of OFC develops and suggest plausible elements responsible for phenotypic heterogeneity, further elucidating the complex genetic architecture of OFCs. |
| publishDate |
2017 |
| dc.date.none.fl_str_mv |
2017-12 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
| format |
article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/11336/45143 Carlson, Jenna C.; Standley, Jennifer; Petrin, Aline; Shaffer, John R.; Butali, Azeez; et al.; Identification of 16q21 as a modifier of nonsyndromic orofacial cleft phenotypes; Wiley-liss, Div John Wiley & Sons Inc; Genetic Epidemiology; 41; 8; 12-2017; 887-897 0741-0395 CONICET Digital CONICET |
| url |
http://hdl.handle.net/11336/45143 |
| identifier_str_mv |
Carlson, Jenna C.; Standley, Jennifer; Petrin, Aline; Shaffer, John R.; Butali, Azeez; et al.; Identification of 16q21 as a modifier of nonsyndromic orofacial cleft phenotypes; Wiley-liss, Div John Wiley & Sons Inc; Genetic Epidemiology; 41; 8; 12-2017; 887-897 0741-0395 CONICET Digital CONICET |
| dc.language.none.fl_str_mv |
eng |
| language |
eng |
| dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/doi/10.1002/gepi.22090 info:eu-repo/semantics/altIdentifier/url/https://onlinelibrary.wiley.com/doi/abs/10.1002/gepi.22090 |
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info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
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openAccess |
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https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
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application/pdf application/pdf |
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Wiley-liss, Div John Wiley & Sons Inc |
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Wiley-liss, Div John Wiley & Sons Inc |
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reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
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Consejo Nacional de Investigaciones Científicas y Técnicas |
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CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
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dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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