Identification of 16q21 as a modifier of nonsyndromic orofacial cleft phenotypes

Jenna C. Carlson, Jennifer Standley, Aline Petrin, John R. Shaffer, Azeez Butali, Carmen J. Buxó, Eduardo Castilla, Kaare Christensen, Frederic W.D. Deleyiannis, Jacqueline T. Hecht, L. Leigh Field, Ariuntuul Garidkhuu, Lina M. Moreno Uribe, Natsume Nagato, Ieda M. Orioli, Carmencita Padilla, Fernando Poletta, Satoshi Suzuki, Alexandre R. Vieira, George L. WehbySeth M. Weinberg, Terri L Beaty, Eleanor Feingold, Jeffrey C. Murray, Mary L. Marazita, Elizabeth J. Leslie

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)887-897
Number of pages11
JournalGenetic Epidemiology
Volume41
Issue number8
DOIs
StatePublished - Dec 1 2017

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Cleft Palate
Phenotype
Central America
South America
Lip
North America
Single Nucleotide Polymorphism
Alleles
Genome
Orofacial Cleft 1

Keywords

  • complex trait
  • genetic modifier
  • gene–gene interaction
  • orofacial cleft

ASJC Scopus subject areas

  • Epidemiology
  • Genetics(clinical)

Cite this

Carlson, J. C., Standley, J., Petrin, A., Shaffer, J. R., Butali, A., Buxó, C. J., ... Leslie, E. J. (2017). Identification of 16q21 as a modifier of nonsyndromic orofacial cleft phenotypes. Genetic Epidemiology, 41(8), 887-897. https://doi.org/10.1002/gepi.22090

Identification of 16q21 as a modifier of nonsyndromic orofacial cleft phenotypes. / Carlson, Jenna C.; Standley, Jennifer; Petrin, Aline; Shaffer, John R.; Butali, Azeez; Buxó, Carmen J.; Castilla, Eduardo; 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; Suzuki, Satoshi; Vieira, Alexandre R.; Wehby, George L.; Weinberg, Seth M.; Beaty, Terri L; Feingold, Eleanor; Murray, Jeffrey C.; Marazita, Mary L.; Leslie, Elizabeth J.

In: Genetic Epidemiology, Vol. 41, No. 8, 01.12.2017, p. 887-897.

Research output: Contribution to journalArticle

Carlson, JC, Standley, J, Petrin, A, Shaffer, JR, Butali, A, Buxó, CJ, Castilla, E, Christensen, K, Deleyiannis, FWD, Hecht, JT, Field, LL, Garidkhuu, A, Moreno Uribe, LM, Nagato, N, Orioli, IM, Padilla, C, Poletta, F, Suzuki, S, Vieira, AR, Wehby, GL, Weinberg, SM, Beaty, TL, Feingold, E, Murray, JC, Marazita, ML & Leslie, EJ 2017, 'Identification of 16q21 as a modifier of nonsyndromic orofacial cleft phenotypes', Genetic Epidemiology, vol. 41, no. 8, pp. 887-897. https://doi.org/10.1002/gepi.22090
Carlson JC, Standley J, Petrin A, Shaffer JR, Butali A, Buxó CJ et al. Identification of 16q21 as a modifier of nonsyndromic orofacial cleft phenotypes. Genetic Epidemiology. 2017 Dec 1;41(8):887-897. https://doi.org/10.1002/gepi.22090
Carlson, Jenna C. ; Standley, Jennifer ; Petrin, Aline ; Shaffer, John R. ; Butali, Azeez ; Buxó, Carmen J. ; Castilla, Eduardo ; 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 ; Suzuki, Satoshi ; Vieira, Alexandre R. ; Wehby, George L. ; Weinberg, Seth M. ; Beaty, Terri L ; Feingold, Eleanor ; Murray, Jeffrey C. ; Marazita, Mary L. ; Leslie, Elizabeth J. / Identification of 16q21 as a modifier of nonsyndromic orofacial cleft phenotypes. In: Genetic Epidemiology. 2017 ; Vol. 41, No. 8. pp. 887-897.
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AU - Carlson, Jenna C.

AU - Standley, Jennifer

AU - Petrin, Aline

AU - Shaffer, John R.

AU - Butali, Azeez

AU - Buxó, Carmen J.

AU - Castilla, Eduardo

AU - Christensen, Kaare

AU - Deleyiannis, Frederic W.D.

AU - Hecht, Jacqueline T.

AU - Field, L. Leigh

AU - Garidkhuu, Ariuntuul

AU - Moreno Uribe, Lina M.

AU - Nagato, Natsume

AU - Orioli, Ieda M.

AU - Padilla, Carmencita

AU - Poletta, Fernando

AU - Suzuki, Satoshi

AU - Vieira, Alexandre R.

AU - Wehby, George L.

AU - Weinberg, Seth M.

AU - Beaty, Terri L

AU - Feingold, Eleanor

AU - Murray, Jeffrey C.

AU - Marazita, Mary L.

AU - Leslie, Elizabeth J.

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N2 - 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.

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