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

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 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 Unido