Genome-wide association study of multiethnic nonsyndromic orofacial cleft families identifies novel loci specific to family and phenotypic subtypes

• Authors: Nandita Mukhopadhyay, University of Pittsburgh; Eleanor Feingold, University of Pittsburgh; Lina Moreno-Uribe, University of Iowa; George Wehby, University of Iowa; Luz Consuelo Valencia-Ramirez, Fundación Clínica Noel; Calle 14 # 43B – 146, Medellín, Antioquia, Colombia; Claudia Restrepo P Muneton, Fundación Clínica Noel; Calle 14 # 43B – 146, Medellín, Antioquia, Colombia; Carmencita Padilla, University of the Philippines; Frederic Deleyiannis, UCHealth Medical Group, Colorado Springs, CO. USA; Kaare Christensen, University of Southern Denmark; Fernando A Poletta, CEMIC CONICET Ctr Med Educ & Clin Res; Ieda M Orioli, Federal University of Rio de Janeiro; Jacqueline T Hecht, University of Texas Health Science Center at Houston; Carmen J Buxo, University of Puerto Rico; Azeez Butali, University of Iowa; Wasiu L Adeyemo, University of Lagos; Alexandre R Vieira, University of Pittsburgh; John R Shaffer, University of Pittsburgh; Jeffrey C Murray, University of Iowa; Seth M Weinberg, University of Pittsburgh; Elizabeth Leslie, Emory University; Mary L Marazita, University of Pittsburgh
• Journal Title: GENETIC EPIDEMIOLOGY
• Volume: Volume 46, Number 3-4
• Publisher: WILEY | 2022-02-22, Pages 182-198
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1002/gepi.22447
• Subjects: Health Sciences, Health Care Management; Health Sciences, Medicine and Surgery
• Keywords: Science & Technology; Life Sciences & Biomedicine; Genetics & Heredity; Mathematical & Computational Biology; comparison of genetic etiology; genome-wide association; multiethnic study; subtypes of orofacial clefts; ORAL CLEFT; LIP; PALATE; RISK; GENE

Abstract

Nonsyndromic orofacial clefts (OFCs) are among the most common craniofacial birth defects worldwide, and known to exhibit phenotypic and genetic heterogeneity. Cleft lip plus cleft palate (CLP) and cleft lip only (CL) are commonly combined together as one phenotype (CL/P), separately from cleft palate alone. In comparison, our study analyzes CL and CLP separately. A sample of 2218 CL and CLP cases, 4537 unaffected relatives of cases, and 2673 pure controls with no family history of OFC were selected from the Pittsburgh Orofacial Cleft (Pitt-OFC) multiethnic study.genome-wide association studies were run for seven specific phenotypes created based on the cleft type(s) observed within these families, as well as the combined CL/P phenotype. Five novel genome-wide significant associations, 3q29 (rs62284390), 5p13.2 (rs609659), 7q22.1 (rs6465810), 19p13.3 (rs628271), and 20q13.33 (rs2427238), and nine associations (p ≤ 1.0E−05) within previously confirmed OFC loci—PAX7, IRF6, FAM49A, DCAF4L2, 8q24.21, ARID3B, NTN1, TANC2 and the WNT9B:WNT3 gene cluster—were observed. We also found that single nucleotide polymorphisms within a subset of the associated loci, both previously known and novel, differ substantially in terms of their effects across cleft- or family-specific phenotypes, indicating not only etiologic differences between CL and CLP, but also genetic heterogeneity within each of the two OFC subtypes.