Genome-Wide Association Study of Non-syndromic Orofacial Clefts in a Multiethnic Sample of Families and Controls Identifies Novel Regions.

Autor:	Mukhopadhyay N; Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, United States., Feingold E; Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, United States.; Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States.; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States., Moreno-Uribe L; Department of Orthodontics, The Iowa Institute for Oral Health Research, College of Dentistry, University of Iowa, Iowa City, IA, United States., Wehby G; Department of Health Management and Policy, College of Public Health, University of Iowa, Iowa City, IA, United States., Valencia-Ramirez LC; Fundación Clínica Noel, Medellín, Colombia., Muñeton CPR; Fundación Clínica Noel, Medellín, Colombia., Padilla C; Department of Pediatrics, College of Medicine, Institute of Human Genetics, National Institutes of Health, University of the Philippines, Manila, Philippines., Deleyiannis F; UCHealth Medical Group, Colorado Springs, CO, United States., Christensen K; Department of Epidemiology, Institute of Public Health, University of Southern Denmark, Odense, Denmark., Poletta FA; CEMIC: Center for Medical Education and Clinical Research, Buenos Aires, Argentina., Orioli IM; Department of Genetics, Institute of Biology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.; Instituto Nacional de Genética Médica Populacional INAGEMP, Porto Alegre, Brazil., Hecht JT; Department of Pediatrics, University of Texas Health Science Center at Houston, Houston, TX, United States., Buxó CJ; Dental and Craniofacial Genomics Core, School of Dental Medicine, University of Puerto Rico, San Juan, Puerto Rico., Butali A; Department of Oral Pathology, Radiology and Medicine, College of Dentistry, Iowa Institute for Oral Health Research, University of Iowa, Iowa City, IA, United States., Adeyemo WL; Department of Oral and Maxillofacial Surgery, College of Medicine, University of Lagos, Lagos, Nigeria., Vieira AR; Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, United States., Shaffer JR; Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, United States.; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States., Murray JC; Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA, United States., Weinberg SM; Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, United States.; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States., Leslie EJ; Department of Human Genetics, Emory University, Atlanta, GA, United States., Marazita ML; Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, United States.; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States.; Clinical and Translational Science, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in cell and developmental biology [Front Cell Dev Biol] 2021 Apr 09; Vol. 9, pp. 621482. Date of Electronic Publication: 2021 Apr 09 (Print Publication: 2021).
DOI:	10.3389/fcell.2021.621482
Abstrakt:	Orofacial clefts (OFCs) are among the most prevalent craniofacial birth defects worldwide and create a significant public health burden. The majority of OFCs are non-syndromic and vary in prevalence by ethnicity. Africans have the lowest prevalence of OFCs (~ 1/2,500), Asians have the highest prevalence (~1/500), Europeans and Latin Americans lie somewhere in the middle (~1/800 and 1/900, respectively). Thus, ethnicity appears to be a major determinant of the risk of developing OFC. The Pittsburgh Orofacial Clefts Multiethnic study was designed to explore this ethnic variance, comprising a large number of families and individuals (~12,000 individuals) from multiple populations worldwide: US and Europe, Asians, mixed Native American/Caucasians, and Africans. In this current study, we analyzed 2,915 OFC cases, 6,044 unaffected individuals related to the OFC cases, and 2,685 controls with no personal or family history of OFC. Participants were grouped by their ancestry into African, Asian, European, and Central and South American subsets, and genome-wide association run on the combined sample as well as the four ancestry-based groups. We observed 22 associations to cleft lip with or without cleft palate at 18 distinct loci with p -values < 1e-06, including 10 with genome-wide significance (<5e-08), in the combined sample and within ancestry groups. Three loci - 2p12 (rs62164740, p = 6.27e-07), 10q22.2 (rs150952246, p = 3.14e-07), and 10q24.32 (rs118107597, p = 8.21e-07) are novel. Nine were in or near known OFC loci - PAX7, IRF6, FAM49A, DCAF4L2 , 8q24.21, NTN1, WNT3-WNT9B, TANC2 , and RHPN2 . The majority of the associations were observed only in the combined sample, European, and Central and South American groups. We investigated whether the observed differences in association strength were (a) purely due to sample sizes, (b) due to systematic allele frequency difference at the population level, or (c) due to the fact certain OFC-causing variants confer different amounts of risk depending on ancestral origin, by comparing effect sizes to observed allele frequencies of the effect allele in our ancestry-based groups. While some of the associations differ due to systematic differences in allele frequencies between groups, others show variation in effect size despite similar frequencies across ancestry groups. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Mukhopadhyay, Feingold, Moreno-Uribe, Wehby, Valencia-Ramirez, Muñeton, Padilla, Deleyiannis, Christensen, Poletta, Orioli, Hecht, Buxó, Butali, Adeyemo, Vieira, Shaffer, Murray, Weinberg, Leslie and Marazita.)
Databáze:	MEDLINE
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