Genome-wide Gene-by-Sex Interaction Studies Identify Novel Nonsyndromic Orofacial Clefts Risk Locus.

Autor: Awotoye W; Iowa Institute for Oral Health Research, University of Iowa, Iowa City, IA, USA., Comnick C; Division of Biostatistics and Computational Biology, College of Dentistry, University of Iowa, Iowa City, IA, USA., Pendleton C; Division of Biostatistics and Computational Biology, College of Dentistry, University of Iowa, Iowa City, IA, USA., Zeng E; Division of Biostatistics and Computational Biology, College of Dentistry, University of Iowa, Iowa City, IA, USA., Alade A; Department of Oral Pathology, Radiology and Medicine, College of Dentistry, University of Iowa, Iowa City, IA, USA.; Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, IA, USA., Mossey PA; Department of Orthodontics, University of Dundee, Dundee, UK., Gowans LJJ; Komfo Anokye Teaching Hospital and Kwame Nkrumah University of Science and Technology, Kumasi, Ghana., Eshete MA; Department of Surgery, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia., Adeyemo WL; Department of Oral and Maxillofacial Surgery, University of Lagos, Lagos, Nigeria., Naicker T; Department of Pediatrics, University of KwaZulu-Natal, Durban, South Africa., Adeleke C; Department of Oral Pathology, Radiology and Medicine, College of Dentistry, University of Iowa, Iowa City, IA, USA., Busch T; Department of Oral Pathology, Radiology and Medicine, College of Dentistry, University of Iowa, Iowa City, IA, USA., Li M; Department of Oral Pathology, Radiology and Medicine, College of Dentistry, University of Iowa, Iowa City, IA, USA., Petrin A; Iowa Institute for Oral Health Research, University of Iowa, Iowa City, IA, USA., Olotu J; Department of Anatomy, University of Port Harcourt, Choba, Nigeria., Hassan M; Department of Orthodontics, University of Dundee, Dundee, UK., Pape J; Department of Oral Pathology, Radiology and Medicine, College of Dentistry, University of Iowa, Iowa City, IA, USA., Miller SE; Iowa Institute for Oral Health Research, University of Iowa, Iowa City, IA, USA., Donkor P; Department of Orthodontics, University of Dundee, Dundee, UK., Anand D; Department of Biological Sciences, University of Delaware, Newark, DE, USA., Lachke SA; Department of Biological Sciences, University of Delaware, Newark, DE, USA.; Center for Bioinformatics and Computational Biology, University of Delaware, Newark, DE, USA., Marazita ML; Center for Craniofacial and Dental Genetics, Departments of Oral Biology and Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA., Adeyemo AA; National Human Genomic Research Institute, Bethesda, MD, USA., Murray JC; Department of Pediatrics, University of Iowa, Iowa City, IA, USA., Albokhari D; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA., Sobreira N; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA., Butali A; Iowa Institute for Oral Health Research, University of Iowa, Iowa City, IA, USA.; Department of Oral Pathology, Radiology and Medicine, College of Dentistry, University of Iowa, Iowa City, IA, USA.
Jazyk: angličtina
Zdroj: Journal of dental research [J Dent Res] 2022 Apr; Vol. 101 (4), pp. 465-472. Date of Electronic Publication: 2021 Oct 23.
DOI: 10.1177/00220345211046614
Abstrakt: Risk loci identified through genome-wide association studies have explained about 25% of the phenotypic variations in nonsyndromic orofacial clefts (nsOFCs) on the liability scale. Despite the notable sex differences in the incidences of the different cleft types, investigation of loci for sex-specific effects has been understudied. To explore the sex-specific effects in genetic etiology of nsOFCs, we conducted a genome-wide gene × sex (GxSex) interaction study in a sub-Saharan African orofacial cleft cohort. The sample included 1,019 nonsyndromic orofacial cleft cases (814 cleft lip with or without cleft palate and 205 cleft palate only) and 2,159 controls recruited from 3 sites (Ethiopia, Ghana, and Nigeria). An additive logistic model was used to examine the joint effects of the genotype and GxSex interaction. Furthermore, we examined loci with suggestive significance ( P  < 1E-5) in the additive model for the effect of the GxSex interaction only. We identified a novel risk locus on chromosome 8p22 with genome-wide significant joint and GxSex interaction effects (rs2720555, p 2df  = 1.16E-08, p GxSex  = 1.49E-09, odds ratio [OR] = 0.44, 95% CI = 0.34 to 0.57). For males, the risk of cleft lip with or without cleft palate at this locus decreases with additional copies of the minor allele ( p  < 0.0001, OR = 0.60, 95% CI = 0.48 to 0.74), but the effect is reversed for females ( p  = 0.0004, OR = 1.36, 95% CI = 1.15 to 1.60). We replicated the female-specific effect of this locus in an independent cohort ( p  = 0.037, OR = 1.30, 95% CI = 1.02 to 1.65), but no significant effect was found for the males ( p  = 0.29, OR = 0.86, 95% CI = 0.65 to 1.14). This locus is in topologically associating domain with craniofacially expressed and enriched genes during embryonic development. Rare coding mutations of some of these genes were identified in nsOFC cohorts through whole exome sequencing analysis. Our study is additional proof that genome-wide GxSex interaction analysis provides an opportunity for novel findings of loci and genes that contribute to the risk of nsOFCs.
Databáze: MEDLINE