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

W Awotoye; C Comnick; C Pendleton; E Zeng; A Alade; P A Mossey; L J J Gowans; M A Eshete; W L Adeyemo; T Naicker; C Adeleke; T Busch; M Li; A Petrin; J Olotu; M Hassan; J Pape; S E Miller; P Donkor; D Anand; S A Lachke; M L Marazita; A A Adeyemo; J C Murray; D Albokhari; N Sobreira; A Butali

doi:10.1177/00220345211046614

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

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

W Awotoye, C Comnick, C Pendleton, E Zeng, A Alade, P A Mossey, L J J Gowans, M A Eshete, W L Adeyemo, T Naicker, …

Journal of dental research, Vol.101(4), pp.465-472

04/2022

DOI: 10.1177/00220345211046614

PMCID: PMC8935575

PMID: 34689653

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https://discovery.dundee.ac.uk/en/publications/769df50d-3bfd-49f0-a469-5afdf686ee73View

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Abstract

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 ( < 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 = 1.16E-08, p = 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 ( < 0.0001, OR = 0.60, 95% CI = 0.48 to 0.74), but the effect is reversed for females ( = 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 ( = 0.037, OR = 1.30, 95% CI = 1.02 to 1.65), but no significant effect was found for the males ( = 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.

Cleft Lip - genetics

Cleft Palate - genetics

Female

Genetic Predisposition to Disease - genetics

Genome-Wide Association Study

Humans

Male

Polymorphism, Single Nucleotide - genetics

Details

Title: Subtitle: Genome-wide Gene-by-Sex Interaction Studies Identify Novel Nonsyndromic Orofacial Clefts Risk Locus
Creators: W Awotoye - University of Iowa
C Comnick - University of Iowa
C Pendleton - University of Iowa
E Zeng - University of Iowa
A Alade - University of Iowa
P A Mossey - University of Dundee
L J J Gowans - Kwame Nkrumah University of Science and Technology
M A Eshete - Addis Ababa University
W L Adeyemo - University of Lagos
T Naicker - University of KwaZulu-Natal
C Adeleke - University of Iowa
T Busch - University of Iowa
M Li - University of Iowa
A Petrin - University of Iowa
J Olotu - University of Port Harcourt
M Hassan - University of Dundee
J Pape - University of Iowa
S E Miller - University of Iowa
P Donkor - University of Dundee
D Anand - University of Delaware
S A Lachke - University of Delaware
M L Marazita - University of Pittsburgh
A A Adeyemo - National Human Genome Research Institute
J C Murray - University of Iowa
D Albokhari - Johns Hopkins University
N Sobreira - Johns Hopkins University
A Butali - University of Iowa
Resource Type: Journal article
Publication Details: Journal of dental research, Vol.101(4), pp.465-472
DOI: 10.1177/00220345211046614
PMID: 34689653
PMCID: PMC8935575
NLM abbreviation: J Dent Res
ISSN: 0022-0345
eISSN: 1544-0591
Grant note: R90 DE024296 / NIDCR NIH HHS R01 DE028300 / NIDCR NIH HHS K99 DE022378 / NIDCR NIH HHS R03 DE024776 / NIDCR NIH HHS R00 DE022378 / NIDCR NIH HHS K43 DE029427 / NIDCR NIH HHS
Language: English
Date published: 04/2022
Academic Unit: Preventive and Community Dentistry; Roy J. Carver Department of Biomedical Engineering; Orthodontics; Oral Pathology, Radiology and Medicine; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Iowa Neuroscience Institute; Biostatistics; Pediatric Dentistry; Craniofacial Anomalies Research Center; Dental Research
Record Identifier: 9984353798802771

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