A Population-Based Study of Effects of Genetic Loci on Orofacial Clefts

L M Moreno Uribe; T Fomina; R G Munger; P A Romitti; M M Jenkins; H K Gjessing; M Gjerdevik; K Christensen; A J Wilcox; J C Murray; R T Lie; G L Wehby

doi:10.1177/0022034517716914

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A Population-Based Study of Effects of Genetic Loci on Orofacial Clefts

Journal article

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A Population-Based Study of Effects of Genetic Loci on Orofacial Clefts

L M Moreno Uribe, T Fomina, R G Munger, P A Romitti, M M Jenkins, H K Gjessing, M Gjerdevik, K Christensen, A J Wilcox, J C Murray, …

Journal of dental research, Vol.96(11), pp.1322-1329

10/2017

DOI: 10.1177/0022034517716914

PMCID: PMC5607104

PMID: 28662356

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Abstract

Prior genome-wide association studies for oral clefts have focused on clinic-based samples with unclear generalizability. Prior samples were also small for investigating effects by cleft type and exclusively studied isolated clefts (those occurring without other birth defects). We estimated the effects of 17 top loci on cleft types in both isolated and nonisolated cases in the largest consortium to date of European-descent population-based studies. Our analytic approach focused on a mother-child dyad case-control design, but it also allowed analyzing mother-only or child-only genotypes to maximize power. Our total sample included 1,875 cases with isolated clefts, 459 cases with nonisolated clefts, and 3,749 controls. After correcting for multiple testing, we observed significant associations between fetal single-nucleotide polymorphisms (SNPs) at IRF6, PAX7, 8q21.3, 8q24, KIAA1598-VAX1, and MAFB and isolated cleft lip only (CLO) and cleft lip and palate (CLP). Significant associations were observed between isolated CLO and fetal SNPs near TPM1 and NOG1 and between CLP and fetal SNPs at ABCA4-ARHGAP29, THADA, FOXE1, and SPRY2. Overall, effects were similar for isolated CLO and CLP, except for ABCA4-ARHGAP29. A protective effect was observed for the fetal NOG1 SNP on cleft palate only, opposite in direction to the effect on CLO. For most fetal SNPs, a dose-response allelic effect was observed. No evidence of parent-of-origin or maternal genome effects was observed. Overall, effect direction and magnitude were similar between isolated and nonisolated clefts, suggesting that several loci are modifiers of cleft risk in both isolated and nonisolated forms. Our results provide reliable estimates of the effects of top loci on risks of oral clefts in a population of European descent.

Genetic Predisposition to Disease

Genome-Wide Association Study

Cleft Lip - embryology

Humans

Genetic Loci - genetics

Cleft Palate - embryology

European Continental Ancestry Group

Genotype

Male

Cleft Palate - genetics

Case-Control Studies

Cleft Lip - genetics

Alleles

Female

Polymorphism, Single Nucleotide

Infant, Newborn

Details

Title: Subtitle: A Population-Based Study of Effects of Genetic Loci on Orofacial Clefts
Creators: L M Moreno Uribe - 1 Department of Orthodontics and Dows Institute, College of Dentistry, University of Iowa, Iowa City, IA, USA
T Fomina - 2 Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway
R G Munger - 3 Department of Nutrition and Food Sciences, Utah State University, Logan, UT, USA
P A Romitti - 4 Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, IA, USA
M M Jenkins - 5 National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USA
H K Gjessing - 6 Norwegian Institute of Public Health, Bergen and Oslo, Norway
M Gjerdevik - 6 Norwegian Institute of Public Health, Bergen and Oslo, Norway
K Christensen - 7 Department of Public Health, University of Southern Denmark; Department of Clinical Genetics and Department of Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark
A J Wilcox - 8 Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, NC, USA
J C Murray - 9 Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
R T Lie - 6 Norwegian Institute of Public Health, Bergen and Oslo, Norway
G L Wehby - 10 Departments of Health Management and Policy, Economics, and Preventive and Community Dentistry, and Public Policy Center, University of Iowa, Iowa City, IA, USA
Resource Type: Journal article
Publication Details: Journal of dental research, Vol.96(11), pp.1322-1329
DOI: 10.1177/0022034517716914
PMID: 28662356
PMCID: PMC5607104
NLM abbreviation: J Dent Res
ISSN: 0022-0345
eISSN: 1544-0591
Publisher: United States
Grant note: U01 DD000492 / NCBDD CDC HHS U01DD001035 / ACL HHS CC999999 / Intramural CDC HHS R01 DE020895 / NIDCR NIH HHS U01 DD001035 / NCBDD CDC HHS
Language: English
Date published: 10/2017
Academic Unit: Preventive and Community Dentistry; Health Management and Policy; Biostatistics; Pediatric Dentistry; Craniofacial Anomalies Research Center; Nursing; Orthodontics; Anatomy and Cell Biology; International Programs; Stead Family Department of Pediatrics; Epidemiology; Economics; Public Policy Center (Archive); Dental Research
Record Identifier: 9983996063802771

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