Facial clefts are one of the most common birth defects, affecting 2 out of every thousand babies. While the main causes of facial clefts are unknown, it is obvious that genetics plays a strong role. We've shown that families with one member affected by clefts are 40 times as likely to have a baby with a cleft. Environmental factors are also presumed to play a role in clefts. For example, clefts are easily produced in experimental animals exposed to teratogens. It is likely that humans vary in their genetic susceptibility to teratogens that cause clefts. More than two decades ago, we anticipated that genetic susceptibility would become an important area of epidemiologic research at NIEHS. Accordingly, we selected facial clefts as a condition with both genetic and environmental causes, and we began in 1992 to develop a study to address the causes of clefts. In 1996 we launched a population-based case-control study of facial clefts in Norway. (Norway has one of the highest rates of cleft lip and palate in the world.) The field phase was completed in 2002. We enrolled 88% of all babies with facial clefts born in Norway between 1996 and 2002 (574 cases), and 76% of eligible control infants (763) selected randomly from the population. Mothers of these infants provided detailed information on occupational and other exposures during pregnancy, as well as on nutrition, personal habits and medical history. Biological samples for DNA analysis were collected from cases and controls as well as their mothers, fathers and siblings. These total nearly 4000 people. DNA has been extracted from these samples and assayed for GWAS. We have also had DNA from our newborn cases and controls assayed for methylation changes. We are participating in a multi-study consortium of GWAS in facial clefts, and have contributed to a series of papers identifying gene variants associated with increased risk of facial clefts. The most recent finds an association of a missense variant of the GRHL3 gene with cleft palate (5). We also are taking part in a large consortium of clefts studies to look at associations between common exposures and the risk of facial clefts. We have been able to show a persuasive association between passive smoke exposure and facial clefts (3) -- the first time that passive smoking has been associated with a birth defect. In an extension of our methylation project, we found that maternal age at the time of her pregnancy was associated with epigenetic changes in her offspring. Not only were we able to confirm this association among newborns in an independent data set, we were able to show that the epigenetic changes were persistent into adulthood (6).

Project Start
Project End
Budget Start
Budget End
Support Year
20
Fiscal Year
2016
Total Cost
Indirect Cost
Name
U.S. National Inst of Environ Hlth Scis
Department
Type
DUNS #
City
State
Country
Zip Code
Magnus, Maria C; Ghaderi, Sara; Morken, Nils-Halvdan et al. (2017) Vanishing twin syndrome among ART singletons and pregnancy outcomes. Hum Reprod 32:2298-2304
Moreno Uribe, L M; Fomina, T; Munger, R G et al. (2017) A Population-Based Study of Effects of Genetic Loci on Orofacial Clefts. J Dent Res 96:1322-1329
Kutbi, Hebah; Wehby, George L; Moreno Uribe, Lina M et al. (2017) Maternal underweight and obesity and risk of orofacial clefts in a large international consortium of population-based studies. Int J Epidemiol 46:190-199
Wehby, George L; Uribe, Lina M Moreno; Wilcox, Allen J et al. (2017) Interaction between smoking and body mass index and risk of oral clefts. Ann Epidemiol 27:103-107.e2
DeRoo, Lisa A; Wilcox, Allen J; Lie, Rolv T et al. (2016) Maternal alcohol binge-drinking in the first trimester and the risk of orofacial clefts in offspring: a large population-based pooling study. Eur J Epidemiol 31:1021-1034
Kummet, Colleen M; Moreno, Lina M; Wilcox, Allen J et al. (2016) Passive Smoke Exposure as a Risk Factor for Oral Clefts-A Large International Population-Based Study. Am J Epidemiol 183:834-41
Arendt, Linn Håkonsen; Ramlau-Hansen, Cecilia Høst; Wilcox, Allen J et al. (2016) Placental Weight and Male Genital Anomalies: A Nationwide Danish Cohort Study. Am J Epidemiol 183:1122-8
Leslie, Elizabeth J; Carlson, Jenna C; Shaffer, John R et al. (2016) A multi-ethnic genome-wide association study identifies novel loci for non-syndromic cleft lip with or without cleft palate on 2p24.2, 17q23 and 19q13. Hum Mol Genet 25:2862-2872
Markunas, Christina A; Wilcox, Allen J; Xu, Zongli et al. (2016) Maternal Age at Delivery Is Associated with an Epigenetic Signature in Both Newborns and Adults. PLoS One 11:e0156361
Leslie, Elizabeth J; Liu, Huan; Carlson, Jenna C et al. (2016) A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3. Am J Hum Genet 98:744-54

Showing the most recent 10 out of 44 publications