Genome-wide Interaction Study Implicates VGLL2 and Alcohol Exposure and PRL and Smoking in Orofacial Cleft Risk

• Type of Material: Article
• Authors: Elizabeth Leslie, Emory University; Jenna C Carlson, University of Pittsburgh; John R Shaffer, University of Pittsburgh; Fred Deleyiannis, UCHealth Medical Group; Jacqueline T Hecht, University of Texas Health Science Center at Houston; George L Wehby, University of Iowa; Kaare Christensen, University of Southern Denmark; Eleanor Feingold, University of Pittsburgh; Seth M Weinberg, University of Pittsburgh; Mary L Marazita, University of Pittsburgh
• Language: English
• Date: 2022-02-10
• Publisher: FRONTIERS MEDIA SA
• Publication Version: Final Published Version
• Copyright Statement: © 2022 Carlson, Shaffer, Deleyiannis, Hecht, Wehby, Christensen, Feingold, Weinberg, Marazita and Leslie.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3389/fcell.2022.621261
• Title of Journal or Parent Work: FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
• Volume: 10
• Start Page: 621261
• End Page: 621261
• Grant/Funding Information: This work was supported by grants from the National Institutes of Health (NIH): R00-DE025060 (EL), X01-HG007485 (MM, EF), R01-DE016148 (MM, SW). Genotyping and data cleaning were provided via an NIH contract to the Johns Hopkins Center for Inherited Disease Research: HHSN268201200008I.
• Keywords: LIP; BIRTH-DEFECTS; ORAL CLEFTS; Science & Technology; PALATE; TOBACCO-SMOKE; Cell Biology; gene-environement interactions; case- control; CONSUMPTION; Life Sciences & Biomedicine; Developmental Biology; orofacial cleft; GENE-ENVIRONMENT INTERACTION; maternal exposures; GWAS; PROLACTIN
• Research Categories: Biology, Biostatistics; Health Sciences, Epidemiology

Abstract

Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect, affecting approximately 1 in 700 births. NSCL/P has complex etiology including several known genes and environmental factors; however, known genetic risk variants only account for a small fraction of the heritability of NSCL/P. It is commonly suggested that gene-by-environment (G×E) interactions may help explain some of the “missing” heritability of NSCL/P. We conducted a genome-wide G×E interaction study in cases and controls of European ancestry with three common maternal exposures during pregnancy: alcohol, smoking, and vitamin use using a two-stage design. After selecting 127 loci with suggestive 2df tests for gene and G x E effects, 40 loci showed significant G x E effects after correcting for multiple tests. Notable interactions included SNPs of 6q22 near VGLL2 with alcohol and 6p22.3 near PRL with smoking. These interactions could provide new insights into the etiology of CL/P and new opportunities to modify risk through behavioral changes.