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

• 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
• Journal Title: FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
• Volume: Volume 10
• Publisher: FRONTIERS MEDIA SA | 2022-02-10, Pages 621261-621261
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.3389/fcell.2022.621261
• Subjects: Health Sciences, Epidemiology; Biology, Biostatistics
• Keywords: Science & Technology; Life Sciences & Biomedicine; Cell Biology; Developmental Biology; orofacial cleft; gene-environement interactions; maternal exposures; GWAS; case- control; GENE-ENVIRONMENT INTERACTION; BIRTH-DEFECTS; TOBACCO-SMOKE; ORAL CLEFTS; PROLACTIN; LIP; CONSUMPTION; PALATE

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.