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

Jenna C Carlson; John R Shaffer; Fred Deleyiannis; Jacqueline T Hecht; George L Wehby; Kaare Christensen; Eleanor Feingold; Seth M Weinberg; Mary L Marazita; Elizabeth J Leslie

doi:10.3389/fcell.2022.621261

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

Front Cell Dev Biol. 2022 Feb 10:10:621261. doi: 10.3389/fcell.2022.621261. eCollection 2022.

Authors

Jenna C Carlson¹, John R Shaffer², Fred Deleyiannis³, Jacqueline T Hecht⁴, George L Wehby⁵, Kaare Christensen⁶, Eleanor Feingold^{1

2}, Seth M Weinberg^{2

6}, Mary L Marazita^{2

7}, Elizabeth J Leslie⁸

Affiliations

¹ Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, United States.
² Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, United States.
³ UCHealth Medical Group, Colorado Springs, United States.
⁴ Department of Pediatrics, University of Texas Health Science Center at Houston, Houston, United States.
⁵ Department of Health Management and Policy, College of Public Health, University of Iowa, Iowa City, United States.
⁶ Department of Epidemiology, Institute of Public Health, University of Southern Denmark, Odense, Denmark.
⁷ Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, United States.
⁸ Department of Human Genetics, Emory University School of Medicine, Atlanta, United States.

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.

Keywords: GWAS; case- control; gene-environement interactions; maternal exposures; orofacial cleft.