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

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

doi:10.3389/fcell.2022.621261

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.

Highlights

Interest in identifying the causal factors for birth defects, including orofacial clefts (OFCs) can be traced back centuries (Marazita, 2012) and has often involved a debate as to the contribution of genetic versus environmental risk factors (Beames and Lipinski, 2020)
As a follow-up study to previous genome-wide association studies (GWAS) identifying marginal gene effects (G) increasing risk for NSCL/P, this study focused on identifying G x E interactions
A locus on 2p23 with strong G effects but no gene-environment interaction (GE) effects was identified in all three analyses but to our knowledge has not been reported before in GWAS of NSCL/P

Summary

Introduction

Interest in identifying the causal factors for birth defects, including orofacial clefts (OFCs) can be traced back centuries (Marazita, 2012) and has often involved a debate as to the contribution of genetic versus environmental risk factors (Beames and Lipinski, 2020). Evidence for a multifactorial model for OFC etiology originated with Fraser’s early studies exposing pregnant mice to cortisone showing that the incidence of corticosteroid induced cleft palate varied by strain. The multifactorial model is favored in human nonsyndromic OFCs, where twin and family studies provide evidence for a strong, but incomplete, genetic component. Many environmental factors have been postulated to modify risk of OFCs including maternal medications, smoking or alcohol consumption (Romitti et al, 2007; Grewal et al, 2008), nutrition (Kelly et al, 2012), obesity (Blomberg and Källén, 2009), gestational diabetes (Figueiredo et al, 2015), and occupational exposures. On the other hand, has been shown to increase risk consistently across many studies with similar effect sizes (Little et al, 2004)

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