Does smoking during pregnancy influence offspring handedness? Extending gene-by-environment Mendelian randomisation to include polygenic risk scores

Hand preference first appears in utero , yet twin studies and GWAS show that the majority of variance in hand preference is explained by environmental factors. Using UK Biobank data and multivariable logistic regression to test associations between potential causes of handedness and offspring hand preference, we found maternal smoking during pregnancy increased the probability of being right-handed after adjustment for covariates. Using a proxy gene-by-environment (GxE) Mendelian randomization design we investigated the potential causal effect of maternal smoking during pregnancy on offspring handedness. We used rs16969968 in the CHRNA5 gene and a polygenic risk score of genome-wide significant smoking-heaviness variants to proxy smoking behaviour. We stratified based on reported maternal smoking during pregnancy because, regardless of genotype, any causal effect of maternal smoking on offspring handedness should only manifest in individuals whose mothers smoked during pregnancy. The GxE MR analyses found no causal effect of maternal smoking during pregnancy on offspring hand-preference. Our study contributes to the understanding of hand preference and its potential early-life determinants. However, the main factors contributing to variation in hand preference remain unresolved.