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Using UK Biobank data and multivariable logistic regression to test associations between potential causes of handedness and offspring hand preference, we then investigated the potential causal effect of maternal smoking during pregnancy on offspring handedness using a proxy gene-by-environment (GxE) Mendelian randomization design. We used rs16969968 in the <jats:italic>CHRNA5<\/jats:italic> 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 heaviness on offspring handedness should only manifest in individuals whose mothers smoked during pregnancy. Using traditional epidemiological methods, we found maternal smoking during pregnancy increased the probability of being right-handed after adjustment for covariates. Despite this, when using the GxE MR analyses we found no strong causal effect of maternal smoking during pregnancy on offspring hand-preference. Our findings using the UK Biobank cohort align with previous findings and emphasise the impact of factors such as birth year, birthweight, being part of a multiple birth and breastfeeding on hand preference. However, we found no strong evidence for a causal link between maternal smoking and offspring handedness. The main factors contributing to variation in hand preference remain unresolved.<\/jats:p>","DOI":"10.1007\/s10519-025-10226-0","type":"journal-article","created":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T04:15:23Z","timestamp":1752639323000},"page":"289-301","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Investigating the Relationship Between Maternal Smoking During Pregnancy and Offspring Handedness: Extending the Proxy Gene-by-Environment Mendelian Randomization Study Design to Include Polygenic Risk Scores"],"prefix":"10.1007","volume":"55","author":[{"given":"Daisy C. 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