# 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

## TL;DR

This study explores if maternal smoking during pregnancy influences offspring handedness using genetic and environmental data from UK Biobank.

## Contribution

Extends proxy gene-by-environment Mendelian randomization to include polygenic risk scores for smoking behavior.

## Key findings

- Maternal smoking during pregnancy was associated with increased right-handedness in offspring using traditional epidemiological methods.
- No strong causal effect of maternal smoking on offspring handedness was found using gene-by-environment Mendelian randomization.
- Factors like birth year, birthweight, and breastfeeding impact hand preference more than maternal smoking.

## Abstract

Hand preference first appears in early development, yet twin studies and GWAS show that only a minority of variance is explained by heritable genetic factors. 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 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 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.

The online version contains supplementary material available at 10.1007/s10519-025-10226-0.