Sex-specific effects of Birth Weight on Longitudinal Behavioural Outcomes; a Mendelian Randomisation Approach using Polygenic Scores

Abstract

AbstractIntroIt is unclear if sex differences in behaviour arising from birth weight (BW) are genuine because of the cross-sectional nature and potential confounding in previous studies. We aimed to test if sex differences associated with birth weight phenotype were reproducible using a Mendelian randomisation approach, i.e. polygenic score for birthweight across childhood and adolescence.MethodUtilising data from the Raine study we had 1484 genotyped participants with a total of 6446 child behaviour checklist assessments across childhood and adolescence. We used BW polygenic scores in linear mixed-effects models to predict parentally-assessed attention, aggression and social problems scales; we also derived estimates and significance for a sex-by-genotype interaction. We used a Bonferroni corrected significance threshold and tested robustness of the results with teacher assessments of behaviour as well as a second polygenic score.ResultsWe found a sex-by-genotype interaction with lower BW polygenic scores (BW-PGS) associated with increased aggression in males compared to females. These findings were consistent across various analyses, including teacher assessments. Surprisingly, a lower BW-PGS showed protective effects in females, while lower BW phenotype had detrimental effects in males with evidence of a genotype-phenotype mismatch increasing aggression problems in males only.ConclusionThis study underscores the genuine nature of behavioural sex differences arising from low BW and highlights the sex-dependent and diverging effects of environmental and genetic BW determinants.