Sex-Specific Effects of Birth Weight on Longitudinal Behavioral Outcomes: A Mendelian Randomization Approach Using Polygenic Scores

Background

It is unclear whether sex differences in behavior arising from birth weight (BW) are genuine because of the cross-sectional nature and potential confounding in previous studies. We aimed to test whether sex differences associated with BW phenotype were reproducible using a Mendelian randomization approach, i.e., association between polygenic score (PGS) for BW and behavior outcomes across childhood and adolescence.

Methods

Using data from the Raine Study, we had 1484 genotyped participants with a total of 6446 Child Behavior Checklist assessments from ages 5 to 17 years. We used BW-PGSs in linear mixed-effect 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 behavior and a second PGS.

Results

We found a sex-by-genotype interaction with lower BW-PGSs associated with increased aggression in males compared with females. These findings were consistent across various analyses, including teacher assessments. Surprisingly, a lower BW-PGS showed protective effects in females, while a lower BW phenotype had detrimental effects in males with evidence of a genotype-phenotype mismatch increasing aggression problems in males only.

Conclusions

This study underscores the genuine nature of behavioral sex differences arising from low BW and highlights the sex-dependent and diverging effects of environmental and genetic BW determinants.