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

Lars Meinertz Byg; Carol Wang; John Attia; Andrew Whitehouse; Craig Pennell

doi:10.1016/j.bpsgos.2024.100387

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

Biol Psychiatry Glob Open Sci. 2024 Aug 26;4(6):100387. doi: 10.1016/j.bpsgos.2024.100387. eCollection 2024 Nov.

Authors

Lars Meinertz Byg^{1

2}, Carol Wang^{1

2}, John Attia^{1

3}, Andrew Whitehouse⁴, Craig Pennell^{1

2

5}

Affiliations

¹ School of Medicine and Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, Newcastle, New South Wales, Australia.
² Mothers and Babies Research Program, Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
³ Division of Medicine, John Hunter Hospital, Newcastle, New South Wales, Australia.
⁴ Telethon Kids Institute, Perth, University of Western Australia, Western Australia, Australia.
⁵ Maternal Fetal Medicine, Division of Maternity and Gynaecology, John Hunter Hospital, Newcastle, New South Wales, Australia.

Abstract

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.

Keywords: Aggression; Birth weight; Child Behavior Checklist; Children and adolescents; Developmental programming; Gene-environment interactions.

Plain language summary

Previous studies have suggested a link between low birth weight and poor behavioral outcomes in children and adolescents, but it is unclear if these effects differ between males and females. We demonstrated that genes influencing birth weight had different effects on aggressive behavior in males and females with effects throughout childhood and adolescence; furthermore, our study suggests that birth weight environment and birth weight genes have different effects on behavior. In males, a mismatch between the genetically determined birth weight and the measured birth weight resulted in more aggressive behavior.