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

Overview

Journal Biol Psychiatry Glob Open Sci

Date 2024 Nov 1

PMID 39483322

Authors

Lars Meinertz Byg

Carol Wang

John Attia

Andrew Whitehouse

Craig Pennell

Affiliations

Soon will be listed here.

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.

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