Byg Lars Meinertz, Wang Carol, Attia John, Whitehouse Andrew, Pennell Craig
School of Medicine and Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, Newcastle, New South Wales, Australia.
Mothers and Babies Research Program, Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
Biol Psychiatry Glob Open Sci. 2024 Aug 26;4(6):100387. doi: 10.1016/j.bpsgos.2024.100387. eCollection 2024 Nov.
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.
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.
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.
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.
由于先前研究的横断面性质和潜在混杂因素，尚不清楚出生体重（BW）引起的行为性别差异是否真实存在。我们旨在使用孟德尔随机化方法检验与BW表型相关的性别差异是否可重复，即BW的多基因评分（PGS）与儿童期和青春期行为结果之间的关联。
利用雷恩研究的数据，我们有1484名进行了基因分型的参与者，从5岁到17岁共进行了6446次儿童行为检查表评估。我们在线性混合效应模型中使用BW-PGS来预测父母评估的注意力、攻击性和社会问题量表；我们还得出了性别与基因型相互作用的估计值和显著性。我们使用了经邦费罗尼校正的显著性阈值，并通过教师对行为的评估和第二个PGS来检验结果的稳健性。
我们发现了性别与基因型的相互作用，与女性相比，较低的BW-PGS与男性攻击性增加有关。这些发现在包括教师评估在内的各种分析中都是一致的。令人惊讶的是，较低的BW-PGS对女性有保护作用，而较低的BW表型对男性有不利影响，有证据表明基因型-表型不匹配仅会增加男性的攻击问题。
本研究强调了低出生体重引起的行为性别差异的真实性，并突出了环境和遗传因素决定的出生体重对性别的依赖性和不同影响。
