Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, South Korea.
Institute of Data Science, Korea University, Seoul, South Korea.
Hum Brain Mapp. 2022 Aug 15;43(12):3857-3872. doi: 10.1002/hbm.25888. Epub 2022 Apr 26.
Sex impacts the development of the brain and cognition differently across individuals. However, the literature on brain sex dimorphism in humans is mixed. We aim to investigate the biological underpinnings of the individual variability of sexual dimorphism in the brain and its impact on cognitive performance. To this end, we tested whether the individual difference in brain sex would be linked to that in cognitive performance that is influenced by genetic factors in prepubertal children (N = 9,658, ages 9-10 years old; the Adolescent Brain Cognitive Development study). To capture the interindividual variability of the brain, we estimated the probability of being male or female based on the brain morphometry and connectivity features using machine learning (herein called a brain sex score). The models accurately classified the biological sex with a test ROC-AUC of 93.32%. As a result, a greater brain sex score correlated significantly with greater intelligence (p < .001, = .011-.034; adjusted for covariates) and higher cognitive genome-wide polygenic scores (GPSs) (p < .001, < .005). Structural equation models revealed that the GPS-intelligence association was significantly modulated by the brain sex score, such that a brain with a higher maleness score (or a lower femaleness score) mediated a positive GPS effect on intelligence (indirect effects = .006-.009; p = .002-.022; sex-stratified analysis). The finding of the sex modulatory effect on the gene-brain-cognition relationship presents a likely biological pathway to the individual and sex differences in the brain and cognitive performance in preadolescence.
性别对个体大脑和认知的发展有不同的影响。然而，人类大脑性别二态性的文献存在差异。我们旨在研究大脑性别二态性个体差异的生物学基础及其对认知表现的影响。为此，我们测试了个体大脑性别差异是否与受遗传因素影响的认知表现个体差异有关，研究对象是青春期前儿童（N=9658 人，年龄 9-10 岁；青少年大脑认知发展研究）。为了捕捉大脑的个体间变异性，我们使用机器学习根据大脑形态和连通性特征估计基于大脑的性别概率（在此称为大脑性别评分）。这些模型能够准确地对生物学性别进行分类，测试的 ROC-AUC 为 93.32%。结果表明，大脑性别评分与智力显著相关（p<0.001，r=0.011-0.034；调整了协变量），与更高的认知全基因组多基因评分（GPS）显著相关（p<0.001，r<0.005）。结构方程模型表明，GPS-智力关联受到大脑性别评分的显著调节，大脑的男性化评分越高（或女性化评分越低），GPS 对智力的正向影响就越大（间接影响 r=0.006-0.009；p=0.002-0.022；性别分层分析）。该研究结果发现了性别对基因-大脑-认知关系的调节作用，为青春期前大脑和认知表现的个体和性别差异提供了一个可能的生物学途径。
