Gene, the Sexual Brain, and Cognition: Machine-Predicted Brain Sex Score Explains Individual Differences in Cognitive Development and Genetic Influence.

Sex impacts the development of the brain and cognition differently across individuals. We investigated the biological underpinnings of the individual variability of sexual dimorphism in the brain and its impact on cognitive development. In prepubertal children (N=9,658, ages 9~10 years old; the Adolescent Brain Cognitive Development study), we tested whether the individual difference in brain sex development was related to that in cognitive development, known to be influenced by genetic factors. We estimated an individual’s brain sex score from machine learning models trained on brain morphometry and diffusion white matter connectomes that accurately classified the biological sex with a test ROC-AUC of 93.32%. A greater brain sex score correlated significantly with greater intelligence (Pfdr<0.001, ηp2=0.034~0.050; adjusted for covariates) and higher cognitive genome-wide polygenic scores (GPSs) (Pfdr<0.001, ηp2<0.005). Structural equation models revealed that the GPS-intelligence association was 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=0.006~0.009; P=0.002~0.022; sex-stratified analysis). The novel gene-brain-cognition relationship reported in this study presents a biological pathway to the individual and sex differences in the brain and cognitive development in preadolescence.