Gene × sex interactions on cognition in the Philadelphia neurodevelopmental cohort

Small differences between females and males in cognitive abilities have been consistently reported, but the factors underlying these sex differences remain unclear. Social and cultural factors are thought to play a key role, but studies on this topic have been inconclusive. Examination of genetic factors may shed some light on the mechanisms underlying cognitive sex differences.

Using data from the Philadelphia Neurodevelopmental Cohort, a large, general population sample of individuals aged 8 to 21 years old (N = 4,694), we tested for sex differences in the genetic factors (i.e., Gene × Sex interactions) underlying cognitive ability. Participants completed the Penn Computerized Neurocognitive Battery, which consists of 14 tests designed to capture accuracy and speed in five domains: 1) executive function (abstraction and mental flexibility, attention, working memory), 2) episodic memory (verbal, facial, spatial), 3) complex cognition (verbal reasoning, nonverbal reasoning, spatial processing), 4) social cognition (emotion identification, emotion differentiation, age differentiation), and 5) speed (motor, sensorimotor). Composite domain scores were derived using confirmatory factor analysis, and general accuracy (g) and speed (gs) using principal component analysis.

Small sex differences were observed on most cognitive measures (standardized mean difference (SMD) = 0.061-0.182). Males showed significantly higher genetic variance and lower environmental variance in executive (female σ²_g = 0.301 v. male σ²_g = 0.598, p = 0.001, female σ²_e = 0.243 v. male σ²_e = 0.024, p = 0.007), and complex (female σ²_g = 0.291 v. male σ²_g = 0.610, p = 0.001, female σ²_e = 0.259 v. male σ²_e = 0.023, p = 0.006) accuracy. Females showed significantly higher genetic and lower environmental variance on complex (female σ²_g = 0.575 v. male σ²_g = 0.135, p = 0.009, female σ²_e = 0.222 v. male σ²_e = 0.641, p = 0.012) and social (female σ²_g = 0.589 v. male σ²_g = 0.129, p = 0.009, female σ²_e = 0.236 v. male σ²_e = 0.672, p = 0.012) speed. Genetic correlations between females and males were not significantly different from 1 on any cognitive measure. Altogether, our results suggest that while the same genetic factors influence cognition in females and males, the magnitude of effect of these genetic factors differs.

We observed small differences between females and males on most cognitive measures, as well as sex differences in heritability on some measures. Future studies are needed to delineate how environmental, genetic, and other biological factors jointly influence cognition.