Adolescence is the starting point of sex-dichotomous COMT genetic effects.

The catechol-o-methyltransferase (COMT) genetic variations produce pleiotropic behavioral/neuroanatomical effects. Some of these effects may vary among sexes. However, the developmental trajectories of COMT-by-sex interactions are unclear. Here we found that extreme COMT reduction, in both humans (22q11.2 deletion syndrome COMT Met) and mice (COMT-/-), was associated to cortical thinning only after puberty and only in females. Molecular biomarkers, such as tyrosine hydroxylase, Akt and neuronal/cellular counting, confirmed that COMT-by-sex divergent effects started to appear at the cortical level during puberty. These biochemical differences were absent in infancy. Finally, developmental cognitive assessment in 22q11DS and COMT knockout mice established that COMT-by-sex-dichotomous effects in executive functions were already apparent in adolescence. These findings uncover that genetic variations severely reducing COMT result in detrimental cortical and cognitive development selectively in females after their sexual maturity. This highlights the importance of taking into account the combined effect of genetics, sex and developmental stage.