Cognitive impact of genetic variation of the serotonin transporter in primates is associated with differences in brain morphology rather than serotonin neurotransmission

A powerful convergence of genetics, neuroimaging and epidemiological research has identified biological pathways mediating individual differences in complex behavioral processes and related risk for disease. Orthologous genetic variation in non-human primates represents a unique opportunity to characterize the detailed molecular and cellular mechanisms which bias behaviorally- and clinically-relevant brain function. We report that a rhesus macaque orthologue of a common polymorphism of the serotonin transporter gene (rh5-HTTLPR) has strikingly similar effects on behavior and brain morphology to those in humans. Specifically, the rh5-HTTLPR Short allele broadly impacts cognitive choice behavior and brain morphology without observably affecting 5-HT transporter or 5-HT(1A) concentrations in vivo. Collectively, our findings indicate that 5-HTTLPR-associated behavioral effects reflect genotype-dependent biases in cortical development rather than static differences in serotonergic signaling mechanisms. Moreover, these data highlight the vast potential of non-human primate models in advancing our understanding of human genetic variation impacting behavior and neuropsychiatric disease liability.