Human-specific evolutionary markers linked to foetal neurodevelopment modulate brain surface area in schizophrenia

ABSTRACT Schizophrenia (SZ) is hypothesised to represent a costly trade-off in the evolution of the neurodevelopmental ontogenetic mechanisms associated with human-specific cognitive capacities. Human Accelerated Regions (HARs) are evolutionary conserved genomic regions that have accumulated human-specific sequence changes. These evolutionary markers function as neurodevelopmental transcription enhancers and have been associated with the brain’s cortical expansion and connectivity, the processing of neural information, and the risk for SZ. We sought to investigate whether HARs’ polygenic load influenced neuroanatomical measures. Our sample consisted of 128 patients with SZ and 115 healthy controls with high-resolution structural T1 MRI and genome-wide genotyping data. We extracted the cortical thickness (CT) and surface area (SA) for the 34 Desikan-Killiany regions per hemisphere. We calculated four polygenic risk scores (PRS): SZ genetic load (Global PRS SZ ), HARs’ specific variability (HARs PRS SZ ), HARs’ variability associated with transcriptional regulatory elements uniquely active in the foetal brain (FB-HARs PRS SZ ) and in the adult brain (AB-HARs PRS SZ ). Through linear regression analyses, we explored whether these four PRSs modulated CT and SA within diagnostic groups and the PRSs and diagnostic interaction on the cortical measures. Results: indicate that FB-HARs PRS SZ influenced patients’ right SA on the lateral orbitofrontal cortex, the superior temporal cortex, the pars triangularis and the paracentral lobule and that a higher SZ risk load in FB-HARs is associated with lower SA values. These findings evidence the involvement of the HARs-foetal gene regulatory activity in SA architecture and the evolutionary component of this regulation in SZ. These data emphasise the importance of HARs in the transcriptional regulatory machinery from early neurodevelopment and their role as the bridging point between the neurodevelopmental and evolutionary hypotheses in SZ.