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

Area of Science:

• Evolutionary biology
• Neurogenetics
• Psychiatric disorders

Background:

• Schizophrenia may stem from evolutionary trade-offs in human neurodevelopment.
• Human Accelerated Regions (HARs) are key evolutionary markers influencing neurodevelopment and potentially schizophrenia risk.
• HARs function as enhancers of neurodevelopmental transcription, impacting brain structure and function.

Purpose of the Study:

• To investigate the impact of polygenic load from HARs on neuroanatomical measures in schizophrenia.
• To assess the relationship between HARs-derived polygenic risk scores (PRS) and brain cortical thickness and surface area.
• To explore interactions between PRS and schizophrenia diagnosis in relation to neuroanatomy.

Main Methods:

• Case-control study with 128 schizophrenia patients and 115 controls.
• Calculation of global schizophrenia PRS, HARs PRS, fetal brain HARs PRS (FB-HARs PRS), and adult brain HARs PRS (AB-HARs PRS).
• Analysis of main effects and PRS x diagnosis interactions on regional cortical thickness and surface area.

Main Results:

• A higher FB-HARs PRS was associated with reduced surface area in the lateral orbitofrontal cortex, superior temporal cortex, pars triangularis, and paracentral lobule in patients.
• No significant effect of HARs-derived PRS on schizophrenia risk was observed.
• Neuroanatomical findings suggest prenatal transcriptional regulation by human-specific HARs influences surface area variability.

Conclusions:

• Human-specific transcriptional regulation during prenatal development, mediated by HARs, plays a role in surface area variability.
• Evolutionary markers like HARs are implicated in the genomic architecture of schizophrenia.
• Further research into HARs' role in neurodevelopmental disorders is warranted.