Multilocus genetic profile in dopaminergic pathway modulates the striatum and working memory

Area of Science:

• Neuroscience
• Psychiatry
• Genetics

Background:

• Dopamine plays a crucial role in schizophrenia pathophysiology and treatment.
• Altered dopaminergic activity is often observed in the dorsal striatum of schizophrenia patients.
• Genetic variations within the dopamine system are implicated in schizophrenia risk.

Purpose of the Study:

• To investigate the relationship between genetic variations in the dopaminergic pathway and striatal function.
• To examine the association between polygenic risk scores for schizophrenia and working memory performance.
• To explore how genetic risk for schizophrenia affects brain functional connectivity.

Main Methods:

• Calculation of polygenic risk scores (PGRS) using genome-wide association study data for dopamine-related genes.
• Assessment of working memory in a healthy general population sample.
• Resting-state functional connectivity analysis using fMRI.

Main Results:

• A higher PGRS was significantly associated with poorer working memory.
• Increased PGRS correlated with stronger connectivity between the left putamen/caudate and the default mode network.
• Higher PGRS was linked to weaker connections between the striatum and the fronto-parietal network.

Conclusions:

• Genetic variations in the dopaminergic pathway contribute to working memory deficits in schizophrenia risk.
• Polygenic effects influence striatal functional connectivity, potentially underlying schizophrenia pathophysiology.
• Findings support and refine the dopamine hypothesis of schizophrenia by highlighting polygenic influences.