The Genetic Landscape of Kynurenine Predicts Neurovascular Pathology and Disrupted White Matter Integrity in Patients...

Low-grade systemic inflammation is linked to cardiometabolic diseases and increased cardiovascular risk. Patients with mood disorders, such as Major Depressive Disorder (MDD) and Bipolar Disorder (BD), also show elevated cardiovascular risk and inflammatory markers, suggesting shared biological pathways between mood and cardiometabolic conditions. The kynurenine (KYN) pathway, activated by inflammatory cytokines and involved in neurotransmitter systems linked to mood, provides a promising area to explore inflammatory-related genetic overlaps in these disorders, with increasing interest in the SH2B3 rs3184504 SNP. Imaging markers like white matter hyperintensities (WMHs) and white matter (WM) microstructure alterations are associated with mood and cardiovascular disorders. This study aimed to investigate the genetic load linked to KYN levels, such as KYN polygenic risk score (PRS) and its effect on white matter hyperintensities (WMHs), outcomes of presumed vascular suffering, and WM microstructure in a sample of 95 MDD and 80 BD patients. Higher PRS for KYN was associated with increased circulating KYN levels and KYN/TRP ratio. KYN PRS predicted the presence of WMHs. The SH2B3 rs3184504 T variant was associated with increased PRS for KYN and a higher number of WMHs. KYN levels and KYN/TRP ratio were not associated with WMHs, while KYN PRS positively correlated with higher axial (AD) and mean diffusivity (MD), with a nominal significance for radial diffusivity (RD). The findings support a genetic contribution to elevated KYN and WM integrity alterations in mood disorders. PRS for KYN indicates a potential predisposition to inflammatory and vascular dysregulation, and SH2B3 rs3184504 may modulate this risk.