The effect of polygenic risk on white matter microstructural degeneration in Parkinson's disease: A longitudinal Diffusion Tensor Imaging study

Abstract

Background and purpose: This study was undertaken to investigate the effect of genetic risk on whole brain white matter (WM) integrity in patients with Parkinson disease (PD). Methods: Data were acquired from the Parkinson's Progression Markers Initiative (PPMI) database. Polygenic load was estimated by calculating weighted polygenic risk scores (PRS) using (i) all available 26 PD-risk single nucleotide polymorphisms (SNPs) (PRS1) and (ii) 23 SNPs with minor allele frequency (MAF) > 0.05 (PRS2). According to the PRS2, and combined with clinical and diffusion tensor imaging (DTI) data over 3-year follow-up, 60 PD patients were screened and assigned to the low-PRS group (n = 30) and high-PRS group (n = 30) to investigate intergroup differences in clinical profiles and WM microstructure measured by DTI cross-sectionally and longitudinally. RESULTS: PRS were associated with younger age at onset in patients with PD (PRS1, Spearman ρ = −0.190, p = 0.003; PRS2, Spearman ρ = −0.189, p = 0.003). The high-PRS group showed more extensive WM microstructural degeneration compared with the low-PRS group, mainly involving the anterior thalamic radiation (AThR) and inferior frontooccipital fasciculus (IFOF) (p < 0.05). Furthermore, WM microstructural changes in AThR correlated with declining cognitive function (r = −0.401, p = 0.028) and increasing dopaminergic deficits in caudate (r = −0.405, p = 0.030).Conclusions: These findings suggest that PD-associated polygenic load aggravates the WM microstructural degeneration and these changes may lead to poor cognition with continuous dopamine depletion. This study provides advanced evidence that combined with a cumulative PRS and DTI methods may predict disease progression in PD patients.

Shared Genetic Architecture between Parkinson's Disease and Brain Structural Phenotypes

“…Traditional methods investigating genetic overlap include genetic correlation and polygenic risk scores (PRSs), which provide a single estimate of genome‐wide genetic overlap. PRS for PD was found to be associated with the neural activity of the hippocampus, parahippocampus, and fusiform gyrus; hippocampal‐prefrontal and fusiform‐temporal connectivity; and gray matter alterations in the orbitofrontal cortex, as well as with whole‐brain white matter (WM) integrity 17,18 . A recent genome‐wide association study (GWAS) of total cortical surface area (SA) and average cortical thickness (TH) discovered, using linkage disequilibrium (LD) score regression (LDSC), a significant positive genetic connection between total SA and PD, indicating that some of the same variables that increase the risk for PD also raise total SA.…”