Effect of polygenic load on striatal dopaminergic deterioration in Parkinson disease.

Abstract

To investigate the effect of polygenic load on the progression of striatal dopaminergic dysfunction in patients with Parkinson disease (PD). Using data from 335 patients with PD in the Parkinson's Progression Markers Initiative (PPMI) database, we investigated the longitudinal association of PD-associated polygenic load with changes in striatal dopaminergic activity as measured by ¹²³I-N-3-fluoropropyl-2-β-carboxymethoxy-3β-(4-iodophenyl) nortropane (¹²³I-FP-CIT) SPECT over 4 years. PD-associated polygenic load was estimated by calculating weighted genetic risk scores (GRS) using 1) all available 27 PD-risk single nucleotide polymorphisms (SNPs) in the PPMI database (GRS1) and 2) 23 SNPs with minor allele frequency >0.05 (GRS2). GRS1 and GRS2 were correlated with younger age at onset in patients with PD (GRS1, Spearman ρ = -0.128, <i>p</i> = 0.019; GRS2, Spearman ρ = -0.109, <i>p</i> = 0.047). Although GRS1 did not show an association with changes in striatal ¹²³I-FP-CIT availability, GRS2 was associated with a slower decline of striatal dopaminergic activity (interactions with disease duration in linear mixed model; caudate nucleus, estimate = 0.399, SE = 0.165, <i>p</i> = 0.028; putamen, estimate = 0.396, SE = 0.137, <i>p</i> = 0.016). Our results suggest that genetic factors for PD risk may have heterogeneous effects on striatal dopaminergic degeneration, and some factors may be associated with a slower decline of dopaminergic activity. Composition of PD progression-specific GRS may be useful in predicting disease progression in patients.