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Abstract
Objective To investigate the effect of polygenic load on the progression of striatal dopaminergic dysfunction in patients with Parkinson disease (PD).
Methods 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).
Results GRS1 and GRS2 were correlated with younger age at onset in patients with PD (GRS1, Spearman ρ = −0.128, p = 0.019; GRS2, Spearman ρ = −0.109, p = 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, p = 0.028; putamen, estimate = 0.396, SE = 0.137, p = 0.016).
Conclusions 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.
Glossary
- DAT=
- dopamine transporter;
- FDR=
- false discovery rate;
- GRS=
- genetic risk scores;
- H&Y=
- Hoehn & Yahr;
- 123I-FP-CIT=
- 123I-N-3-fluoropropyl-2-β-carboxymethoxy-3β-(4-iodophenyl) nortropane;
- LMM=
- linear mixed model;
- MAF=
- minor allele frequency;
- MDS-UPDRS III=
- Movement Disorders Society–sponsored Unified Parkinson's Disease Rating Scale part III;
- OR=
- odds ratio;
- PC=
- principal component;
- PD=
- Parkinson disease;
- PPMI=
- Parkinson's Progression Markers Initiative;
- SBR=
- specific binding ratio;
- SNP=
- single nucleotide polymorphism
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
↵* These authors contributed equally to this work.
- Received October 21, 2018.
- Accepted in final form March 21, 2019.
- © 2019 American Academy of Neurology
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