Myung Jun Lee1, Kyoungjune Pak2, Jong Hun Kim2, Yun Joong Kim2, Jeehee Yoon2, Jinwoo Lee1, Chul Hyoung Lyoo2, Hyung Jun Park2, Jae-Hyeok Lee1, Na-Yeon Jung2. 1. From the Departments of Neurology (M.J.L.) and Nuclear Medicine (K.P.), Pusan National University Hospital, Pusan National University School of Medicine and Biomedical Research Institute, Busan; Department of Neurology (J.H.K.), National Health Insurance Service Ilsan Hospital, Goyang; Department of Neurology (Y.J.K.), Hallym University College of Medicine, Anyang; Department of Computer Engineering (J.Y., J.L.), Hallym University, Chuncheon; Department of Neurology (C.H.L.), Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul; Department of Neurology (H.J.P.), Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung; and Department of Neurology (J.-H.L., N.-Y.J.), Pusan National University Yangsan Hospital, Pusan National University School of Medicine and Biomedical Research Institute, Yangsan, Republic of Korea. mslayer9@gmail.com. 2. From the Departments of Neurology (M.J.L.) and Nuclear Medicine (K.P.), Pusan National University Hospital, Pusan National University School of Medicine and Biomedical Research Institute, Busan; Department of Neurology (J.H.K.), National Health Insurance Service Ilsan Hospital, Goyang; Department of Neurology (Y.J.K.), Hallym University College of Medicine, Anyang; Department of Computer Engineering (J.Y., J.L.), Hallym University, Chuncheon; Department of Neurology (C.H.L.), Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul; Department of Neurology (H.J.P.), Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung; and Department of Neurology (J.-H.L., N.-Y.J.), Pusan National University Yangsan Hospital, Pusan National University School of Medicine and Biomedical Research Institute, Yangsan, Republic of Korea.
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.
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.
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