Dopamine pathway and Parkinson's risk variants are associated with levodopa-induced dyskinesia.

Background: Levodopa-induced dyskinesia (LID) is a common adverse effect of levodopa, one of the main therapeutics used to treat the motor symptoms of Parkinson's disease (PD). Previous evidence suggests a connection between LID and a disruption of the dopaminergic system as well as genes implicated in PD, including GBA1 and LRRK2. Objectives: To investigate the effects of genetic variants on risk and time to LID. Methods: We performed a genome-wide association study (GWAS) and analyses focused on GBA1 and LRRK2 variants. We also calculated polygenic risk scores including risk variants for PD and variants in genes involved in the dopaminergic transmission pathway. To test the influence of genetics on LID risk we used logistic regression, and to examine its impact on time to LID we performed Cox regression including 1,612 PD patients with and 3,175 without LID. Results: We found that GBA1 variants were associated with LID risk (OR=1.65, 95% CI=1.21-2.26, p=0.0017) and LRRK2 variants with reduced time to LID onset (HR=1.42, 95% CI=1.09-1.84, p=0.0098). The fourth quartile of the PD PRS was associated with increased LID risk (ORfourth_quartile=1.27, 95% CI=1.03-1.56, p=0.0210). The third and fourth dopamine pathway PRS quartiles were associated with a reduced time to development of LID (HRthird_quartile=1.38, 95% CI=1.07-1.79, p=0.0128; HRfourth_quartile=1.38, 95% CI=1.06-1.78, p=0.0147). Conclusions: This study suggests that variants implicated in PD and in the dopaminergic transmission pathway play a role in the risk/time to develop LID. Further studies will be necessary to examine how these findings can inform clinical care.

LRRK2 and Parkinson's disease: from genetics to targeted therapy.

LRRK2 variants are implicated in both familial and sporadic PD. LRRK2-PD has a generally benign clinical presentation and variable pathology, with inconsistent presence of Lewy bodies and marked Alzheimer's disease pathology. The mechanisms underlying LRRK2-PD are still unclear, but inflammation, vesicle trafficking, lysosomal homeostasis, and ciliogenesis have been suggested, among others. As novel therapies targeting LRRK2 are under development, understanding the role and function of LRRK2 in PD is becoming increasingly important. Here, we outline the epidemiological, pathophysiological, and clinical features of LRRK2-PD, and discuss the arising therapeutic approaches targeting LRRK2 and possible future directions for research.

Rare PSAP Variants and Possible Interaction with GBA in REM Sleep Behavior Disorder.

BACKGROUND: PSAP encodes saposin C, the co-activator of glucocerebrosidase, encoded by GBA. GBA mutations are associated with idiopathic/isolated REM sleep behavior disorder (iRBD), a prodromal stage of synucleinopathy. OBJECTIVE: To examine the role of PSAP mutations in iRBD. METHODS: We fully sequenced PSAP and performed Optimized Sequence Kernel Association Test in 1,113 iRBD patients and 2,324 controls. We identified loss-of-function (LoF) mutations, which are very rare in PSAP, in three iRBD patients and none in controls (uncorrected p = 0.018). RESULTS: Two variants were stop mutations, p.Gln260Ter and p.Glu166Ter, and one was an in-frame deletion, p.332_333del. All three mutations have a deleterious effect on saposin C, based on in silico analysis. In addition, the two carriers of p.Glu166Ter and p.332_333del mutations also carried a GBA variant, p.Arg349Ter and p.Glu326Lys, respectively. The co-occurrence of these extremely rare PSAP LoF mutations in two (0.2%) GBA variant carriers in the iRBD cohort, is unlikely to occur by chance (estimated co-occurrence in the general population based on gnomAD data is 0.00035%). Although none of the three iRBD patients with PSAP LoF mutations have phenoconverted to an overt synucleinopathy at their last follow-up, all manifested initial signs suggestive of motor dysfunction, two were diagnosed with mild cognitive impairment and all showed prodromal clinical markers other than RBD. Their probability of prodromal PD, according to the Movement Disorder Society research criteria, was 98% or more. CONCLUSION: These results suggest a possible role of PSAP variants in iRBD and potential genetic interaction with GBA, which requires additional studies.

Fine mapping of the HLA locus in Parkinson's disease in Europeans.

We fine mapped the leukocyte antigen (HLA) region in 13,770 Parkinson's disease (PD) patients, 20,214 proxy-cases, and 490,861 controls of European origin. Four HLA types were associated with PD after correction for multiple comparisons, HLA-DQA1*03:01, HLA-DQB1*03:02, HLA-DRB1*04:01, and HLA-DRB1*04:04. Haplotype analyses followed by amino acid analysis and conditional analyses suggested that the association is protective and primarily driven by three specific amino acid polymorphisms present in most HLA-DRB1*04 subtypes-11V, 13H, and 33H (OR = 0.87, 95% CI: 0.83-0.90, p < 8.23 × 10-9 for all three variants). No other effects were present after adjustment for these amino acids. Our results suggest that specific HLA-DRB1 variants are associated with reduced risk of PD, providing additional evidence for the role of the immune system in PD. Although effect size is small and has no diagnostic significance, understanding the mechanism underlying this association may lead to the identification of new targets for therapeutics development.

Analysis of PTRHD1 common and rare variants in European patients with Parkinson's disease.

Three studies in Iranian and African families identified three different variants in the peptidyl-tRNA hydrolase domain containing 1 gene (PTRHD1) in patients affected by parkinsonism with intellectual impairment. In the current study, our objective was to investigate whether PTRHD1 variants are associated with Parkinson's disease (PD) risk and age at onset (AAO). To evaluate the association between PTRHD1 and PD risk, we analyzed whole genome sequencing data of 1647 PD cases and 1050 healthy controls, as well as genome-wide imputed genotyping data on 14,671 PD cases and 17,667 controls, all of European ancestry. Furthermore, we examined the association of PTRHD1 with PD risk and AAO using summary statistics data from the most recent PD genome-wide association study meta-analyses. Our results show no association between PTRHD1 and PD risk or AAO. We conclude that PTRHD1 does not play a major role in PD in the European population. Further large-scale studies including subjects with different ancestry and family trios are required.

LRRK2 p.M1646T is associated with glucocerebrosidase activity and with Parkinson's disease.

The LRRK2 p.G2019S Parkinson's disease (PD) variant is associated with elevated glucocerebrosidase (GCase) activity in peripheral blood. We aimed to evaluate the association of other LRRK2 variants with PD and its association with GCase activity. LRRK2 and GBA were fully sequenced in 1123 PD patients and 576 controls from the Columbia and PPMI cohorts, in which GCase activity was measured in dried blood spots by liquid chromatography-tandem mass spectrometry. LRRK2 p.M1646T was associated with increased GCase activity in the Columbia University cohort (ß = 1.58, p = 0.0003), and increased but not significantly in the PPMI cohort (ß = 0.29, p = 0.58). p.M1646T was associated with PD (odds ratio = 1.18, 95% confidence interval = 1.09-1.28, p = 7.33E-05) in 56,306 PD patients and proxy-cases, and 1.4 million controls. Our results suggest that the p.M1646T variant is associated with risk of PD with a small effect and with increased GCase activity in peripheral blood.

Biomarkers for REM sleep behavior disorder in idiopathic and narcoleptic patients.

To search for discriminating biomarkers, 30 patients with idiopathic rapid-eye-movements sleep behavior disorder (iRBD) were compared with 17 patients with RBD within narcolepsy type 1. Both groups underwent extensive examinations, including skin biopsy searching for phosphorylated α-synuclein deposits and whole-night video-polysomnography. Skin biopsy was positive for phosphorylated α-synuclein deposits in 86.7% of iRBD patients and in none of narcoleptic patients. The analysis of video-polysomnographic motor events showed differences in their occurrence throughout the night in the two groups. iRBD and RBD due to narcolepsy do have different clinical and pathological findings, confirming a different pathophysiology.