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.
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.
Background and objectives: 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.Methods: LRRK2 and GBA were fully sequenced in 1,123 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.
Results: LRRK2 p.M1646T was associated with increased GCase activity in the ColumbiaUniversity cohort (β=1.58, p=0.0003), and increased but not significantly in the PPMI cohort (β=0.29, p=0.58). p.M1646T was associated with PD (OR=1.18, 95%CI=1.09-1.28, p=7.33E-05) in 56,306 PD patients and proxy-cases, and 1.4 million controls.
Conclusions: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..
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