Using genome-wide association data, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's (PD) or Alzheimer's (AD) disease versus controls across ancestry groups. A shared genetic association was observed across diseases at rs601945 (PD: odds ratio (OR)=0.84; 95% confidence interval, [0.80; 0.88]; p=2.2x10-13; AD: OR=0.91[0.89; 0.93]; p=1.8x10-22), and with a protective HLA association recently reported in amyotrophic lateral sclerosis (ALS). Hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03, and absent for HLA-DRB1*04:05. The same signal was associated with decreased neurofibrillary tangles (but not neuritic plaque density) in postmortem brain and was more strongly associated with Tau levels than A{beta}42 levels in the cerebrospinal fluid. Finally, protective HLA-DRB1*04 subtypes strongly bound aggregation-prone Tau PHF6 sequence, but only when acetylated at K311, a modification central to aggregation. A HLA-DRB1*04-mediated adaptive immune response, potentially against Tau, decreases PD, AD and ALS risk, offering the possibility of new therapeutic avenues.

AbstractObjectiveTo examine the role of autosomal dominant (AD) and recessive (AR) Parkinsonism genes in the risk of isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD).MethodsTen genes implicated in AD and AR Parkinsonism were fully sequenced using targeted next-generation sequencing in 1,039 iRBD patients and 1,852 controls of European ancestry. These include the AR genes PRKN, DJ-1 (PARK7), PINK1, VPS13C, ATP13A2, FBXO7 and PLA2G6, and the AD genes LRRK2, GCH1 and VPS35. To examine the role of rare heterozygous variants in these genes, burden test and SKAT-O analyses were performed. The contribution of homozygous and compound heterozygous variants was further examined in the AR genes. Copy number variants (CNVs) in PRKN were tested in a subset of samples (n=374) using multiplex ligation-dependent probe amplification followed by analysis of all samples using ExomeDepth.ResultsWe found no association between rare heterozygous variants in the tested genes and risk for iRBD. Several homozygous and compound heterozygous carriers were identified with variants of unknown significance, yet there was no overrepresentation in iRBD patients versus controls.ConclusionOur results do not support a major role for variants in PRKN, PARK7, PINK1, VPS13C, ATP13A2, FBXO7, PLA2G6, LRRK2, GCH1 and VPS35 in the risk of iRBD.

Objective: Many common and rare genetic factors have been associated with Parkinson's disease (PD) susceptibility, improving our understanding of the related underlying biological mechanisms. The involvement of rare variants in DNAJC13, UCHL1, HTRA2, GIGYF2 and EIF4G1 loci have been poorly studied or produced contradicting results across cohorts. Here, we aimed to examine the role of these genes in PD using a large cohort of patients and controls.

Objective: To examine whether NPC1 genetic variants may be associated with Parkinson's disease (PD).

Objective: Hereditary spastic paraplegias (HSP) are heterogeneous and rare neurodegenerative disorders with diverse pathophysiological mechanisms. There are about 80 different known genetic sub-types, unified predominantly by lower limb spasticity and weakness with or without additional symptoms. More than half of HSP patients remain genetically unsolved due to different reasons, including rarity of private mutations, small number of large cohort studies, methodological limitations and potentially due to an oversimplified view of HSP as a distinct monogenic Mendelian disorder. We aimed to address some of these limitations by analyzing data from one of the world's largest HSP cohorts (CanHSP) using multiple in silico tools.