Exploring the genetic and genomic connection underlying neurodegeneration with brain iron accumulation and the risk for Parkinson's disease.

Neurodegeneration with brain iron accumulation (NBIA) represents a group of neurodegenerative disorders characterized by abnormal iron accumulation in the brain. In Parkinson's Disease (PD), iron accumulation is a cardinal feature of degenerating regions in the brain and seems to be a key player in mechanisms that precipitate cell death. The aim of this study was to explore the genetic and genomic connection between NBIA and PD. We screened for known and rare pathogenic mutations in autosomal dominant and recessive genes linked to NBIA in a total of 4481 PD cases and 10,253 controls from the Accelerating Medicines Partnership Parkinsons' Disease Program and the UKBiobank. We examined whether a genetic burden of NBIA variants contributes to PD risk through single-gene, gene-set, and single-variant association analyses. In addition, we assessed publicly available expression quantitative trait loci (eQTL) data through Summary-based Mendelian Randomization and conducted transcriptomic analyses in blood of 1886 PD cases and 1285 controls. Out of 29 previously reported NBIA screened coding variants, four were associated with PD risk at a nominal p value < 0.05. No enrichment of heterozygous variants in NBIA-related genes risk was identified in PD cases versus controls. Burden analyses did not reveal a cumulative effect of rare NBIA genetic variation on PD risk. Transcriptomic analyses suggested that DCAF17 is differentially expressed in blood from PD cases and controls. Due to low mutation occurrence in the datasets and lack of replication, our analyses suggest that NBIA and PD may be separate molecular entities.

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.

A population scale analysis of rare SNCA variation in the UK Biobank.

Parkinson's disease (PD) is a complex neurodegenerative disease with a variety of genetic and environmental factors contributing to disease. The SNCA gene encodes for the alpha-synuclein protein which plays a central role in PD, where aggregates of this protein are one of the pathological hallmarks of disease. Rare point mutations and copy number gains of the SNCA gene have been shown to cause autosomal dominant PD, and common DNA variants identified using Genome-Wide Association Studies (GWAS) are a moderate risk factor for PD. The UK Biobank is a large-scale population prospective study including ~500,000 individuals that has revolutionized human genetics. Here we assessed the frequency of SNCA variation in this cohort and identified 30 subjects carrying variants of interest including duplications (n = 6), deletions (n = 6) and large complex likely mosaic events (n = 18). No known pathogenic missense variants were identified. None of these subjects were reported to be a PD case, although it is possible that these individuals may develop PD at a later age, and whilst three had known prodromal features, these did not meet defined clinical criteria for being considered 'prodromal' cases. Seven of the 18 large complex carriers showed a history of blood based cancer. Overall, we identified copy number variants in the SNCA region in a large population based cohort without reported PD phenotype and symptoms. Putative mosaicism of the SNCA gene was identified, however, it is unclear whether it is associated with PD. These individuals are potential candidates for further investigation by performing SNCA RNA and protein expression studies, as well as promising clinical trial candidates to understand how duplication carriers potentially escape PD.

Comprehensive assessment of PINK1 variants in Parkinson's disease.

Multiple genes have been associated with monogenic Parkinson's disease and Parkinsonism syndromes. Mutations in PINK1 (PARK6) have been shown to result in autosomal recessive early-onset Parkinson's disease. In the past decade, several studies have suggested that carrying a single heterozygous PINK1 mutation is associated with increased risk for Parkinson's disease. Here, we comprehensively assess the role of PINK1 variants in Parkinson's disease susceptibility using several large data sets totalling 376,558 individuals including 13,708 cases with Parkinson's disease and 362,850 control subjects. After combining these data, we did not find evidence to support a role for heterozygous PINK1 mutations as a robust risk factor for Parkinson's disease.