Exploring the Genetic and Genomic Connection Underlying Neurodegeneration with Brain Iron Accumulation and the Risk for Parkinson’s Disease

AbstractBackgroundNeurodegeneration with brain iron accumulation (NBIA) represents a group of neurodegenerative disorders characterized by abnormal iron accumulation and the presence of axonal spheroids 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.ObjectivesThe aim of this present study was to comprehensively explore the genetic and genomic connection between NBIA and PD etiology.MethodsWe screened the presence of known and rare pathogenic mutations in autosomal dominant and recessive genes linked to NBIA in a total of 4,481 PD cases and 10,253 controls from the Accelerating Medicines Partnership Parkinsons’ Disease Program and the UKBiobank. We further examined whether a genetic burden of NBIA variants contributes to PD risk through single-gene, gene-set, and single-variant association analyses. To investigate the potential effect of NBIA gene expression on PD, we assessed publicly available expression quantitative trait loci (eQTL) data through Summary-based Mendelian Randomization and conducted transcriptomic analyses in blood of 1,886 PD cases and 1,285 controls.ResultsOut of 28 previously reported NBIA screened coding variants, four missense were found to be associated with PD risk at a nominal p value < 0.05 (p.T402M-ATP13A2, p.T207M-FA2H, p.P60L-C19orf12, p.C422S-PANK2). 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.ConclusionsTaking into account the very low mutation occurrence in the datasets and the lack of replication, our analyses suggest that NBIA and PD may be separate molecular entities, supporting the notion that the mechanisms underpinning iron accumulation in PD are likely not shared with NBIA. Elevated nigral iron levels may not contribute to PD etiology and may vary with anti-parkinsonian drugs used for treatment, environmental factors, or iron sequestration in tissue as a response to PD pathological change.