Alvarez Jerez, PilarAlcantud, Jose LuisReyes-Ramírez, Lucia de losMoore, AnniRuz, ClaraVives Montero, FranciscoRodriguez-Losada, NoelaSaini, PrabhjyotGan-Or, ZivAlvarado, Chelsea X.Makarious, Mary B.Billingsley, Kimberley J.Blauwendraat, CornelisNoyce, Alastair J.Singleton, Andrew B.Duran, RaquelBandres-Ciga, Sara2023-09-212023-09-212023Alvarez Jerez P, Alcantud JL, de los Reyes-Ramírez L, Moore A, Ruz C, Vives Montero F, Rodriguez-Losada N, Saini P, Gan-Or Z, Alvarado CX, Makarious MB, Billingsley KJ, Blauwendraat C, Noyce AK, Singleton AB, Duran R, Bandres-Ciga S. Exploring the genetic and genomic connection underlying neurodegeneration with brain iron accumulation and the risk for Parkinson’s disease. NPJ Parkinsons Dis. 2023;9:54. DOI: 10.1038/s41531-023-00496-y2373-8057http://hdl.handle.net/10230/57935Neurodegeneration 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.application/pdfengThis is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41531-023-00496-yGenetic association studyGenomicsinfo:eu-repo/semantics/openAccess