Exploring the genetic and genomic connection underlying neurodegeneration with brain iron accumulation and the risk for Parkinson’s disease
Abstract 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 p...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-04-01
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| Series: | npj Parkinson's Disease |
| Online Access: | https://doi.org/10.1038/s41531-023-00496-y |
| _version_ | 1797417595056422912 |
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| author | Pilar Alvarez Jerez Jose Luis Alcantud Lucia de los Reyes-Ramírez Anni Moore Clara Ruz Francisco Vives Montero Noela Rodriguez-Losada Prabhjyot Saini Ziv Gan-Or Chelsea X. Alvarado Mary B. Makarious Kimberley J. Billingsley Cornelis Blauwendraat Alastair J. Noyce Andrew B. Singleton Raquel Duran Sara Bandres-Ciga |
| author_facet | Pilar Alvarez Jerez Jose Luis Alcantud Lucia de los Reyes-Ramírez Anni Moore Clara Ruz Francisco Vives Montero Noela Rodriguez-Losada Prabhjyot Saini Ziv Gan-Or Chelsea X. Alvarado Mary B. Makarious Kimberley J. Billingsley Cornelis Blauwendraat Alastair J. Noyce Andrew B. Singleton Raquel Duran Sara Bandres-Ciga |
| author_sort | Pilar Alvarez Jerez |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-09T06:20:58Z |
| format | Article |
| id | doaj.art-a74e40ce5b164c6c979708ea36164d99 |
| institution | Directory Open Access Journal |
| issn | 2373-8057 |
| language | English |
| last_indexed | 2024-03-09T06:20:58Z |
| publishDate | 2023-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Parkinson's Disease |
| spelling | doaj.art-a74e40ce5b164c6c979708ea36164d992023-12-03T11:43:25ZengNature Portfolionpj Parkinson's Disease2373-80572023-04-01911910.1038/s41531-023-00496-yExploring the genetic and genomic connection underlying neurodegeneration with brain iron accumulation and the risk for Parkinson’s diseasePilar Alvarez Jerez0Jose Luis Alcantud1Lucia de los Reyes-Ramírez2Anni Moore3Clara Ruz4Francisco Vives Montero5Noela Rodriguez-Losada6Prabhjyot Saini7Ziv Gan-Or8Chelsea X. Alvarado9Mary B. Makarious10Kimberley J. Billingsley11Cornelis Blauwendraat12Alastair J. Noyce13Andrew B. Singleton14Raquel Duran15Sara Bandres-Ciga16Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of HealthInstitute of Neurosciences “Federico Olóriz”, Centro de Investigación Biomédica, Universidad de GranadaLaboratory of Neuropharmacology. Dept. Medicine and Life Sciences, Universitat Pompeu FabraMolecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of HealthInstitute of Neurosciences “Federico Olóriz”, Centro de Investigación Biomédica, Universidad de GranadaInstitute of Neurosciences “Federico Olóriz”, Centro de Investigación Biomédica, Universidad de GranadaDepartment Human Physiology, Faculty of Medicine, Biomedicine Research Institute of Malaga (IBIMA C07), University of MalagaMontreal Neurological Institute, McGill UniversityMontreal Neurological Institute, McGill UniversityCenter for Alzheimer’s and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of HealthMolecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of HealthMolecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of HealthMolecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of HealthDepartment of Clinical and Movement Neurosciences, UCL Queen Square Institute of NeurologyMolecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of HealthInstitute of Neurosciences “Federico Olóriz”, Centro de Investigación Biomédica, Universidad de GranadaMolecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of HealthAbstract 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.https://doi.org/10.1038/s41531-023-00496-y |
| spellingShingle | Pilar Alvarez Jerez Jose Luis Alcantud Lucia de los Reyes-Ramírez Anni Moore Clara Ruz Francisco Vives Montero Noela Rodriguez-Losada Prabhjyot Saini Ziv Gan-Or Chelsea X. Alvarado Mary B. Makarious Kimberley J. Billingsley Cornelis Blauwendraat Alastair J. Noyce Andrew B. Singleton Raquel Duran Sara Bandres-Ciga Exploring the genetic and genomic connection underlying neurodegeneration with brain iron accumulation and the risk for Parkinson’s disease npj Parkinson's Disease |
| title | Exploring the genetic and genomic connection underlying neurodegeneration with brain iron accumulation and the risk for Parkinson’s disease |
| title_full | Exploring the genetic and genomic connection underlying neurodegeneration with brain iron accumulation and the risk for Parkinson’s disease |
| title_fullStr | Exploring the genetic and genomic connection underlying neurodegeneration with brain iron accumulation and the risk for Parkinson’s disease |
| title_full_unstemmed | Exploring the genetic and genomic connection underlying neurodegeneration with brain iron accumulation and the risk for Parkinson’s disease |
| title_short | Exploring the genetic and genomic connection underlying neurodegeneration with brain iron accumulation and the risk for Parkinson’s disease |
| title_sort | exploring the genetic and genomic connection underlying neurodegeneration with brain iron accumulation and the risk for parkinson s disease |
| url | https://doi.org/10.1038/s41531-023-00496-y |
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