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

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

doi:10.1038/s41531-023-00496-y

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

NPJ Parkinsons Dis. 2023 Apr 6;9(1):54. doi: 10.1038/s41531-023-00496-y.

Authors

Pilar Alvarez Jerez^{1

2

3}, Jose Luis Alcantud⁴, Lucia de Los Reyes-Ramírez⁵, Anni Moore¹, Clara Ruz⁴, Francisco Vives Montero⁴, Noela Rodriguez-Losada⁶, Prabhjyot Saini^{7

8}, Ziv Gan-Or^{7

8

9}, Chelsea X Alvarado^{2

10}, Mary B Makarious^{1

11}, Kimberley J Billingsley^{1

2}, Cornelis Blauwendraat^{1

2}, Alastair J Noyce^{11

12}, Andrew B Singleton^{1

2}, Raquel Duran⁴, Sara Bandres-Ciga^{13

14}

Affiliations

¹ Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
² Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
³ Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK.
⁴ Institute of Neurosciences "Federico Olóriz", Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain.
⁵ Laboratory of Neuropharmacology. Dept. Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
⁶ Department Human Physiology, Faculty of Medicine, Biomedicine Research Institute of Malaga (IBIMA C07), University of Malaga, Malaga, Spain.
⁷ Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
⁸ Department of Human Genetics, McGill University, Montréal, QC, Canada.
⁹ Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada.
¹⁰ Data Tecnica International, Washington, DC, USA.
¹¹ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
¹² Preventive Neurology Unit, Centre for Prevention, Detection and Diagnosis, Wolfson Institute of Population Health, Queen Mary University of London, London, UK.
¹³ Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. sara.bandresciga@nih.gov.
¹⁴ Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. sara.bandresciga@nih.gov.

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.