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

Abstract

Abstract Background: Neurodegeneration 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. Objectives: The aim of this present study was to comprehensively explore the genetic and genomic connection between NBIA and PD etiology. Methods: We 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. Results: Out 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. Conclusions: Taking 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.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

No external funding was received for this manuscript.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

All data was taking from the publicly available and access-controlled Accelerating Medicines Partnership Program for Parkinson's Disease (www.amp-pd.org) and UKBiobank (https://www.ukbiobank.ac.uk/)

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

Data Availability

All data used in the present study are available upon request from AMP-PD and UKB. Additionally, scripts and data produced are contained in the manuscript or available upon request to the authors.

https://github.com/neurogenetics/NBIA_PD

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