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PROTECTMOVE

Identifying Parkinson’s disease penetrance-modifying factors in the population-based Cooperative Health Research in South Tyrol (CHRIS) cohort

Genes causative for recessively inherited Parkinson’s disease (PD) include Parkin (PRKN) and PINK1; rare homozygous mutations in these genes result in definite symptom expression. On the other hand, evidence suggests that heterozygous mutations – a relatively common occurrence – may predispose to PD in a dominant manner with highly reduced penetrance. The largest described pedigree of PRKN mutation carriers (n=77) originates from South Tyrol and includes numerous heterozygous carriers of PRKN mutations who develop overt symptoms of Parkinson’s disease (PD), while others may have prodromal, or no obvious symptoms. In this project, we aim to dissect out the factors that modify the penetrance of these variants, using additional PRKN mutation carriers identified in the Cooperative Health Research in South Tyrol (CHRIS) study (comprising n=13,490 individuals from the same geographical region). By testing whether factors that influence mitochondrial function can alter penetrance of nuclear mutations, we observed an increased burden of heteroplasmic mtDNA mutations in affected vs. unaffected heterozygous PRKN and PINK1 mutation carriers, which might explain the phenotypic (clinical, sub-clinical) discordance in these individuals with similar nuclear genetic background. In addition, induced pluripotent stem cell (iPSC)-derived neurons of non-PD manifesting heterozygous mutation carriers displayed several phenotypes of altered mitochondrial function. This project was part of the DFG (Deutsche Forschungsgemeinschaft) funded research group ProtectMove (FOR2488).

Project duration: December 2016 - June 2024
Project status:
Website: http://protect-move.de/
Institute: Institute for Biomedicine

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CHRIS parkinson health

Scientific Publications

Journal article2023

Molecular phenotypes of mitochondrial dysfunction in clinically non-manifesting heterozygous PRKN variant carriers

Castelo Rueda MP, Zanon A, Gilmozzi V, Lavdas AA, Raftopoulou AA, Delcambre S, Del Greco M F, Klein C,

Andrew Hicks, Irene Pichler, Alexandros Lavdas, Peter P. Pramstaller

Homozygous or compound heterozygous (biallelic) variants in PRKN are causal for PD with highly penetrant symptom expression, while the much more common heterozygous variants may predispose to PD with highly reduced penetrance, through altered mitochondrial function. In the presence of pathogenic heterozygous variants, it is therefore important to test for mitochondrial alteration in cells derived from variant carriers to establish potential presymptomatic molecular markers. We generated lymphoblasts (LCLs) and human induced pluripotent stem cell (hiPSC)-derived neurons from non-manifesting heterozygous PRKN variant carriers and tested them for mitochondrial functionality. In LCLs, we detected hyperactive mitochondrial respiration, and, although milder compared to a biallelic PRKN-PD patient, hiPSC-derived neurons of non-manifesting heterozygous variant carriers also displayed several phenotypes of altered mitochondrial function. Overall, we identified molecular phenotypes that might be used to monitor heterozygous PRKN variant carriers during the prodromal phase. Such markers might also be useful to identify individuals at greater risk of eventual disease development and for testing potential mitochondrial function-based neuroprotective therapies before neurodegeneration advances.

DOI

DOI: 10.1038/s41531-023-00499-9

Journal article2022

A Mendelian randomization study investigating the causal role of inflammation on Parkinson's disease

Bottigliengo D, Foco L, Seibler P, Klein C, König IR, Del Greco M F

Luisa Foco

There is increasing evidence on inflammation as a determinant in the pathogenesis of Parkinson's disease. But, its role in parkinsonian neurodegeneration remains elusive: it´s not clear if inflammatory cascades are causes or consequences of dopamine neurons death. In the present study, we aim at performing an in-depth statistical investigation of the causal relationship between inflammation and Parkinson's disease using a two-sample Mendelian randomization design. Genetic instruments were selected using summary-level data from the largest to date genome-wide association studies (sample size ranging from 13,955 to 204,402 individuals) conducted on European population for the following inflammation biomarkers: C-reactive protein, interleukin-6, interleukin 1 receptor antagonist, and tumor necrosis factor α. Genetic association data on Parkinson's disease (56,306 cases and 1,417,791 controls) and age at onset of Parkinson's disease (28,568 cases) were obtained from the International Parkinson's Disease Genomics Consortium. On primary analysis, causal associations were estimated on sets of strong (P-value < 5 × 10-8; F-statistic > 10) and independent (linkage disequilibrium r2<0.001) genetic instruments using the inverse-variance weighted method. In sensitivity analysis, we estimated causal effects using robust Mendelian randomization methods and after removing pleiotropic genetic variants. Reverse causation was also explored. We repeated the analysis on different data sources for inflammatory biomarkers to check findings' consistency. In all the three data sources selected for interleukin-6, we found statistical evidence for earlier age at onset of Parkinson's disease associated with increased interleukin-6 concentration (years difference per 1 log-unit increase = -2.364, 95% CI = -4.789 to 0.060; years difference per 1 log-unit increase = -2.011, 95% CI = -3.706 to -0.317; years difference per 1 log-unit increase = -1.569, 95% CI = -2.891 to -0.247; ). We did not observe any statistical evidence for causal effects of C-reactive protein, interleukin 1 receptor antagonist, and tumor necrosis factor α on both Parkinson's disease and its age at onset. Results after excluding possible pleiotropic genetic variants were consistent with findings from primary analyses. When investigating reverse causation, we did not find evidence for a causal effect of Parkinson's disease or age at onset on any biomarkers of inflammation. We found evidence for a causal association between the onset of Parkinson's disease and interleukin-6. The findings of this study suggest that the pro-inflammatory activity of the interleukin-6 cytokine could be a determinant of prodromal Parkinson's disease.

DOI

DOI: 10.1093/brain/awac193

Journal article2022

Mitochondrial DNA heteroplasmy distinguishes disease manifestation in PINK1/PRKN-linked Parkinson's disease

Trinh J, Hicks AA, König IR, Delcambre S, Lüth T, Schaake S, Wasner K, Ghelfi J,

Andrew Hicks, Irene Pichler, Peter P. Pramstaller

Biallelic mutations in PINK1/PRKN cause recessive Parkinson’s disease. Given the established role of PINK1/Parkin in regulating mitochondrial dynamics, we explored mitochondrial DNA integrity and inflammation as disease modifiers in carriers of mutations in these genes. Mitochondrial DNA integrity was investigated in a large collection of biallelic (n = 84) and monoallelic (n = 170) carriers of PINK1/PRKN mutations, idiopathic Parkinson’s disease patients (n = 67) and controls (n = 90). In addition, we studied global gene expression and serum cytokine levels in a subset. Affected and unaffected PINK1/PRKN monoallelic mutation carriers can be distinguished by heteroplasmic mitochondrial DNA variant load (area under the curve = 0.83, CI 0.74–0.93). Biallelic PINK1/PRKN mutation carriers harbour more heteroplasmic mitochondrial DNA variants in blood (P = 0.0006, Z = 3.63) compared to monoallelic mutation carriers. This enrichment was confirmed in induced pluripotent stem cell-derived (controls, n = 3; biallelic PRKN mutation carriers, n = 4) and post-mortem (control, n = 1; biallelic PRKN mutation carrier, n = 1) midbrain neurons. Last, the heteroplasmic mitochondrial DNA variant load correlated with IL6 levels in PINK1/PRKN mutation carriers (r = 0.57, P = 0.0074). PINK1/PRKN mutations predispose individuals to mitochondrial DNA variant accumulation in a dose- and disease-dependent manner.

DOI

DOI: 10.1093/brain/awac464

Journal article2022

Systematic review of Mendelian randomization studies on Parkinson’s disease

Kappen S, Bottigliengo D, Caliebe A, Del Greco M F, König IR

Background
Parkinson‘s disease (PD) is known to be associated with non-genetic factors. To infer causality, Mendelian randomization (MR) studies are increasingly used. Here, genetic variants are used as instrumental variables for the risk factor but have no direct effect on PD themselves.

Methods
We performed a systematic literature review on MR studies for PD. Studies were identified searching the PubMed database. Upon data extraction, we evaluated the methodological quality and summarized the evidence.

Results
Twelve articles were included. Most studies showed “good” methodological quality, but most did not report proper power estimations. Twelve analyses yielded nominally significant effects.

Conclusions
Our systematic review shows that most MR studies were well performed and allow to identify causal exposures, which may inform further studies on the prevention and early intervention of PD.

DOI Source

DOI: 10.1515/medgen-2022-2139

All Publications

Identifying Parkinson’s disease penetrance-modifying factors in the population-based Cooperative Health Research in South Tyrol (CHRIS) cohort
Gilmozzi V (2025)
PhD thesis

Accounting for the between-study heterogeneity when selecting instrumental variables for two-sample Mendelian randomisation studies
Del Greco MF, Pontali G, Foco L, Pattaro C (2024)
Presentation/Speech

Conference: 45th Annual Conference of the International Society for Clinical Biostatistics | Thessaloniki | 21.7.2024 - 25.7.2024

Combining Datasets in a Mendelian Randomization Design: Metabolomics and Parkinson's Disease Case Study
Pontali G, Filosi M, Borsche M, König I, Paglia G, Foco L, Del Greco MF (2023)
Presentation/Speech

Conference: 44th Annual Conference of the International Society for Clinical Biostatistics (ISCB2023) | Milan | 27.8.2023 - 31.8.2023

Our partners

University of Lübeck, Institute of Neurogenetics

University of Luxembourg, Luxembourg Centre for Systems Biomedicine

Project Team

Andrew Hicks

Irene Pichler

Martin Lang

Fabiola Del Greco M.

Valentina Gilmozzi

Team Member

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Journal article2022

A Mendelian randomization study investigating the causal role of inflammation on Parkinson's disease

Bottigliengo D, Foco L, Seibler P, Klein C, König IR, Del Greco M F

Luisa Foco

DOI

DOI: 10.1093/brain/awac193

PROTECTMOVE