Mitochondria function associated genes contribute to Parkinson’s Disease risk and later age at onset

Kj, Billingsley; Ia, Barbosa; Bandrés‐Ciga, Sara; Quinn, JP; Vj, Bubb; Deshpande, Charu; Ja, Botía; Reynolds, Regina H; Zhang, David; Simpson, Michael A.; Blauwendraat, Cornelis; Gan‐Or, Ziv; Gibbs, J. Raphael; Ma, Ning; Singleton, Andrew B.; Ryten, Mina; Kõks, Sulev

doi:10.1038/s41531-019-0080-x

Cited by 114 publications

(99 citation statements)

References 59 publications

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“…Interestingly it was shown that the exclusion of all SNVs located in genomic regions with known PD susceptibility loci did not reduce predictive power of the PD polygenic risk scores (Reynolds et al 2019). Focusing on variants in mitochondrial genes a polygenic risk of small effect variants was shown to contribute to disease risk and AAO in PD (Billingsley et al 2019). These findings suggest that mainly common variants with small effect sizes (not reaching genome-wide significance in GWAS) are contributing to disease risk.…”

Section: Polygenic Risk Scoresmentioning

confidence: 99%

Missing heritability in Parkinson’s disease: the emerging role of non-coding genetic variation

2020

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Parkinson's disease (PD) is a neurodegenerative disorder caused by a complex interplay of genetic and environmental factors. For the stratification of PD patients and the development of advanced clinical trials, including causative treatments, a better understanding of the underlying genetic architecture of PD is required. Despite substantial efforts, genome-wide association studies have not been able to explain most of the observed heritability. The majority of PD-associated genetic variants are located in non-coding regions of the genome. A systematic assessment of their functional role is hampered by our incomplete understanding of genotype-phenotype correlations, for example through differential regulation of gene expression. Here, the recent progress and remaining challenges for the elucidation of the role of non-coding genetic variants is reviewed with a focus on PD as a complex disease with multifactorial origins. The function of gene regulatory elements and the impact of non-coding variants on them, and the means to map these elements on a genome-wide level, will be delineated. Moreover, examples of how the integration of functional genomic annotations can serve to identify disease-associated pathways and to prioritize disease-and cell type-specific regulatory variants will be given. Finally, strategies for functional validation and considerations for suitable model systems are outlined. Together this emphasizes the contribution of rare and common genetic variants to the complex pathogenesis of PD and points to remaining challenges for the dissection of genetic complexity that may allow for better stratification, improved diagnostics and more targeted treatments for PD in the future.

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Section: Polygenic Risk Scoresmentioning

confidence: 99%

Missing heritability in Parkinson’s disease: the emerging role of non-coding genetic variation

2020

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“…Furthermore, recruiting patients from the QPN Participant Registry provides an opportunity to access a large number of patients who are of French-Canadian ancestry, which was critical for the recent identification of a founder mutation in the GBA gene in French-Canadian patients with PD or RBD [25]. Genome-wide association study (GWAS) data from QPN patients have also been used for recent largescale genetic analyses of mitochondria-related genes and GWAS of AAO in PD [47,48]. The GWAS data are currently being used to accurately determine the ancestry of all participants, and these data will be made available for the users of QPN data.…”

Section: Recent Studies and Trials Facilitated By The Quebec Parkinsomentioning

confidence: 99%

The Quebec Parkinson Network: A Researcher-Patient Matching Platform and Multimodal Biorepository

Gan‐Or

Rao

Léveillé

et al. 2020

JPD

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Background: Genetic, biologic and clinical data suggest that Parkinson's disease (PD) is an umbrella for multiple disorders with clinical and pathological overlap, yet with different underlying mechanisms. To better understand these and to move towards neuroprotective treatment, we have established the Quebec Parkinson Network (QPN), an open-access patient registry, and data and bio-samples repository. Objective: To present the QPN and to perform preliminary analysis of the QPN data. Methods: A total of 1,070 consecutively recruited PD patients were included in the analysis. Demographic and clinical data were analyzed, including comparisons between males and females, PD patients with and without RBD, and stratified analyses comparing early and late-onset PD and different age groups. Results: QPN patients exhibit a male:female ratio of 1.8:1, an average age-at-onset of 58.6 years, an age-at-diagnosis of 60.4 years, and average disease duration of 8.9 years. REM-sleep behavior disorder (RBD) was more common among men, and RBD was associated with other motor and non-motor symptoms including dyskinesia, fluctuations, postural hypotension and hallucinations. Older patients had significantly higher rates of constipation and cognitive impairment, and longer disease duration was associated with higher rates of dyskinesia, fluctuations, freezing of gait, falls, hallucinations and cognitive impairment. Since QPN's creation, over 60 studies and 30 publications have included patients and data from the QPN. Conclusions: The QPN cohort displays typical PD demographics and clinical features. These data are open-access upon application (http://rpq-qpn.ca/en/), and will soon include genetic, imaging and bio-samples. We encourage clinicians and researchers to perform studies using these resources.

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“…Comparably, we report a highly significant down-regulation of mitochondria, exosome, and brain expressed miRNAs over time in PD. In particular, mitochondria dysfunction seems to play a major role in the disease, although it is still unclear whether it's part of the cause or a consequence of the disease 43 . Shamir et al 44 described affected gene interactions networks in iPD to be associated with oxidation, ubiquitination and other hallmarks of PD, an effect that is mirrored by the dys-regulated miRNAs revealed in our analysis of the PPMI cohort.…”

Section: Discussionmentioning

confidence: 99%

Deep sncRNA-seq of the PPMI cohort to study Parkinson’s disease progression

Kern

Fehlmann

Violich

et al. 2020

Preprint

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Coding and non-coding RNAs have diagnostic and prognostic importance in Parkinson's diseases (PD). We studied circulating small non-coding RNAs (sncRNAs) in 7, 003 samples from two longitudinal PD cohorts (Parkinson's Progression Marker Initiative (PPMI) and Luxembourg Parkinson's Study (NCER-PD)) and modelled their influence on the transcriptome. First, we sequenced sncRNAs in 5, 450 blood samples of 1, 614 individuals in PPMI. The majority of 323 billion reads (59 million reads per sample) mapped to miRNAs. Other covered RNA classes include piRNAs, rRNAs, snoRNAs, tRNAs, scaRNAs, and snRNAs. De-regulated miRNAs were associated with the disease and disease progression and occur in two distinct waves in the third and seventh decade of live. Originating mostly from a characteristic set of immune cells they resemble a systemic inflammation response and mitochondrial dysfunction, two hallmarks of PD. By profiling 1, 553 samples from 1, 024 individuals in the NCER-PD cohort using an independent technology, we validate relevant findings from the sequencing study. Finally, network analysis of sncRNAs and transcriptome sequencing of the original cohort identified regulatory modules emerging in progressing PD patients.miRNA studies to date, covering over 3, 000 patients and controls 21 .Advanced biomarker studies however require carefully designed cohorts. Already a few large-scale PD studies aiming to advance diagnosis, prognosis and therapeutics fulfil respective requirements 22-24 . Among them, the Parkinson's Progression Marker Initiative (PPMI) is a multi-cohort, longitudinal observational study designed to discover and validate objective biomarkers of Parkinson's 25 . The PPMI project constitutes a global effort of 33 clinical sites in 11 countries with regular study participant assessments (Figure 1a). It also features comprehensive clinical phenotyping to observe hundreds of characteristics of the known subtypes of the disease, such as the idiopathic and genetic forms. Further, longitudinal biosampling following rigorous Standard Operating Procedures (SOPs) is performed to set a framework for the discovery and validation of early-onset and prognostic biomarkers. To identify potential non-coding RNA and transcriptomic markers in PPMI we performed RNA-seq on blood samples drawn at each clinical visit. For short and long RNAs, we carried out optimized assays and sequenced separate aliquots from the same blood samples for paired RNA analyses. Here, we present the evaluation of the sncRNA-seq fraction for disease detection and progression tracking. We examine the potential of different classes of small RNAs but emphasise the role of miRNAs. We also validate relevant findings for miRNAs on the Luxembourg Parkinson's Study in the framework of the National Centre for Excellence in Research on PD (NCER-PD) cohort 22 , which was performed independently and with a different technology. Finally, we provide insights on how the key non-coding RNAs regulate gene expression by utilizing the long RNA sequencing data. Specific ana...

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Mitochondria function associated genes contribute to Parkinson’s Disease risk and later age at onset

Cited by 114 publications

References 59 publications

Missing heritability in Parkinson’s disease: the emerging role of non-coding genetic variation

Missing heritability in Parkinson’s disease: the emerging role of non-coding genetic variation

The Quebec Parkinson Network: A Researcher-Patient Matching Platform and Multimodal Biorepository

Deep sncRNA-seq of the PPMI cohort to study Parkinson’s disease progression

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