Identification of genetic risk factors for Parkinson’s disease

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dc.contributor.advisor Heutink, Peter (Prof. Dr.) Illarionova, Anastasia 2023-04-03T07:48:02Z 2023-04-03T07:48:02Z 2023-04-03
dc.identifier.uri de_DE
dc.description.abstract Parkinson's disease (PD) is a common progressive neurodegenerative disorder with a complex and heterogeneous genetic landscape. Approximately 90% of all PD cases are driven by the cumulative effect of several common low-risk genetic variants. Over the last years, genetic studies of familial and sporadic PD cases identified a range of high and low-risk variants, representing approximately 40% of estimated heritability. However, the role of structural variants (SV) in the PD missing heritability remains understudied. Therefore, we investigated SVs in the human cohort enriched for the PD phenotype to expand our knowledge about the putative PD genetic risk factors. We leveraged the matching omics datasets obtained from 95 iPSC lines differentiated into the dopaminergic neuronal-like state to run the SV calling and to directly assess their impact on the gene and transcript expression. We demonstrated a conceptual approach for the genome-wide SV annotation and pathogenicity assessment, addressing the challenges of functional SV effect prediction based on the known properties of genome regions and available multi-omics data. Using this approach, we prioritized a group of non-coding SVs absent in the healthy controls with a strong association with the differential expression of genes whose dysregulation can trigger the development of PD or PD-related phenotype. Discovered variation impacts molecular mechanisms involved in the regulation of signaling processes, oxidative stress response, and neuronal DNA reparation. Additional analysis on the larger PD patient and control cohort has to be conducted for variant-expression association validation and exploration of the allele effect size and penetrance of the prioritized hits. The dataset is publicly available to facilitate the further discovery of SV PD risk association as well as to study sequence signatures and neurological disease-specific SV hot spots. en
dc.language.iso en de_DE
dc.publisher Universität Tübingen de_DE
dc.rights ubt-podok de_DE
dc.rights.uri de_DE
dc.rights.uri en
dc.subject.classification Parkinson-Krankheit , Genetik de_DE
dc.subject.ddc 570 de_DE
dc.subject.other Structural variants en
dc.subject.other neurodegenerative disorders en
dc.title Identification of genetic risk factors for Parkinson’s disease en
dc.type PhDThesis de_DE
dcterms.dateAccepted 2023-03-15
utue.publikation.fachbereich Medizin de_DE
utue.publikation.fakultaet 4 Medizinische Fakultät de_DE
utue.publikation.noppn yes de_DE


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