The Foundational data initiative for Parkinsons disease (FOUNDIN-PD): enabling efficient translation from genetic maps to mechanism
Melanie M Cobb,
Michelle G. Webb,
Francis P. Grenn,
Caroline B Pantazis,
Clifton L Dalgard,
The American Genome Center,
Dena G. Hernandez,
Brooke E Hjelm,
Mike A Nalls,
J. Raphael Gibbs,
Mark R Cookson,
Kendall Van Keuren-Jensen,
David W. Craig,
Andrew B. Singleton,
Posted 03 Jun 2021
bioRxiv DOI: 10.1101/2021.06.03.446785
Posted 03 Jun 2021
In the FOUNdational Data INitiative for Parkinsons Disease (FOUNDIN-PD) we sought to produce a multi-layered molecular dataset in a large cohort of 95 Induced pluripotent stem cells (iPSC) lines at multiple timepoints during differentiation to dopaminergic (DA) neurons, a major affected cell type in Parkinsons Disease (PD). The lines are derived from the Parkinsons Progression Markers Initiative (PPMI) study that includes both people with PD and unaffected individuals across a wide range of polygenic risk scores (PRS) with both risk variants identified by genome-wide association studies (GWAS), and monogenic causal alleles. We generated genetic, epigenetic, regulatory, transcriptomic, proteomic, and longitudinal cellular imaging data from iPSC-derived DA neurons to understand key molecular relationships between disease associated genetic variation and proximate molecular events in a PD relevant cell-type. Analyses of all data modalities collected in FOUNDIN-PD suggest that the differentiation to DA neurons, while not fully mature, was successful and robust. Interrogation of PD genetic risk in this relevant cellular context may elucidate the functional effects of some of these risk variants alone or in combination with other variants. These data reveal that DA neurons derived from human iPSC provide a valuable cellular context and foundational atlas for modeling PD-related genetic risk. In addition to making the data and analyses for this molecular atlas readily available, we have integrated these data into the browsable FOUNDIN-PD data portal (https://www.foundinpd.org) to be used as a resource for understanding the molecular pathogenesis of PD.
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