The Foundational Data Initiative for Parkinson Disease: Enabling efficient translation from genetic maps to mechanism

Elisangela Bressan; Xylena Reed; Vikas Bansal; Elizabeth Hutchins; Melanie M Cobb; Michelle G Webb; Eric Alsop; Francis P Grenn; Anastasia Illarionova; Natalia Savytska; Ivo Violich; Stefanie Broeer; Noémia Fernandes; Ramiyapriya Sivakumar; Alexandra Beilina; Kimberley J Billingsley; Joos Berghausen; Caroline B Pantazis; Vanessa Pitz; Dhairya Patel; Kensuke Daida; Bessie Meechoovet; Rebecca Reiman; Amanda Courtright-Lim; Amber Logemann; Jerry Antone; Mariya Barch; Robert Kitchen; Yan Li; Clifton L Dalgard; American Genome Center; Patrizia Rizzu; Dena G Hernandez; Brooke E Hjelm; Mike Nalls; J Raphael Gibbs; Steven Finkbeiner; Mark R Cookson; Kendall Van Keuren-Jensen; David W Craig; Andrew B Singleton; Peter Heutink; Cornelis Blauwendraat

doi:10.1016/j.xgen.2023.100261

The Foundational Data Initiative for Parkinson Disease: Enabling efficient translation from genetic maps to mechanism

Cell Genom. 2023 Feb 6;3(3):100261. doi: 10.1016/j.xgen.2023.100261. eCollection 2023 Mar 8.

Authors

Elisangela Bressan¹, Xylena Reed^{2

3}, Vikas Bansal¹, Elizabeth Hutchins⁴, Melanie M Cobb⁵, Michelle G Webb⁶, Eric Alsop⁴, Francis P Grenn², Anastasia Illarionova¹, Natalia Savytska¹, Ivo Violich⁶, Stefanie Broeer¹, Noémia Fernandes¹, Ramiyapriya Sivakumar⁶, Alexandra Beilina², Kimberley J Billingsley², Joos Berghausen², Caroline B Pantazis^{2

3}, Vanessa Pitz², Dhairya Patel², Kensuke Daida², Bessie Meechoovet⁴, Rebecca Reiman⁴, Amanda Courtright-Lim⁴, Amber Logemann⁴, Jerry Antone⁴, Mariya Barch⁵, Robert Kitchen⁷, Yan Li⁸, Clifton L Dalgard^{9

10}; American Genome Center; Patrizia Rizzu¹, Dena G Hernandez², Brooke E Hjelm⁶, Mike Nalls^{2

3

11}, J Raphael Gibbs², Steven Finkbeiner^{5

12}, Mark R Cookson², Kendall Van Keuren-Jensen⁴, David W Craig⁶, Andrew B Singleton^{2

3}, Peter Heutink¹, Cornelis Blauwendraat^{2

3}

Affiliations

¹ German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
² Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
³ Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
⁴ Division of Neurogenomics, The Translational Genomics Research Institute, Phoenix, AZ, USA.
⁵ Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA, USA.
⁶ Department of Translational Genomics, Keck School of Medicine, University of Southern California, 1450 Biggy Street, Los Angeles, CA, USA.
⁷ Massachusetts General Hospital, Cardiovascular Research Center, Charlestown, MA, USA.
⁸ Protein/Peptide Sequencing Facility, National Institute of Neurological, Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
⁹ The American Genome Center, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
¹⁰ Department of Anatomy, Physiology & Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
¹¹ Data Tecnica International, Washington, DC, USA.
¹² Departments of Neurology and Physiology, University of California, San Francisco, San Francisco, CA, USA.

Abstract

The Foundational Data Initiative for Parkinson Disease (FOUNDIN-PD) is an international collaboration producing fundamental resources for Parkinson disease (PD). FOUNDIN-PD generated a multi-layered molecular dataset in a cohort of induced pluripotent stem cell (iPSC) lines differentiated to dopaminergic (DA) neurons, a major affected cell type in PD. The lines were derived from the Parkinson's Progression Markers Initiative study, which included participants with PD carrying monogenic PD variants, variants with intermediate effects, and variants identified by genome-wide association studies and unaffected individuals. We generated genetic, epigenetic, regulatory, transcriptomic, and longitudinal cellular imaging data from iPSC-derived DA neurons to understand molecular relationships between disease-associated genetic variation and proximate molecular events. These data reveal that iPSC-derived DA neurons provide a valuable cellular context and foundational atlas for modeling PD genetic risk. We have integrated these data into a FOUNDIN-PD data browser as a resource for understanding the molecular pathogenesis of PD.

Keywords: Parkinson disease; dopaminergic neurons; genetic risk; induced pluripotent stem cell; omics single-cell RNA sequencing single-cell ATAC sequencing SNCA LRRK2 GBA1.