Functional regulatory variants implicate distinct transcriptional networks in dementia
Abstract
Predicting functionality of noncoding variation is one of the major challenges in modern genetics. We employed massively parallel reporter assays to screen 5,706 variants from genome-wide association studies for both Alzheimer's disease (AD) and Progressive Supranuclear Palsy (PSP). We identified 320 functional regulatory polymorphisms (SigVars) comprising 27 of 34 unique tested loci, including multiple independent signals across the complex 17q21.31 region. We identify novel risk genes including PLEKHM1 in PSP and APOC1 in AD, and perform gene-editing to validate four distinct causal loci, confirming complement 4 (C4A) as a novel genetic risk factor for AD. Moreover, functional variants preferentially disrupt transcription factor binding sites that converge on enhancers with differential cell-type specific activity in PSP and AD, implicating a neuronal SP1-driven regulatory network in PSP pathogenesis. These analyses support a novel mechanism underlying noncoding genetic risk, whereby common genetic variants drive disease risk via their aggregate activity on specific transcriptional programs.
Additional Information
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license. This version posted June 15, 2021. We would like to thank Geschwind lab members Gayatri Nair and Samie Patel for their assistance with cell culture, and the UCLA TCGB and Flow Cytometry cores for their assistance and technical expertise. Funding: National Institute of Aging fellowship 1F30AG064832 (YAC); UCLA-Caltech MSTP training grant T32-GM008042 (YAC) National Institute of Neurological Disorders and Stroke grant 5UG3NS104095-04 (DHG, GC) Rainwater Charitable Foundation award 20180629 (DHG, GC). Author contributions: Conceptualization: YAC, GC, DHG. Data Curation: YAC. Formal Analysis: YAC. Funding Acquisition: YAC, GC, DHG. Investigation: YAC. Methodology: YAC, JED, SK. Project Administration: YAC, GC, DHG. Resources: SK, GC, DHG. Software: YAC. Supervision: SK, GC, DHG. Validation: YAC. Visualization: YAC. Writing – original draft: YAC, DHG. Writing – review and editing: YAC, JED, SK, GC, DHG. Competing interests: S.K. is an employee and holds equity in Octant, Inc. The authors have no additional competing interests to declare.Attached Files
Submitted - 2021.06.14.448395v1.full.pdf
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Additional details
- Eprint ID
- 109508
- Resolver ID
- CaltechAUTHORS:20210621-182411050
- 1F30AG064832
- NIH
- T32-GM008042
- NIH Predoctoral Fellowship
- 5UG3NS104095-04
- NIH
- 20180629
- Rainwater Charitable Foundation
- UCLA-Caltech Medical Scientist Training Program
- Created
-
2021-06-21Created from EPrint's datestamp field
- Updated
-
2021-11-16Created from EPrint's last_modified field