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Functional regulatory variants implicate distinct transcriptional networks in dementia

Cooper, Yonatan A. and Davis, Jessica E. and Kosuri, Sriram and Coppola, Giovanni and Geschwind, Daniel H. (2021) Functional regulatory variants implicate distinct transcriptional networks in dementia. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20210621-182411050

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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.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/2021.06.14.448395DOIDiscussion Paper
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE163855Related ItemData/Code
https://github.com/ycooper27/Tauopathy-MPRARelated ItemData/Code
ORCID:
AuthorORCID
Cooper, Yonatan A.0000-0001-8353-8516
Kosuri, Sriram0000-0002-4661-0600
Coppola, Giovanni0000-0003-2105-1061
Geschwind, Daniel H.0000-0003-2896-3450
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.
Funders:
Funding AgencyGrant Number
NIH1F30AG064832
NIH Predoctoral FellowshipT32-GM008042
NIH5UG3NS104095-04
Rainwater Charitable Foundation20180629
UCLA-Caltech Medical Scientist Training ProgramUNSPECIFIED
Record Number:CaltechAUTHORS:20210621-182411050
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20210621-182411050
Official Citation:Functional regulatory variants implicate distinct transcriptional networks in dementia. Yonatan A. Cooper, Jessica E. Davis, Sriram Kosuri, Giovanni Coppola, Daniel H. Geschwind. bioRxiv 2021.06.14.448395; doi: https://doi.org/10.1101/2021.06.14.448395
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:109508
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:21 Jun 2021 19:57
Last Modified:21 Jun 2021 19:57

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