Functional regulatory variants implicate distinct transcriptional networks in dementia-Reference-Cited by-同舟云学术

Functional regulatory variants implicate distinct transcriptional networks in dementia

Published:2022-08-19 Issue:6608 Volume:377 Page:
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Cooper Yonatan A.¹²³^ORCID,Teyssier Noam⁴,Dräger Nina M.⁴,Guo Qiuyu³^ORCID,Davis Jessica E.⁵^ORCID,Sattler Sydney M.⁴^ORCID,Yang Zhongan³^ORCID,Patel Abdulsamie³,Wu Sarah³,Kosuri Sriram⁵^ORCID,Coppola Giovanni³⁶^ORCID,Kampmann Martin⁴⁷^ORCID,Geschwind Daniel H.¹⁸⁹¹⁰^ORCID

Affiliation:

1. Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.

2. Medical Scientist Training Program, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.

3. Center for Neurobehavioral Genetics, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095, USA.

4. Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94158, USA.

5. Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095, USA.

6. Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.

7. Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143, USA.

8. Program in Neurogenetics, Department of Neurology, University of California, Los Angeles, CA 90095, USA.

9. Center for Autism Research and Treatment, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095, USA.

10. Institute of Precision Health, University of California, Los Angeles, CA 90095, USA.

Abstract

Predicting the function of noncoding variation is a major challenge in modern genetics. In this study, we used massively parallel reporter assays to screen 5706 variants identified from genome-wide association studies for both Alzheimer’s disease (AD) and progressive supranuclear palsy (PSP), identifying 320 functional regulatory variants (frVars) across 27 loci, including the complex 17q21.31 region. We identified and validated multiple risk loci using CRISPR interference or excision, including complement 4 ( C4A ) and APOC1 in AD and PLEKHM1 and KANSL1 in PSP. Functional variants disrupt transcription factor binding sites converging on enhancers with cell type–specific activity in PSP and AD, implicating a neuronal SP1-driven regulatory network in PSP pathogenesis. These analyses suggest that noncoding genetic risk is driven by common genetic variants through their aggregate activity on specific transcriptional programs.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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