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O4‐01‐04: CIRCULAR RNAS IN ALZHEIMER'S DISEASE BRAIN TISSUES
Author(s) -
Dube Umber,
Del-Aguila Jorge L.,
Li Zeran,
Budde John P.,
Jiang S.H.A.N.,
Harari Oscar,
Cruchaga Carlos
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.06.2912
Subject(s) - circular rna , biology , context (archaeology) , computational biology , rna , neuroscience , genetics , bioinformatics , gene , paleontology
to understand altered gene regulatory functions at genome scale. This approach provides a framework for translating genetic associations into molecular mechanisms, and ultimately, clinical applications.Methods:We carried out theMassively Parallel Reporter Assay (MPRA), an allele-specific, scalable, and cost-effective method to screen for functional non-coding variants associated with AD. We selected a total of 2,002 variants in high linkage disequilibrium with the index variants in the ADGWAS loci and performedMPRAs in multiple AD-relevant cell types. In particular, we used the human monocytic cell line THP-1 to comprehensively screen for allelespecific transcriptional regulatory output, given the previous work demonstrating that non-coding AD GWAS variants are enriched in transcriptional enhancers active in monocytes and exhibit monocyte-specific expression quantitative trait loci effects. We also performed MPRAs in the SH-SY5Y cell line to screen for neuronal-specific regulatory function. Results: Our data indicates that multiple variants in ADGWAS-identified loci exhibit functional effects on transcriptional output in an alleleand cell-type-specific manner. We are currently investigating the molecular mechanisms by which top candidate variants dysregulate the expression of both proximal and distal coding target genes by causally linking sequence variants to transcriptional outputs through the use of CRISPR/Cas9 genome editing strategies. Conclusions:To our knowledge, this study is the first large-scale screen for functional non-coding AD-associated genetic variation. Our results support the hypothesis that non-coding AD GWAS variants exert their effects on disease risk through cell type-specific modulation of transcriptional regulation.