Yonatan A. Cooper, Noam Teyssier, Nina M. Dräger, Qiuyu Guo, Jessica E. Davis et al.
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.
Yonatan A. Cooper, Noam Teyssier, Nina M. Dräger, Qiuyu Guo, Jessica E. Davis, Sydney M. Sattler, Zhongan Yang, Abdulsamie Patel, Sarah Wu, Sriram Kosuri, Giovanni Coppola, Martin Kampmann, Daniel H. Geschwind. Functional regulatory variants implicate distinct transcriptional networks in dementia. 2022-08-19. https://doi.org/10.1126/science.abi8654
MPRA2 used the same 162-bp episomal HEK293T reporter library to re-test selected MPRA1 SigVars and dropouts, negative controls, orientation/position controls, and 483 additional variants from 11 Alzheimer's disease and four progressive supranuclear palsy loci. Six RNA libraries and four plasmid-DNA libraries are represented in the public mapped-count matrix.
Both alleles of 5,223 noncoding variants selected from 14 Alzheimer's disease and five progressive supranuclear palsy GWAS loci were tested as 162-bp native-context oligos in an episomal MPRA in HEK293T cells. Six RNA libraries and five plasmid-DNA libraries are represented in the public mapped-count matrix.
Original supplemental and deposited inputs retained for this study. Download files individually or together as a ZIP; nested folders are preserved. Source reuse terms apply, and sequencing reads may be omitted.
Download all 7 files (ZIP)GSE163855_MPRA1_merged_counts.txt.gzGSE163855_MPRA1_variant_list.tsv.gzGSE163855_MPRA2_merged_counts.txt.gzGSE163855_MPRA2_variant_list.tsv.gzMPRA1_variant_metadata.tsvMPRA2_variant_metadata.tsvsource_notes.txt