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P1‐146: WHOLE EXOME SEQUENCING IN PATIENTS WITH EARLY‐ONSET ALZHEIMER'S DISEASE AND FRONTOTEMPORAL DEMENTIA: MUTATION DETECTION IN CAUSAL AND RISK GENES FOR DEMENTIA
Author(s) -
Lladó Albert,
Sanchez-Valle Raquel,
Falgas Neus,
Balasa Mircea,
Rodríguez-Santiago Benjamin,
Armengol Lluis,
Grau Oriol,
Fernandez Guadalupe,
Bosch Beatriz,
Olives Jaume,
Muñoz Cristina,
Leon Maria,
Castellvi Magdalena,
Tort Adria,
Antonell Anna
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.2018.06.149
Subject(s) - frontotemporal dementia , exome sequencing , genetics , psen1 , dementia , missense mutation , exome , age of onset , biology , frameshift mutation , mutation , candidate gene , medicine , alzheimer's disease , disease , gene , amyloid precursor protein
functional support. Results: INFERNO identified 1,044 LDexpanded variants across all 19 loci, 852 of which affected enhancers and TFBSs, with enrichment of enhancer overlaps in the immune-related blood (p1⁄40.0126) and the fibroblast-containing connective tissue categories (p1⁄40.0038). INFERNO identified 154 co-localized GWAS-eQTL signals for 67 genes across 15 IGAP regions, including 59 signals overlapping concordant enhancers in matching tissue categories for 35 genes in 10 regions (ABCA7, BIN1, CASS4, CD2AP, CD33, CELF1, CLU, EPHA1, INPP5D, ZCWPW1). Among these were 4 lncRNAs with 332 predicted targets enriched for dozens of immune response-related pathways. Other regulatory signals included effects on DNA damage repair and disruption of binding sites for 40 microRNAs. Allele-specific enhancer activity was validated by luciferase assays in K562 cells for strongly supported variants at the EPHA1, CD33, and BIN1 loci. Conclusions: INFERNO was used to integrate GWAS signals with functional genomics data to infer the perturbed genes, tissue contexts, and regulatory mechanisms affected by noncoding AD-associated variants. This provided novel post-GWAS insights into the role of immunity in genetic susceptibility to AD and identified potential therapeutic targets for future investigation.