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O4–01–05: Rare variants in APP and PSEN1 genes associated with extreme levels of beta‐amyloid 42 and tau protein in cerebrospinal fluid
Author(s) -
Benitez Bruno,
Karch Celeste,
Jin Sheng Chih,
Carrel David,
Cooper Breanna,
Bertelsen Sarah,
Morris John,
Holtzman David,
Goate Alison,
Cruchaga Carlos
Publication year - 2013
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.2013.04.338
Subject(s) - psen1 , apolipoprotein e , cerebrospinal fluid , proband , allele , alzheimer's disease , biology , medicine , gene , genetics , mutation , disease , amyloid precursor protein
for these variables and population substructure, we replicated associations to immediate recall for 11 candidate genes (See same Table) and identified a novel genome-wide significant association within an intron of FASTKD2 (See Figure.). Association of FASTKD2 SNPs proximal to the GWAS hit were replicated in the ROS/MAP (rs72959512, 1.2kb upstream, p 1⁄40.001, N 1⁄41,666) and ADNI (rs35535884, 6.5kb downstream, p 1⁄40.005, N 1⁄41,146) cohorts. Pathways exhibiting enrichment of association in the discovery sample included prion disorders (p1⁄40.00097), epidermal growth factor receptor (EGFR) signaling (p 1⁄40.0019), CBL-mediated regulation of EGFRs (p 1⁄40.0028), and IL-10 anti-inflammatory signaling (p 1⁄40.0033). Conclusions: Multiple factors associated with memory were identified, including a novel microRNA-overlapped gene (FASTKD2) with suggested roles in mitochondrial apoptosis (Ghezzi et al. AJHG 2008) and the EGFR pathway which has been proposed as a target for treating beta-amyloid-induced memory loss (Wang et al. PNAS 2012). These findings nominate or highlight targets for future studies of normal cognitive aging and dementia.