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[IC‐P‐063]: KLK8 AS A MODULATOR OF ALZHEIMER's DISEASE PATHOLOGY: NEUROIMAGING GENETICS
Author(s) -
Nho Kwangsik,
Kim Sungeun,
Horgousluoglu Emrin,
Risacher Shan L.,
Saykin Andrew J.
Publication year - 2017
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.2017.06.2336
Subject(s) - neuroimaging , medicine , neuroscience , single nucleotide polymorphism , alzheimer's disease neuroimaging initiative , endophenotype , pathology , psychology , alzheimer's disease , genotype , disease , biology , genetics , cognition , gene
Figure 2. Disease progression score stratified by diagnostic group (left) and by MCI progression status (right). Background: Genome-wide association studies (GWAS) in Alzheimer’s disease (AD) using neuroimaging-based phenotypes are typically derived from a single imaging modality. However, AD is a complex disorder involving different inter-linked pathogenic pathways. To explore genetic influences on disease progression, we generated a novel disease progression score (DPS) comprising cortical b-amyloid levels and hippocampal volume, then using it as a quantitative phenotype in GWAS. Methods:Study participants were part of the ADNeuroimaging Initiative (ADNI). Hippocampal volumes were computed with FreeSurfer from T1-weighted MRI scans. Cortical Ab42 levels were computed as standardised uptake values ratio (SUVR) from florbetapir PET scans. The AD-DPS was computed by jointly modelling the long-term time evolution of hippocampal volume and cortical SUVR for 1088 individuals, using the growth models via alternating conditional expectation (GRACE) algorithm. We used this DPS as a continuous phenotype for a GWAS in 846 subjects of Caucasian ancestry, covarying for sex, age, APOE4 status, baseline SUVR and 2 principal components of population structure. Additionally, we repeated the analysis stratified by APOE4 status. Results: Progression curves were in good agreement with proposed models of AD biomarker evolution (Figures 1-2). A genome-wide significant association with ADDPS was found on chromosome 4 for rs3733541 (p1⁄49.45e-09), located 300 kbp upstream of the KIT gene (Figure 3). This association was not found when testing hippocampal volume and Ab42 burden separately. There were no genome-wide significant SNPs in the stratified analyses. However, the standardised effect size for rs3733541 was greater in APOE4 non-carriers (b1⁄4-0.116 0.02, p1⁄49.5e-5) than in APOE4 carriers (b1⁄4-0.0860.02, p1⁄43e3). Conclusions:We describe the first use of a DPS derived from