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O2‐06‐03: Tissue‐Specific Genome‐Wide Predictions of Genetically Regulated Expression in Alzheimer's Disease
Author(s) -
Below Jennifer,
Petty Lauren,
Hu Hao,
Huff Chad,
DeStefano Anita L.,
Fornage Myriam,
Bis Joshua C.,
Haines Johnathan L.,
Pericak-Vance Margaret A.,
Mayeux Richard,
Schellenberg Gerard D.,
Duijn Cornelia M.,
Wijsman Ellen,
Seshadri Sudha,
Boerwinkle Eric
Publication year - 2016
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.2016.06.426
Subject(s) - biology , genome , genetics , gene , genome wide association study , disease , pedigree chart , computational biology , genotype , expression quantitative trait loci , single nucleotide polymorphism , medicine , pathology
values from peripheral blood samples (PaxGene RNA tubes) were pre-processed followed by standard quality control (QC) procedures on samples and probe sets. Statistical analysis of microarray data was performed using a linear regression model to evaluate differences in gene expression between LOAD and cognitively normal controls (CN). Meta-analysis was performed using a fixed-effect, inverse-variance-weighted model. Significant associations were determined using FDR adjustment and Bonferroni correction for multiple testing. Results: Of the 21,150 probe sets in ADNI represented on the array after QC, 18 probe sets (16 genes) were significantly up-regulated and 8 probe sets (7 genes) were significantly down-regulated in LOAD after controlling for multiple testing (FDR-corrected p<0.05) (Fig.1). Of the 23 differentially expressed genes, 6 genes were replicated in the meta-analysis (Table 1). The most significantly altered gene was CREB5 (up-regulated). Whole-brain cortical thickness analysis identified and replicated brain regions, especially entorhinal cortex, significantly associated with expression of CREB5 (Fig. 2). Individuals with lower expression showed greater cortical thickness (corrected p<0.05). cis-eQTL mapping analyses of CREB5 detected 5 significant associations with p < 5x10 (Fig. 3). cis-eQTL of rs56388170 (most significant) was replicated (Fig. 3) and was significantly associated with global cortical Ab load (measured by [F]Florbetapir PET) and CSF Ab1-42 (Fig. 4). Conclusions:RNA from peripheral blood indicated a differential gene expression pattern between AD patients and controls. Genes identified in this study have been implicated in biological processes that may be relevant to AD. CREB is a key component of nervous system development, cell survival, plasticity and learning and memory (Sakamoto et al. 2011).