Epistasis analysis links immune cascades and cerebral amyloidosis.
|Title||Epistasis analysis links immune cascades and cerebral amyloidosis.|
|Publication Type||Journal Article|
|Year of Publication||2015|
|Authors||Benedet AL, Labbe A, Lemay P, Zimmer ER, Pascoal TA, Leuzy A, Mathotaarachchi S, Mohades S, Shin M, Dionne-Laporte A, Beaudry T, Picard C, Gauthier S, Poirier J, Rouleau G, Rosa-Neto P|
|Corporate Authors||Alzheimer’s Disease Neuroimaging Initiative|
|Date Published||2015 Dec 01|
|Keywords||Aged, Aged, 80 and over, Alzheimer Disease, Amyloidosis, Cognitive Dysfunction, Epistasis, Genetic, Female, Humans, Male, Middle Aged|
BACKGROUND: Several lines of evidence suggest the involvement of neuroinflammatory changes in Alzheimer's disease (AD) pathophysiology such as amyloidosis and neurodegeneration. In fact, genome-wide association studies (GWAS) have shown a link between genes involved in neuroinflammation and AD. In order to further investigate whether interactions between candidate genetic variances coding for neuroinflammatory molecules are associated with brain amyloid β (Aβ) fibrillary accumulation, we conducted an epistasis analysis on a pool of genes associated with molecular mediators of inflammation.METHODS: [(18)F]Florbetapir positron emission tomography (PET) imaging was employed to assess brain Aβ levels in 417 participants from ADNI-GO/2 and posteriorly 174 from ADNI-1. IL-1β, IL4, IL6, IL6r, IL10, IL12, IL18, C5, and C9 genes were chosen based on previous studies conducted in AD patients. Using the [(18)F]florbetapir standardized uptake value ratio (SUVR) as a quantitative measure of fibrillary Aβ, epistasis analyses were performed between two sets of markers of immune-related genes using gender, diagnosis, and apolipoprotein E (APOE) as covariates. Voxel-based analyses were also conducted. The results were corrected for multiple comparison tests. Cerebrospinal fluid (CSF) Aβ1-42/phosphorylated tau (p-tau) ratio concentrations were used to confirm such associations.RESULTS: Epistasis analysis unveiled two significant single nucleotide polymorphism (SNP)-SNP interactions (false discovery rate (FDR) threshold 0.1), both interactions between C9 gene (rs261752) and IL6r gene (rs4240872, rs7514452). In a combined sample, the interactions were confirmed (p ≤ 10-5) and associated with amyloid accumulation within cognitively normal and AD spectrum groups. Voxel-based analysis corroborated initial findings. CSF biomarker (Aβ1-42/p-tau) confirmed the genetic interaction. Additionally, rs4240872 and rs7514452 SNPs were shown to be associated with CSF and plasma concentrations of IL6r protein.CONCLUSIONS: Certain allele combinations involving IL6r and C9 genes are associated with Aβ burden in the brain. Hypothesis-driven search for epistasis is a valuable strategy for investigating imaging endophenotypes in complex neurodegenerative diseases.
|Alternate Journal||J Neuroinflammation|
|PubMed Central ID||PMC4666175|
|Grant List||U01 AG024904 / AG / NIA NIH HHS / United States |
MOP-11-51-31 / / Canadian Institutes of Health Research / Canada