Format

Send to

Choose Destination
J Neuroinflammation. 2015 Dec 1;12:227. doi: 10.1186/s12974-015-0436-z.

Epistasis analysis links immune cascades and cerebral amyloidosis.

Author information

1
Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, 6825 LaSalle Blvd, H4H 1R3, Montreal, QC, Canada. andrea.benedet@mail.mcgill.ca.
2
CAPES Foundation, Ministry of Education of Brazil, Brasília, Brazil. andrea.benedet@mail.mcgill.ca.
3
Douglas Hospital Research Centre, McGill University, Montreal, Canada. aurelie.labbe@mcgill.ca.
4
Department of Epidemiology, Biostatistics & Occupational Health, McGill University, Montreal, Canada. aurelie.labbe@mcgill.ca.
5
Department of Psychiatry, McGill University, Montreal, Canada. aurelie.labbe@mcgill.ca.
6
Department of Biochemistry, Université de Montréal, Montréal, Canada. lemayph@gmail.com.
7
Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, 6825 LaSalle Blvd, H4H 1R3, Montreal, QC, Canada. erzimmer@gmail.com.
8
Department of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil. erzimmer@gmail.com.
9
Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil. erzimmer@gmail.com.
10
Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, 6825 LaSalle Blvd, H4H 1R3, Montreal, QC, Canada. tharick.alipascoal@mail.mcgill.ca.
11
Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, 6825 LaSalle Blvd, H4H 1R3, Montreal, QC, Canada. antoine.leuzy@ki.se.
12
Department of NVS, Center for Alzheimer Research, Translational Alzheimer Neurobiology, Karolinska Institutet, Stockholm, Sweden. antoine.leuzy@ki.se.
13
Alzheimer's Disease Research Unit, McGill University Research Centre for Studies in Aging, McGill University, Montreal, Canada. antoine.leuzy@ki.se.
14
Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, 6825 LaSalle Blvd, H4H 1R3, Montreal, QC, Canada. mathotaarachchi.mathotaarachchi@mail.mcgill.ca.
15
Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, 6825 LaSalle Blvd, H4H 1R3, Montreal, QC, Canada. sara.mohades@gmail.com.
16
Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, 6825 LaSalle Blvd, H4H 1R3, Montreal, QC, Canada. monica.shin@mail.mcgill.ca.
17
Department of Neurology and Neurosurgery, McGill University, Montreal, Canada. alexandre.dionne-laporte@mcgill.ca.
18
Montreal Neurological Institute, Montreal, Canada. alexandre.dionne-laporte@mcgill.ca.
19
Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, 6825 LaSalle Blvd, H4H 1R3, Montreal, QC, Canada. waveflux@gmail.com.
20
Douglas Hospital Research Centre, McGill University, Montreal, Canada. cynthia.picard@mail.mcgill.ca.
21
Department of Neurology and Neurosurgery, McGill University, Montreal, Canada. serge.gauthier@mcgill.ca.
22
Douglas Hospital Research Centre, McGill University, Montreal, Canada. judes.poirier@mcgill.ca.
23
Alzheimer's Disease Research Unit, McGill University Research Centre for Studies in Aging, McGill University, Montreal, Canada. judes.poirier@mcgill.ca.
24
Department of Neurology and Neurosurgery, McGill University, Montreal, Canada. judes.poirier@mcgill.ca.
25
Department of Neurology and Neurosurgery, McGill University, Montreal, Canada. guy.rouleau@mcgill.ca.
26
Montreal Neurological Institute, Montreal, Canada. guy.rouleau@mcgill.ca.
27
Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, 6825 LaSalle Blvd, H4H 1R3, Montreal, QC, Canada. pedro.rosa@mcgill.ca.
28
Alzheimer's Disease Research Unit, McGill University Research Centre for Studies in Aging, McGill University, Montreal, Canada. pedro.rosa@mcgill.ca.
29
Department of Neurology and Neurosurgery, McGill University, Montreal, Canada. pedro.rosa@mcgill.ca.
30
Montreal Neurological Institute, Montreal, Canada. pedro.rosa@mcgill.ca.

Abstract

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.

PMID:
26626881
PMCID:
PMC4666175
DOI:
10.1186/s12974-015-0436-z
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center