title: Epistasis analysis links immune cascades and cerebral amyloidosis.
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.
authors.affiliation: Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, 6825 LaSalle Blvd, H4H 1R3, Montreal, QC, Canada. andrea.benedet@mail.mcgill.ca.|CAPES Foundation, Ministry of Education of Brazil, Brasília, Brazil. andrea.benedet@mail.mcgill.ca.
authors.forename: Andréa L
authors.initials: AL
authors.lastname: Benedet
authors.affiliation: Douglas Hospital Research Centre, McGill University, Montreal, Canada. aurelie.labbe@mcgill.ca.|Department of Epidemiology, Biostatistics & Occupational Health, McGill University, Montreal, Canada. aurelie.labbe@mcgill.ca.|Department of Psychiatry, McGill University, Montreal, Canada. aurelie.labbe@mcgill.ca.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Labbe
authors.affiliation: Department of Biochemistry, Université de Montréal, Montréal, Canada. lemayph@gmail.com.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lemay
authors.affiliation: Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, 6825 LaSalle Blvd, H4H 1R3, Montreal, QC, Canada. erzimmer@gmail.com.|Department of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil. erzimmer@gmail.com.|Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil. erzimmer@gmail.com.
authors.forename: Eduardo R
authors.initials: ER
authors.lastname: Zimmer
authors.affiliation: Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, 6825 LaSalle Blvd, H4H 1R3, Montreal, QC, Canada. tharick.alipascoal@mail.mcgill.ca.
authors.forename: Tharick A
authors.initials: TA
authors.lastname: Pascoal
authors.affiliation: Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, 6825 LaSalle Blvd, H4H 1R3, Montreal, QC, Canada. antoine.leuzy@ki.se.|Department of NVS, Center for Alzheimer Research, Translational Alzheimer Neurobiology, Karolinska Institutet, Stockholm, Sweden. antoine.leuzy@ki.se.|Alzheimer's Disease Research Unit, McGill University Research Centre for Studies in Aging, McGill University, Montreal, Canada. antoine.leuzy@ki.se.
authors.forename: Antoine
authors.initials: A
authors.lastname: Leuzy
authors.affiliation: Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, 6825 LaSalle Blvd, H4H 1R3, Montreal, QC, Canada. mathotaarachchi.mathotaarachchi@mail.mcgill.ca.
authors.forename: Sulantha
authors.initials: S
authors.lastname: Mathotaarachchi
authors.affiliation: Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, 6825 LaSalle Blvd, H4H 1R3, Montreal, QC, Canada. sara.mohades@gmail.com.
authors.forename: Sara
authors.initials: S
authors.lastname: Mohades
authors.affiliation: Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, 6825 LaSalle Blvd, H4H 1R3, Montreal, QC, Canada. monica.shin@mail.mcgill.ca.
authors.forename: Monica
authors.initials: M
authors.lastname: Shin
authors.affiliation: Department of Neurology and Neurosurgery, McGill University, Montreal, Canada. alexandre.dionne-laporte@mcgill.ca.|Montreal Neurological Institute, Montreal, Canada. alexandre.dionne-laporte@mcgill.ca.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Dionne-Laporte
authors.affiliation: Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, 6825 LaSalle Blvd, H4H 1R3, Montreal, QC, Canada. waveflux@gmail.com.
authors.forename: Thomas
authors.initials: T
authors.lastname: Beaudry
authors.affiliation: Douglas Hospital Research Centre, McGill University, Montreal, Canada. cynthia.picard@mail.mcgill.ca.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Picard
authors.affiliation: Department of Neurology and Neurosurgery, McGill University, Montreal, Canada. serge.gauthier@mcgill.ca.
authors.forename: Serge
authors.initials: S
authors.lastname: Gauthier
authors.affiliation: Douglas Hospital Research Centre, McGill University, Montreal, Canada. judes.poirier@mcgill.ca.|Alzheimer's Disease Research Unit, McGill University Research Centre for Studies in Aging, McGill University, Montreal, Canada. judes.poirier@mcgill.ca.|Department of Neurology and Neurosurgery, McGill University, Montreal, Canada. judes.poirier@mcgill.ca.
authors.forename: Judes
authors.initials: J
authors.lastname: Poirier
authors.affiliation: Department of Neurology and Neurosurgery, McGill University, Montreal, Canada. guy.rouleau@mcgill.ca.|Montreal Neurological Institute, Montreal, Canada. guy.rouleau@mcgill.ca.
authors.forename: Guy
authors.initials: G
authors.lastname: Rouleau
authors.affiliation: Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, 6825 LaSalle Blvd, H4H 1R3, Montreal, QC, Canada. pedro.rosa@mcgill.ca.|Alzheimer's Disease Research Unit, McGill University Research Centre for Studies in Aging, McGill University, Montreal, Canada. pedro.rosa@mcgill.ca.|Department of Neurology and Neurosurgery, McGill University, Montreal, Canada. pedro.rosa@mcgill.ca.|Montreal Neurological Institute, Montreal, Canada. pedro.rosa@mcgill.ca.
authors.forename: Pedro
authors.initials: P
authors.lastname: Rosa-Neto
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis / Q000235:genetics / Q000276:immunology*; D000686:Amyloidosis / Q000175:diagnosis / Q000235:genetics / Q000276:immunology*; D060825:Cognitive Dysfunction / Q000175:diagnosis / Q000235:genetics / Q000276:immunology*; D004843:Epistasis, Genetic / Q000235:genetics / Q000276:immunology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged