Genome-wide association interaction analysis for Alzheimer's disease

GERAD1 Consortium

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

We propose a minimal protocol for exhaustive genome-wide association interaction analysis that involves screening for epistasis over large-scale genomic data combining strengths of different methods and statistical tools. The different steps of this protocol are illustrated on a real-life data application for Alzheimer's disease (AD) (2259 patients and 6017 controls from France). Particularly, in the exhaustive genome-wide epistasis screening we identified AD-associated interacting SNPs-pair from chromosome 6q11.1 (rs6455128, the KHDRBS2 gene) and 13q12.11 (rs7989332, the CRYL1 gene) (. p= 0.006, corrected for multiple testing). A replication analysis in the independent AD cohort from Germany (555 patients and 824 controls) confirmed the discovered epistasis signal (. p= 0.036). This signal was also supported by a meta-analysis approach in 5 independent AD cohorts that was applied in the context of epistasis for the first time. Transcriptome analysis revealed negative correlation between expression levels of KHDRBS2 and CRYL1 in both the temporal cortex (β=-0.19, p= 0.0006) and cerebellum (β=-0.23, p < 0.0001) brain regions. This is the first time a replicable epistasis associated with AD was identified using a hypothesis free screening approach.

Original languageEnglish (US)
Pages (from-to)2436-2443
Number of pages8
JournalNeurobiology of Aging
Volume35
Issue number11
DOIs
StatePublished - Nov 1 2014

Fingerprint

Genome-Wide Association Study
Alzheimer Disease
Gene Expression Profiling
Temporal Lobe
Cerebellum
Genes
France
Single Nucleotide Polymorphism
Germany
Meta-Analysis
Chromosomes
Genome
Brain

Keywords

  • Alzheimer
  • Complex trait analysis
  • Epistasis
  • GWAI
  • Replication

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)
  • Aging
  • Developmental Biology
  • Geriatrics and Gerontology

Cite this

Genome-wide association interaction analysis for Alzheimer's disease. / GERAD1 Consortium.

In: Neurobiology of Aging, Vol. 35, No. 11, 01.11.2014, p. 2436-2443.

Research output: Contribution to journalArticle

GERAD1 Consortium. / Genome-wide association interaction analysis for Alzheimer's disease. In: Neurobiology of Aging. 2014 ; Vol. 35, No. 11. pp. 2436-2443.
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AU - Bellenguez, Céline

AU - Cuyvers, Elise

AU - Colon, Samuel

AU - Graff Radford, Neill R

AU - Petersen, Ronald Carl

AU - Dickson, Dennis W

AU - Mahachie John, Jestinah M.

AU - Bessonov, Kyrylo

AU - Van Broeckhoven, Christine

AU - Harold, Denise

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AU - Amouyel, Philippe

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