TY - JOUR
T1 - Genome-wide association interaction analysis for Alzheimer's disease
AU - GERAD1 Consortium
AU - Gusareva, Elena S.
AU - Carrasquillo, Minerva M.
AU - Bellenguez, Céline
AU - Cuyvers, Elise
AU - Colon, Samuel
AU - Graff-Radford, Neill R.
AU - Petersen, Ronald C.
AU - Dickson, Dennis W.
AU - Mahachie John, Jestinah M.
AU - Bessonov, Kyrylo
AU - Van Broeckhoven, Christine
AU - Harold, Denise
AU - Williams, Julie
AU - Amouyel, Philippe
AU - Sleegers, Kristel
AU - Ertekin-Taner, Nilüfer
AU - Lambert, Jean Charles
AU - Van Steen, Kristel
N1 - Publisher Copyright:
© 2014 The Authors.
PY - 2014/11/1
Y1 - 2014/11/1
N2 - 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.
AB - 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.
KW - Alzheimer
KW - Complex trait analysis
KW - Epistasis
KW - GWAI
KW - Replication
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UR - http://www.scopus.com/inward/citedby.url?scp=84922938637&partnerID=8YFLogxK
U2 - 10.1016/j.neurobiolaging.2014.05.014
DO - 10.1016/j.neurobiolaging.2014.05.014
M3 - Article
C2 - 24958192
AN - SCOPUS:84922938637
SN - 0197-4580
VL - 35
SP - 2436
EP - 2443
JO - Neurobiology of aging
JF - Neurobiology of aging
IS - 11
ER -