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 - Funding Information:
The authors thank all participating subjects of this study. They thank François Van Lishout and Bärbel Maus (Systems and Modeling Unit, Montefiore Institute, University of Liege, Belgium) for sharing with us their complementary experience and for their stimulating discussions during all stages of the statistical analyses. They thank Steven G. Younkin (Mayo Clinic Florida, Department of Neuroscience, Jacksonville, FL, USA) for important contribution of data. The research in Liege, Belgium is funded by the Belgian Science Policy Office Phase VII IAP network “Dynamical systems, control and optimization” (DYSCO II) (IAP VII/19 - DYSCO) and the Fonds De La Recherche Scientifique (FNRS) (postdoctoral grant “Charge de Recherches” A4/5 - XH/SC - 5954, FC 95176). Research in the Lille group was supported by the National Foundation for Alzheimer's disease and related disorders , the Institut Pasteur de Lille , the Centre National de Génotypage , National Institute of Health and Medical Research , FRC (fondation pour la recherche sur le cerveau) and Rotary , and the LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease). The Three-City Study in France was performed as part of collaboration between the Institut National de la Santé et de la Recherche Médicale (Inserm), the Victor Segalen Bordeaux II University, and Sanofi-Synthélabo. The Fondation pour la Recherche Médicale (SPF20110421400) funded the preparation and initiation of the study. The Three-City Study was also funded by the Caisse Nationale Maladie des Travailleurs Salariés , Direction Générale de la Santé , MGEN , Institut de la Longévité , Agence Française de Sécurité Sanitaire des Produits de Santé , the Aquitaine and Bourgogne Regional Councils , Fondation de France , and the joint French Ministry of Research/INSERM “Cohortes et collections de données biologiques” programme. Lille Génopôle received an unconditional grant from Eisai . Research at the Antwerp site is funded in part by the Belgian Science Policy Office Interuniversity Attraction Poles program, the Foundation Alzheimer Research (SAO-FRA), the Flemish government initiated the Methusalem Excellence Program, the Research Foundation Flanders (FWO), the Agency for Innovation by Science and Technology (IWT), and the University of Antwerp Research Fund , Belgium. Elise Cuyver has a doctoral fellowship of the IWT, Belgium. The Antwerp site authors thank the personnel of the VIB Genetic Service Facility, the Biobank of the Institute Born-Bunge, the Departments of Neurology and Memory Clinics at the Hospital Network Antwerp, and the University Hospitals Leuven. Nilüfer Ertekin-Taner receives grant support from the National Institutes of Health grants: National Institute on Aging ( R01 AG032990 , P50 AG016574 ). Ronald C. Petersen receives grant support from the National Institute on Aging ( Mayo Alzheimer's Disease Research Center [ P50 AG016574 ] and Mayo Clinic Study of Aging [ U01 AG006786 ]). Minerva M Carrasquillo is supported partly by GHR Foundation grant. GERAD1 acknowledgements: Cardiff University was supported by the Wellcome Trust (GR082604MA) , Medical Research Council (MRC) (G0300429), Alzheimer’s Research UK , and the Welsh Assembly Government . Alzheimer’s Research UK supported sample collections at the Kings College London , the South West Dementia Bank , Universities of Cambridge , Nottingham , Manchester , and Belfast . The Belfast group acknowledges support from the Alzheimer's Society , Ulster Garden Villages , N.Ireland R&D Office , and the Royal College of Physicians and/or Dunhill Medical Trust . The MRC and Mercer's Institute for Research on Ageing supported the Trinity College group . The South West Dementia Brain Bank acknowledges support from Bristol Research into Alzheimer's and Care of the Elderly . The Charles Wolfson Charitable Trust supported the OPTIMA group . Washington University was funded by NIH grants (PO1-AG026276, PO1-AG03991, RO1-AG16208, P50-AG05681), Barnes Jewish Foundation , and the Charles and Joanne Knight Alzheimer's Research Initiative . Patient recruitment for the MRC Prion Unit/UCL Department of Neurodegenerative Disease collection was supported by the UCLH/UCL Biomedical Centre . UCL was supported by the NIHR Queen Square Dementia Biomedical Research Unit . LASER-AD was funded by Lundbeck SA . The Bonn group was supported by the German Federal Ministry of Education and Research (BMBF) (Kompetenznetz Demenzen 01GI0420), Competence Network Dementia (Förderkennzeichen 01GI0102) and Competence Network Degenerative Dementia (Förderkennzeichen 01GI0711), and by the Alfried Krupp von Bohlen und Halbach-Stiftung . The GERAD1 Consortium also used samples ascertained by the NIMH AD Genetics Initiative. The KORA F4 studies were financed by Helmholtz Zentrum München ; German Research Center for Environmental Health ; BMBF ; German National Genome Research Network , and the Munich Center of Health Sciences . The Heinz Nixdorf Recall cohort was funded by the Heinz Nixdorf Foundation (Dr jur. G.Schmidt, Chairman) and BMBF . Coriell Cell Repositories is supported by National Institute of Neurological Disorders and Stroke and the Intramural Research Program of the National Institute on Aging. They acknowledge the use of genotype data from the 1958 Birth Cohort collection, funded by the MRC (G0000934) and the Wellcome Trust (068545/Z/02) , which was genotyped by the Wellcome Trust Case Control Consortium and the Type-1 Diabetes Genetics Consortium, sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases , National Institute of Allergy and Infectious Diseases , National Human Genome Research Institute , National Institute of Child Health and Human Development , and Juvenile Diabetes Research Foundation International (JDRF) (U01 DK062418).
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
UR - http://www.scopus.com/inward/record.url?scp=84922938637&partnerID=8YFLogxK
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 -