Both common variations and rare non-synonymous substitutions and small insertion/deletions in CLU are associated with increased Alzheimer risk

Autor: Rik Vandenberghe, Maria Mattheijssens, Kristel Sleegers, Nathalie Brouwers, Nathalie Le Bastard, Ekaterina Rogaeva, Richard Mayeux, Jean-Charles Lambert, Sebastiaan Engelborghs, Peter St George-Hyslop, Peter Paul De Deyn, Christine Van Broeckhoven, Steven Vermeulen, Karolien Bettens, Philippe Amouyel, Florence Pasquier, Karin Peeters, Jasper Van Dongen
Přispěvatelé: St George-Hyslop, Peter [0000-0003-0796-7209], Apollo - University of Cambridge Repository, Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Institute Born-Bunge, University of Antwerp (UA), Department of Neurology and Memory Clinic, Hospital Network Antwerp Middelheim and Hoge Beuken, Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Medicine (Neurology), University of Toronto-Centre for Research in Neurodegenerative Diseases, Department of Neurology, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven)-University Hospitals Leuven [Leuven], Gertrude H. Sergievsky Center, Columbia University [New York], Department of Clinical Neurosciences [Cambridge], University of Cambridge [UK] (CAM), The research at the Antwerp site was in part supported by the Interuniversity Attraction Poles program P6/43 of the Belgian Science Policy Office (BELSPO, http://www.belspo.be/), the Foundation for Alzheimer Research (SAO/FRMA, http://alzh.org/), a Methusalem Excellence Grant of the Flemish Government (EWI, http://www.ewi-vlaanderen.be/), the Research Foundation Flanders (FWO, http://www.fwo.be/), the Special Research Fund of the University of Antwerp (UA, http://www.ua.ac.be/), the Antwerp Medical Research Foundation and Neurosearch, Belgium. KB, NB and KS are postdoctoral fellows, and RV a senior clinical investigator of the FWO. The Lille site was funded in part by the National Foundation for Alzheimer's disease and related disorders, the Institute Pasteur de Lille and INSERM. The Toronto site was supported by grants from the Canadian Institutes of Health Research, Ontario Research Fund, Weston foundation (PSH), the Howard Hughes Medical Institute, The Wellcome Trust, the Alzheimer Society of Ontario (PSH)., BMC, Ed., Clinical sciences, Neurology
Rok vydání: 2012
Předmět:
Male
Genome-wide association study
lcsh:Geriatrics
lcsh:RC346-429
Cohort Studies
clusterin gene (CLU)
0302 clinical medicine
Gene Frequency
Risk Factors
b?β?-chain domain
European Continental Ancestry Group/genetics
genomic resequencing
Sequence Deletion
Medicine(all)
Aged
80 and over
Genetics
0303 health sciences
biology
Alzheimer's disease--Research
Chromosome Mapping
Exons
Middle Aged
[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Female
Research Article
Canada
Genotype
Clinical Neurology
Single-nucleotide polymorphism
Locus (genetics)
Medical sciences
Polymorphism
Single Nucleotide
White People
Amino acid sequence
03 medical and health sciences
Cellular and Molecular Neuroscience
Alzheimer Disease
insertions/deletions
Humans
SNP
[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Allele
Molecular Biology
Allele frequency
lcsh:Neurology. Diseases of the nervous system
Alleles
Aged
030304 developmental biology
Genetic association
Alzheimer Disease/genetics
Clusterin
FOS: Clinical medicine
Neurosciences
Genetic Variation
β-chain domain
meta-analysis
lcsh:RC952-954.6
non-synonymous substitutions
Mutagenesis
Insertional
Nervous system--Degeneration--Genetic aspects
FOS: Biological sciences
insertions/ deletions
biology.protein
Human medicine
Neurology (clinical)
Clusterin/genetics
030217 neurology & neurosurgery
Genome-Wide Association Study
Zdroj: Molecular neurodegeneration
Molecular Neurodegeneration
Molecular Neurodegeneration, BioMed Central, 2012, 7 (1), pp.3. ⟨10.1186/1750-1326-7-3⟩
Molecular Neurodegeneration, 2012, 7 (1), pp.3. ⟨10.1186/1750-1326-7-3⟩
Molecular Neurodegeneration, Vol 7, Iss 1, p 3 (2012)
ISSN: 1750-1326
DOI: 10.1186/1750-1326-7-3
Popis: Background We have followed-up on the recent genome-wide association (GWA) of the clusterin gene (CLU) with increased risk for Alzheimer disease (AD), by performing an unbiased resequencing of all CLU coding exons and regulatory regions in an extended Flanders-Belgian cohort of Caucasian AD patients and control individuals (n = 1930). Moreover, we have replicated genetic findings by targeted resequencing in independent Caucasian cohorts of French (n = 2182) and Canadian (n = 573) origin and by performing meta-analysis combining our data with previous genetic CLU screenings. Results In the Flanders-Belgian cohort, we identified significant clustering in exons 5-8 of rare genetic variations leading to non-synonymous substitutions and a 9-bp insertion/deletion affecting the CLU β-chain (p = 0.02). Replicating this observation by targeted resequencing of CLU exons 5-8 in 2 independent Caucasian cohorts of French and Canadian origin identified identical as well as novel non-synonymous substitutions and small insertion/deletions. A meta-analysis, combining the datasets of the 3 cohorts with published CLU sequencing data, confirmed that rare coding variations in the CLU β-chain were significantly enriched in AD patients (ORMH = 1.96 [95% CI = 1.18-3.25]; p = 0.009). Single nucleotide polymorphisms (SNPs) association analysis indicated the common AD risk association (GWA SNP rs11136000, p = 0.013) in the 3 combined datasets could not be explained by the presence of the rare coding variations we identified. Further, high-density SNP mapping in the CLU locus mapped the common association signal to a more 5' CLU region. Conclusions We identified a new genetic risk association of AD with rare coding CLU variations that is independent of the 5' common association signal identified in the GWA studies. At this stage the role of these coding variations and their likely effect on the β-chain domain and CLU protein functioning remains unclear and requires further studies.
Databáze: OpenAIRE
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