Both common variations and rare non-synonymous substitutions and small insertion/deletions in CLU are associated with increased Alzheimer risk. Bettens, K., Brouwers, N., Engelborghs, S., Lambert, J., Rogaeva, E., Vandenberghe, R., Le Bastard, N., Pasquier, F., Vermeulen, S., Van Dongen, J., Mattheijssens, M., Peeters, K., Mayeux, R., St George-Hyslop, P., Amouyel, P., De Deyn, P. P., Sleegers, K., & Van Broeckhoven, C. Molecular Neurodegeneration, 7:3, January, 2012.
doi  abstract   bibtex   
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 (OR(MH) = 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.
@article{bettens_both_2012,
	title = {Both common variations and rare non-synonymous substitutions and small insertion/deletions in {CLU} are associated with increased {Alzheimer} risk},
	volume = {7},
	issn = {1750-1326},
	doi = {10.1186/1750-1326-7-3},
	abstract = {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 (OR(MH) = 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.},
	language = {eng},
	journal = {Molecular Neurodegeneration},
	author = {Bettens, Karolien and Brouwers, Nathalie and Engelborghs, Sebastiaan and Lambert, Jean-Charles and Rogaeva, Ekaterina and Vandenberghe, Rik and Le Bastard, Nathalie and Pasquier, Florence and Vermeulen, Steven and Van Dongen, Jasper and Mattheijssens, Maria and Peeters, Karin and Mayeux, Richard and St George-Hyslop, Peter and Amouyel, Philippe and De Deyn, Peter P. and Sleegers, Kristel and Van Broeckhoven, Christine},
	month = jan,
	year = {2012},
	pmid = {22248099},
	pmcid = {PMC3296573},
	keywords = {Aged, Alzheimer Disease, Humans, Female, Male, Middle Aged, Aged, 80 and over, Cohort Studies, Gene Frequency, Risk Factors, Alleles, Genotype, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Clusterin, European Continental Ancestry Group, Genetic Variation, Canada, Chromosome Mapping, Exons, Mutagenesis, Insertional, Sequence Deletion},
	pages = {3}
}
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