1. Deep sequencing of the nicastrin gene in pooled DNA, the identification of genetic variants that affect risk of Alzheimer's disease
- Author
-
Kathryn Lord, Simon Lovestone, Michelle K. Lupton, Bruno Vellas, Patrizia Mecocci, Richard Wroe, Gillian Hamilton, John Powell, Makrina Danillidou, Denise Harold, Magda Tsolaki, Hilkka Soininen, Megan Pritchard, Paul Hollingworth, Iwona Kłoszewska, Petroula Proitsi, and Belinda M. Martin
- Subjects
Enzyme complex ,Validation Studies as Topic ,Bioinformatics ,0302 clinical medicine ,Gene Frequency ,Risk Factors ,Neurobiology of Disease and Regeneration ,Genome Sequencing ,Aged, 80 and over ,Genetics ,Medicine(all) ,0303 health sciences ,Membrane Glycoproteins ,Multidisciplinary ,Agricultural and Biological Sciences(all) ,High-Throughput Nucleotide Sequencing ,Genomics ,Middle Aged ,Neurology ,Medicine ,Research Article ,Science ,Nicastrin ,Single-nucleotide polymorphism ,Biology ,Polymorphism, Single Nucleotide ,Deep sequencing ,Specimen Handling ,03 medical and health sciences ,Meta-Analysis as Topic ,Alzheimer Disease ,Genetic variation ,Humans ,Genetic Predisposition to Disease ,Allele frequency ,Genotyping ,Genetic Association Studies ,Aged ,030304 developmental biology ,Genetic association ,Biochemistry, Genetics and Molecular Biology(all) ,Genetic Variation ,Human Genetics ,DNA ,R1 ,Case-Control Studies ,Genetics of Disease ,Genetic Polymorphism ,biology.protein ,Dementia ,Amyloid Precursor Protein Secretases ,Population Genetics ,030217 neurology & neurosurgery ,Neuroscience - Abstract
Nicastrin is an obligatory component of the c-secretase; the enzyme complex that leads to the production of Ab fragments critically central to the pathogenesis of Alzheimer's disease (AD). Analyses of the effects of common variation in this gene on risk for late onset AD have been inconclusive. We investigated the effect of rare variation in the coding regions of the Nicastrin gene in a cohort of AD patients and matched controls using an innovative pooling approach and next generation sequencing. Five SNPs were identified and validated by individual genotyping from 311 cases and 360 controls. Association analysis identified a non-synonymous rare SNP (N417Y) with a statistically higher frequency in cases compared to controls in the Greek population (OR 3.994, CI 1.105-14.439, p = 0.035). This finding warrants further investigation in a larger cohort and adds weight to the hypothesis that rare variation explains some of genetic heritability still to be identified in Alzheimer's disease.
- Published
- 2011
- Full Text
- View/download PDF