Deep sequencing of nicastrin gene provides new information about rare genetic variants in Alzheimer's disease


Alzheimer's disease is the most common neurodegenerative disease of the elderly and with an increasingly aging population in many countries the burden of disease will continue to rise inexorably. Until recently, the ε4 allele of the APOE gene was the only well established genetic risk factor for the typical late-onset form of the disease. However, recent results from two of the largest genome wide association studies have identified and replicated several novel loci with high significance. Nicastrin is an obligatory component of the γ-secretase; the enzyme complex that leads to the production of Aβ fragments critically central to the pathogenesis of Alzheimer's disease. Analyses of the effects of common variation in this gene on risk for late onset Alzheimer’s disease have been inconclusive.

An international team of researchers involving Professor of Neurology Hilkka Soininen at the UEF investigated the effect of rare variation in the coding regions of the Nicastrin gene in a cohort of Alzheimer’s disease patients and matched controls using an innovative pooling approach and next generation sequencing. Five single-nucleotide polymorphisms were identified and validated by individual genotyping from 311 cases and 360 controls. Association analysis identified a non-synonymous rare single-nucleotide polymorphism with a statistically higher frequency in cases compared to controls in the Greek population.

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.

For further information, please contact Professor Hilkka Soininen, email:

Original article:

Michelle K. Lupton, Petroula Proitsi, Makrina Danillidou, Magda Tsolaki, Gillian Hamilton, Richard Wroe, Megan Pritchard, Kathryn Lord, Belinda M. Martin, Iwona Kloszewska, Hilkka Soininen, Patrizia Mecocci, Bruno Vellas, Denise Harold, Paul Hollingworth, Simon Lovestone, John F. Powell (2011). Deep Sequencing of the Nicastrin Gene in Pooled DNA, the Identification of Genetic Variants That Affect Risk of Alzheimer's Disease. PLoS ONE 6(2): e17298. doi:10.1371/journal.pone.0017298

Artikkelin kirjoitusvuosi: 2011

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