mardi 15 juin 2010

Susceptibility loci for Alzheimer disease

While we have understood the bases for mendelian, early-onset Alzheimer disease for nearly 2 decades, elucidation of the genetic risks for late-onset disease beyond the apolipoprotein E locus, discovered in 1993, had been painfully slow until the last year.

From 1993 to 2009, thousands of genetic association studies on Alzheimer disease had been published without any becoming generally accepted as true risk loci for the disease.

With the benefit of hindsight, we now have some indication of why no other risk loci were found during this period; simply, there are no other loci with similar effect sizes to apolipoprotein E to be found.

Now, however, with the advent of whole-genome associations, we are beginning to find the weaker risk loci for the disease.

Whole-genome associations rely on the observation that, within a certain population, genetic variability at 1 point predicts (tags), with reasonable accuracy, the other genetic variability within approximately 20 kilobases (kb).

This means that assessment of variability across the whole genome can be achieved by assessment of these tagging single-nucleotide polymorphisms.

In practice, this means that genetic variability across the genome can be systematically tested for association with disease by genotyping about 400 000 evenly spaced tagging single-nucleotide polymorphisms in large numbers of cases and controls. The larger the series of cases and controls, the smaller the effect that can be detected.

Through the application of this technology and the use of approximately 2000 Alzheimer cases and a greater number of controls, 2 recent studies have identified 3 loci as being clearly implicated in Alzheimer disease6-7: CLU, CRI, and PICALM, with other loci, including BIN1 and CNTN5, almost reaching significance.


- Identification of Alzheimer Risk Factors Through Whole-Genome Analysis. John Hardy, PhD; Julie Williams, PhD. Arch Neurol. 2010;67(6):663-664.

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