New Genetic Clues to Alzheimer's Disease Risk
New Genetic Clues to Alzheimer's Disease Risk
Abstract & Commentary
By M. Elizabeth Ross, MD, PhD, Professor of Neurology and Neuroscience, Laboratory of Neurogenetics and Development, Weill Cornell Medical College. Dr. Ross reports no financial relationships relevant to this field of study.
Synopsis: Recent breakthroughs in genetic research will bring us closer to being able to diagnose an individual's risk of developing late-onset sporadic Alzheimer's disease.
Source: Harold D, et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nature Genetics 2009;41:1088-1093. Lambert JC, et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nature Genetics 2009;41:1094-1099.
Two genome-wide association (GWA) studies published in the October issue of Nature Genetics report three additional genes whose common variants contribute to sporadic late-onset Alzheimer's disease (LOAD). These studies promise to improve capabilities for accurate assessment of Alzheimer's disease (AD) risk and provide new targets for research toward understanding and preventing LOAD.
The most common form of dementia, sporadic LOAD, is thought to result from heritable factors in at least 76% of cases. The first and still the strongest association with LOAD is the 4e allele of apolipoprotein E (APOE). The presence in an individual's genome of two of these alleles on chromosome 19q increases the lifetime risk for AD from 20% to 90% and hastens the age of onset to 68 compared to 84 years. It has been estimated that APOE 4e may account for up to 50% of the risk for sporadic LOAD. However, finding other gene alleles contributing smaller effects to the risk of developing LOAD has been challenging. GWA studies examine the frequency with which gene variants commonly found in a population occur in association with a particular disease. This is a powerful way to identify minor changes (single nucleotide polymorphisms or SNPs) that alter function of a gene and can increase the likelihood of developing a disorder. Although once heralded as the great advance toward mapping the genetic contributions to common diseases, relatively few GWA investigations have yielded risk associations that have survived more detailed scrutiny. Experience indicates that a successful GWA study requires a large effect size of the allele-that is, a frequent coincidence of that allele with the disease. The lower the effect size of a given allele, the more patients and controls that will have to be examined in order to detect a statistically significant SNP-disease association. This translates into thousands of cases and controls needed for a successful study, at a steep cost for processing of DNA arrays (SNP chips). Another lesson has been the critical importance of replicating the finding in a second cohort of patients and controls, further increasing the cost of an adequate study. This has led to some recent loss of enthusiasm for the approach, with detractors pointing out the poor yield on investment, while others maintain that common disorders including AD may be more often associated with rare variant alleles (i.e., SNPs present in <1% of the population), many of which are currently unknown.
The two independent studies published in Nature Genetics may restore some enthusiasm for the GWA study approach. Together, these studies encompass data on 6,000 late-onset AD patients and 13,000 controls with replication in another 6,000 patients and 5,600 controls, or a total of over 30,000 subjects. They identified convincing associations in four genes. Again, by far the strongest association was with the APOE 4e allele, validating the data treatment. Both studies found new significant associations with clusterin (CLU), another major brain lipoprotein that is known to cooperate with APOE in suppressing the deposition Ab peptide once cleaved from APP and modulating Ab clearance at the blood-brain barrier. The French-EU group also found an association with PICALM (a phosphatidylinositol-binding clathrin assembly protein), which has been shown to be involved the endocytic retrieval of APP from the cell surface and disruption of this process leads to altered Ab levels. The UK-American group further identified an association with complement (3b/4b) component receptor 1 (CR1), which may be involved in Ab clearance via the complement system. Interestingly, all of these proteins have putative or demonstrated roles in Ab processing. The work now begins with the goal of understanding how these SNPs, and other polymorphisms yet to be found in these genes, result in LOAD and to put this knowledge to use for diagnosis, prevention and treatment.
Commentary
These and other recent GWA studies for complex disorders clearly illustrate the potential value of the approach for the identification of additional susceptibility loci for Alzheimer's and other neurological diseases. Going forward, focus should be placed on the pooling of investigator efforts to achieve even larger sample sizes and for updating meta-analyses of existing data. GWA approaches are likely to experience a renaissance as the 1000 genome sequencing project comes to fruition that will fully sequence the DNA of 1000 random individuals-an effort sure to add many rare variants of genes to the human genome database. Advances in methodologies for GWA studies, detection of copy number variations (CNVs), and even direct sequencing of the 'exome' (all the DNA in the genome that is transcribed into RNA) is accelerating disease gene discovery at a breathtaking pace. Utilization of this genetic knowledge will demand that biologists and clinicians join forces in unprecedented, close partnerships.
Recent breakthroughs in genetic research will bring us closer to being able to diagnose an individual's risk of developing late-onset sporadic Alzheimer's disease.Subscribe Now for Access
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