This web page was produced as an assignment for Genetics 677, an undergraduate course at UW-Madison Spring 2009
Scientific Article Review
Below I review the 2006 Nature Genetics article "The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease" by Ekaterina Rogaeva et al.
The Rogaeva article is a good example of an experiment that was sufficiently controlled and verified. In my opinion, one of the more elegant aspects of the results are the number of things done to ensure that there is scientific validity backing up the results and not experimental coincidence. For instance, the paper claims that six single nucleotide polymorphisms (SNPs) are in the gene SORL1 are associated with late onset Alzheimer’s disease. To make this conclusion stronger, the authors investigated the chance that APOE (another gene that has been shown to associate with Alzheimer’s) was causing the newly observed association with SORL1. After controlling for APOE genotype, the authors were able to more forcefully conclude that the association with SORL1 is a causal association.
Another aspect of the study that speaks well for its robustness is the fact that the results were replicated in numerous different populations. It was important to examine different populations to control for any possible naturally existing confounding conditions including allelic heterogeneity. Not only do the results accomplish this, but by observing the same SNPs associated with Alzheimer’s disease across different populations lends further evidence that there is a biological basis to the results.
In addition to the statistical calculations performed, the authors also investigated the biological interactions of SORL1. Because the SNPs associated with Alzheimer’s were in intronic regions of SORL1, the authors propose that they play a role in the tissue specific expression of SORL1. They investigated this further and found that SORL1 haplotypes account for only 14% of the variance in SORL1 expression. Obviously these results indicated that while SORL1 is part of the picture, there is certainly a lot more going on.
For the most part I enjoyed the logical progression of the study. However, there was one area where I was not clear. The authors stated that “…we investigated genetic associates between Alzheimer disease and SNPs in selected members of the vacuolar protein sorting (VPS) gene family…” I wish they would have explained why they chose the SNPs they did. Was it based on previously published results? Were these the only SNPs they had reliable genotyping data available in a large enough quantity for? I’m sure there must have been a reason that they did not test all the members of the VPS gene family and I would like to know why. Perhaps there is another member of the VPS gene family that has a stronger association with Alzheimer’s disease than SORL1.
Finally, the authors do a good job of stating clearly and without inflation the meaning and results of their study. “Taken together, our results suggest that genetic and possibly environmentally specified changes in SORL1 expression or function are causally linked to the pathogenesis of Alzheimer disease and have a modest effect on risk for this disease.” I think this clearly indicates that the cellular biology performed indicates SORL1 plays a role in Alzheimer plaque formation and that the association with Alzheimer’s disease and SORL1 is a modest one. The authors don’t claim to have finished to problem but do indicated the importance and significance of their find.
References
Rogaeva, E., et al. 2006. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nature Genetics, 39 (2).
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Last Updated 5/13/09
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