Using the annotated file from the app from basespace makes moving through the exome quite easy. Simply searching for "Alzheimer" is useful. When this was done the Hemochromatosis, Prion Protein / Jacob Creutzfeldt, Bleomycin, Sortilin1, ABPP4, Plasminogen activator, NOS3, and A2M AD variants popped up. Some of these variants sound scary (especially the Prion Protein/ Jacob Creutzfeldt one), though only the HFE is rare and none of them is likely the variant of interest. So, in terms of the above board read out, there was nothing much to report.
The underground search found much more interesting results. When I used the search word "amyloid", the genes/diseases
Amyloid beta A4 precursor protein-binding, family A, member 3
Beta-site amyloid beta A4 precursor protein-cleaving enzyme 2 (Down syndrome region aspartic protease)
Amyloidosis, primary localized cutaneous, 1, 105250 (3)
Amyloid beta A4 precursor protein-binding, family B, member-1
Beta-site amyloid beta A4 precursor protein-cleaving enzyme (secretase, beta; memapsin 2)
I also noticed that there were quite a few BACE2 (BACE2 beta-site APP-cleaving enzyme 2) mutations and there was a full page of spinocerebellar ataxia mutations.
The genetics community is struggling with the rare variants found in some of the above genes. All the genes with amyloid or BACE2 gave me a very bad feeling. If there were a mutation in a gene that cuts amyloid that obviously could be a concern. There were many other scary mutations with the words microtubule, Sirtuin etc. . You just need to have some recognition of these words to know that if they were malfunctioning that this could have significant implications for AD disease risk. Many other genes with bland unobtrusive names might also be involved in AD pathogenesis: they just did not seem scary.
I wanted the members of the forum to realize that the really interesting variants are likely still beyond grasp of current technology.
The variants that occur at a frequency of .1% or less were not on the commercial gene chips and are only now accessible to the research community through full genome scans. The recent deCODE study with 2,600 full AD genomes is the next wave of genetics research. These studies will finally unlock the genome and make analysis of a genome routine. As it is now, an exome
will contain thousands of "variants of unknown significance".
If you wait a year or two, this likely will all be sorted out. At that time a $50 Alzchip might be able to give you a precise risk assessment without the stress.