Cheung VG, Spielman RS, Ewens KG, Weber TM, Morley M, Burdick JT.
Mapping determinants of human gene expression by regional and genome-wide association.
Nature. 2005 Oct 27;437(7063):1365-9.
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With the completion of the HapMap and its commercialization by Illumina and Affymetrix, it should be possible for researchers to find susceptibility alleles which have an odds ratio of >2 for any disorder, including Alzheimer disease, over the next couple of years. The expense will be high: Sample sizes of about 500 cases and 500 controls will be needed, and the cost per sample is on the order of $900. But if there are anymore genes with the effect size of ApoE out there, for AD or other diseases, we should now be able to find them.
Q&A with Lars Bertram.
Q: Does the map provide enough resolution?
A: On average, the haplotype map has investigated about 1 SNP every 5,000 bases (i.e., 5 kb). For most applications this density should be sufficient to allow linkage disequilibrium mapping of common variants with at least moderate effects in genetically complex diseases. However, a phase 2 of the HapMap is planned which will probably more than quadruple this resolution.
Q: Is there anything particular about Alzheimer disease that makes
haplotyping any more or less useful than for other diseases?
A: The good news for AD is that its heritability, even of the late-onset form, is relatively well established. Even after excluding the effects of ApoE, this means that there are probably several additional genetic risk factors waiting to be identified. The bad news is that AD is a late-onset disease which usually means that parents are deceased when their offspring develop the disease and no parental samples are available to precisely reconstruct
("phase") haplotypes. Nonetheless, the HapMap data was assembled based on child-parent trios, so much of the haplotype phasing has already been done.
Q: Will the HapMap help in complex diseases, where several variants on
different chromosomes must interact, for example?
A: While the HapMap has many valuable uses in designing and interpreting future genetic association in AD and other diseases, it will unfortunately not help to better understand interactions between different genetic loci or non-genetic factors, because such interactions likely vary from phenotype to phenotype.
Q: Will the HapMap help in diseases where gene silencing, mRNA
splicing, and other post-transcriptional and post-translational
modifications are key to the pathophysiology?
A: If these pathophysiological changes are actually caused by common genetic variants in the genome, HapMap will definitely help us find them. It will still require a good number of experiments, though, to actually prove the causal relationship between associated SNPs on the one hand, and differences in mRNA splicing (for instance) on the other hand.
Q: Is the principle of tagging haplotypes scientifically sound, or
does it run the risk of missing out on haplotypes that are low in
frequency but high
A: The principle of tagging haplotypes to cover untyped common genetic variants is certainly sound, and—with the data provided by the current HapMap release—has just become a whole lot easier. As everything in science, it does have limitations (such as finding very low-frequency polymorphisms or haplotypes). However, this is a rapidly evolving field and the planned phase 2 release of the HapMap, together with novel analytic strategies, should facilitate even the search for such uncommon variants in the near future.