Rare variants with small disease risk may be extremely

d

Rare variants with small disease risk may be extremely

difficult to detect, since prohibitively large sample sizes may be required to demonstrate any significant association. It is likely, however, that even after the identification of all common and rare risk variants a substantial fraction of the familial clustering will remain unexplained. This “missing heritability” in complex diseases is the subject of intense debate and several potential explanations have been proposed, including epistasis and epigenetic mechanisms.62-64 Inhibitors,research,lifescience,medical It will be necessary to apply VE-821 clinical trial specific research strategies to further investigate this issue, although these may require prohibitively large sample sizes or tissue samples that are difficult to access in human subjects. It is not yet clear whether any of the association findings identified by GWASs represent causal variants. Systematic resequencing of the associated genomic regions will provide a comprehensive overview of such variants. In cases where Inhibitors,research,lifescience,medical association findings are due to linkage disequilibrium,

it is possible that the causal variants have a stronger genetic effect than has been previously suspected. It is also theoretically possible that a given association finding is not attributable to a common causal variant. A simulation study has shown that the “synthetic” Inhibitors,research,lifescience,medical effect of multiple rare variants may Inhibitors,research,lifescience,medical be responsible for signals detected for common variants. It has also been shown that the location of these variants may be relatively far (up to 2 megabases) from the site identified in GWASs.65 If this were the case for an associated locus, resequencing over large genomic distances in large samples would be required to identify the true causative variants. Ultimately, it is necessary to identify a direct functional effect for each potential causal variant, such as an effect on the function or expression of a gene. GWASs performed to date have indicated that certain genes contribute to a susceptibility

to both schizophrenia and bipolar disorder. It is clear that some of these Inhibitors,research,lifescience,medical genes convey a rather nonspecific susceptibility that overlaps diagnostic boundaries, and it is highly probable that this also overlaps aminophylline with other psychiatric disorders. Other genes, however, convey specific effects. Future studies of the phenotypic dimensions that are most strongly associated with a specific gene will include analysis of clinical symptoms and endophenotypes. The latter may be particularly suited to guiding researchers in the selection of the most promising phenotypes for animal studies.66 The identification of disease-associated genes is likely to increase our knowledge of the underlying pathophysiology of psychiatric disorders in an as-yet unforeseen manner. The identification of biological pathways has the potential to revolutionize diagnostics and treatment.

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