July 05, 2005

Genetics of Complex Diseases

Read more... Schizophrenia Biology

A team of scientists at Johns Hopkins University have just announced that susceptibility to a certain complex birth defect is not related to normal gene inheritance. Instead of occuring within a section of gene that codes for a protein molecule, the anomoly occurs in a section of gene that regulates the expression of other genes. This type of interaction, where one gene influences the activity of another, is known as epigenetic interaction. Ways that one gene can influence another include sequences that determine the probability that a gene is turned on (making protein) or off, how much of the protein product it makes, and with what frequency.

"Our finding really underscores the fact that health and disease can be affected by all regions of a gene," says study leader Aravinda Chakravarti, Ph.D., director of the McKusick-Nathans Institute of Genetic Medicine. "For diseases like diabetes and heart disease, just as for Hirschsprung disease, multiple inherited factors contribute to the disease, and these factors are not just going to be in protein-coding regions."

Epigenetic interactions may be a place to look for schizophrenia or bipolar genetic susceptibility as well. It is well-known that while a family history increases one's risk for developing serious psychiatric diseases (see http://www.schizophrenia.com/research/hereditygen.htm), the genetic heritability is not a simple, single-gene affair. It is not a matter of gene-X coding for schizophrenia traits, and the presence of gene-X determines the presence or absence of that disease trait. Monozygotic identical twin studies have shown us that even if two people have the exact same genotype, one may still develop schizophrenia or bipolar disorder while the other will not.

Searching for epigenetic factors in schizophrenia and other heritable psychiatric disorders can provide both new hypotheses for causes, and new targets for treatment. For example, valproic acid - a mood stabilizer used to treat bipolar disorder - seems to have an effect on the epigenetics of gene expression, in that it affects the chromatin structure (proteins that DNA is wrapped around when it is not being expressed) that determines which genes are being expressed and when (source: Schizophr Res. 2005 Jan 1;72(2-3):79-90
). Epigenetic factors that affect gene regulation may partially explain why there is such a wide variability in symptom severity, disease course, and family heritability. There are also many environmental factors to consider (see http://www.schizophrenia.com/hypo.html)

Searching for non-coding, epigenetic regions of DNA that are associated with schizophrenia and bipolar disorder may help scientists to determine exactly what effects they are are having on gene expression in the brain, and what can be done to normalize regulation.

More recent papers on epigenetics and schizophrenia (abstracts available at http://www.pubmed.com):

1) Schizophrenia, epigenetics and ligand-activated nuclear receptors: a framework for chromatin therapeutics. Schizophr Res. 2005 Jan 1;72(2-3):79-90.

2) Genetics and Epigenetics in Major Psychiatric Disorders: Dilemmas, Achievements, Applications, and Future Scope. Am J Pharmacogenomics. 2005;5(3):149-160.
3) Incidental neurodevelopmental episodes in the etiology of schizophrenia: an expanded model involving epigenetics and development. Clin Genet. 2004 Jun;65(6):435-40.

Source article: Gene Regions Beyond Protein Instructions Important In Disease. Science Daily (http://www.sciencedaily.com), July 4 2005.


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