01 July 2009

Genetic Schizophrenia Risk

"Schizophrenia is a severe mental disorder . . . characterized by hallucinations, delusions and cognitive deficits."

[G]enetic factors, estimated to account for 80 percent of the total risk of getting schizophrenia . . . . a person with schizophrenia probably has hundreds or thousands of risk-increasing variants. . . .

[E]ach of . . . three studies compared several thousand DNA samples from people diagnosed with schizophrenia with samples from thousands of others, some healthy and some with other diseases. Association studies are designed to find single letter differences, called SNPs, at many points along the DNA. Such variants popping up more frequently in the schizophrenia patients’ DNA are presumed to markers of regions of the genome that contribute to the disease.

Many thousands of common DNA variants (those found in about 5 percent of the total population) turned up more often in people with schizophrenia . . . . On their own, each variant identified in the new studies raises the risk of schizophrenia just slightly — from 1 percent (the risk in the general population) to, in some cases, around 1.2 percent. Collectively, common variants may account for about a third of the overall genetic risk of schizophrenia. . . . Other factors that contribute to genetic risk include variations in the number of copies of certain genes and rare but high-risk variants of specific DNA letters. . . .

Although few of the variants could be identified conclusively . . . some of the variants were found in stretches of the genome previously linked to schizophrenia. Such regions occurred near genes involved in the formation of brain cell connections and genes involved in controlling the activity of other genes. . . . DNA variations in a region of chromosome 6 called the major histocompatibility complex were also found in the schizophrenia patients’ DNA . . . This region contains genes that make proteins that are important for immune system function. Earlier studies have suggested a link between disruptions in the immune system with a heightened risk of schizophrenia. . . .

If the link between immunity and schizophrenia is confirmed, treatments for autoimmune diseases may also prove useful for alleviating the psychiatric disease, . . . currently only 30 to 40 percent of schizophrenia patients respond well to treatments.

From here.

Schizophrenia is increasingly looking like the mental health equivalent of friction, the cumulative effect of lots of little issues.

The variation frequency model is consistent with the empirical fact that prevalence of schizophrenia is more even than many heavily genetic conditions. Prevalence a condition with many more or less independent genetic sources is evened out by the law of averages; prevalence of a condition caused by a few key genes should vary more from population to population. It is also consistent with the empirical evidence that schitzophrenia is paternal age related, which would suggest that a variety of random genetic mutations can make it more likely. One would not expect age related mutations to be tied to a small number of specific SNPs, but would expect it to be tied to the overall number of mutations in a person's genome.

The report I read did not identify any "typing" that distinguishes, for example, between the genetic issues in treatment responsive schizophrenia, and those in individuals not responsive to drugs. The studies are suggestive, however, of the possibility that schizophrenia might be a matter of degree rather than an all or nothing affair. Someone with 500 risk producing variants might be prone, all other things being equal, to have a milder case of schizophrenia than someone with 5000 risk producing variants.

One of the studies also suggested that cumulative component of genetic risk (but not the immune system component of genetic risk) may overlap between schizophrenia and bipolar disorder.

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