Looking for a new schizophrenia drug is probably like looking for a needle in a haystack, but as of today, the haystack got a lot smaller.
Using a genome-wide association study of more than 150,000 people, researchers found around 100 genetic variants that contribute to schizophrenia, more than tripling the known number of locations associated with the mental illness, according to a paper published in the journal Nature.
Schizophrenia is a peculiarly loaded disease. Its biological roots "have often been denied," according to an editorial accompanying today's paper. Most damagingly for patients, some doctors in the 1970s didn't believe it was a real illness. Because of its heritability, some researchers such as Ernst Rüdin have said that patients shouldn't have children -- justifying sterilization and murder of the mentally ill.
Today's findings show the illness is heavily-genetically influenced. All of the genetic variants are common, contributing to most - or possibly all -- cases of schizophrenia.
Genome-wide association studies generally find a genetic locus -- a neighborhood -- rather than a specific gene that causes all the trouble. Still, the loci are close to certain genes we know to be involved with brain function.
One previous hypothesis for schizophrenia suggested abnormal signalling from neurons, using dopamine as a transmitter; researchers had noticed that the efficacy of antipsychotic drugs was linked to dopamine blockades. This theory may be validated -- since a dopamine-receptor gene, DRD2 was found to be associated with the illness. Other dopamine genes were untouched.
But the most significant association may be the loci found in areas of the genome associated with the immune system. An association on chromosome 6 -- the strongest association found -- suggested that the major histocompatibility complex is somehow involved. The MHC binds fragments of pathogens to the surface of cells, marking them for destruction by the immune system's T cells. Some of the other links are to areas that help govern acquired immunity -- that is, immunity to pathogens the body has seen before.
If schizophrenia is somehow linked to misfires of the immune system, it may open new avenues for treating the disease; the immune system wasn't even considered a major culprit in the illness until now. Previous epidemiological evidence has suggested that babies whose mothers were sick with flu during pregnancy were more likely to be schizophrenic later in life.
The findings are especially important because no drugs with new methods of action have been introduced against schizophrenia since the 1950s -- the antipsychotics. A second generation of these medications was introduced in the 1990s. In the last 10 years, Eli Lilly & Co. attempted to target schizophrenia using another drug, one that targeted the brain transmitter glutamate. Unfortunately, that drug was no better than placebo in phase 2 clinical trials. Targeting the DRD2 gene may lead to new drugs, and the immune system's involvement suggests other methods might be worth trying as well.
Of course some of the gene associations found may be due to the environment. Many schizophrenics smoke; variations in a certain gene cluster (with thte memorable name of CHRNA5-A3-B4) are known to be associated with heavy smoking. This cluster was tagged by today's researchers -- but it may not be directly involved with the disease. Rather, it may be an indirect effect of schizophrenia. Probably other indirect genes have been tagged as well; researchers now are tasked with sorting through today's results to find the most promising targets, leaving aside genetic associations that might be secondary or indirect.
