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Common Gene Variants Implicated in Schizophrenia

Three international research teams have detected many tiny and common gene variations that together could account for at least one-third of the genetic risk for schizophrenia. Although none of these variants alone significantly boosts the chances of developing schizophrenia, in combination they seem to exert a powerful effect on disease risk.

Schizophrenia is a severe brain disorder that affects about 1 in 100 adults nationwide. Symptoms usually first appear in older teens or young adults. Those affected sometimes hear voices others don't hear, believe that others are broadcasting their thoughts to the world or become convinced that others are plotting to harm them.

Scientists estimate that at least 70% of schizophrenia cases can be traced to inherited gene variants. Earlier reports identified several large but rare gene deletions or duplications that raise schizophrenia risk. However, schizophrenia arises from a complex set of genetic and environmental factors that are still largely unknown.

In the new studies, 3 research consortia—each supported in part by NIH's National Institute of Mental Health (NIMH)—independently performed genome-wide analyses of thousands of patients with and without schizophrenia. They tested for hundreds of thousands of tiny variations called single nucleotide polymorphisms (SNPs) in strands of DNA. They then shared their data with each other, which allowed a combined analysis of more than 8,000 patients with schizophrenia and 19,000 people who didn't have the disorder. Their findings were reported in the advance online edition of Nature on July 1, 2009.

All 3 studies found a link between schizophrenia and a region of chromosome 6 that is known to harbor genes involved in the immune system and in controlling how and when genes turn on and off. This genetic hotspot lends support to the notion that immune system dysfunction may play a role in schizophrenia.

Another possible link to immune involvement was found on chromosome 1, where a variant gene previously implicated in multiple sclerosis, an autoimmune disorder, was also associated with schizophrenia risk. The researchers believe that other variants found on chromosomes 11 and 18 might help account for the thinking and memory deficits of schizophrenia.

One of the research teams traced schizophrenia and bipolar disorder, in part, to the same chromosomal neighborhoods. “There was substantial overlap in the genetic risk for schizophrenia and bipolar disorder that was specific to mental disorders,” says study co-leader Dr. Pamela Sklar of Harvard University. “We saw no association between the suspect gene variants and half a dozen common non-psychiatric disorders.”

These and earlier findings could eventually lead to multi-gene tests to aid the diagnosis and treatment of schizophrenia. As more is learned about the gene pathways involved in the disorder, it may be possible to sort out what's shared by, or unique to, schizophrenia and other mental disorders.