A 15-year study in more than 100 families and 1,000 subjects provides the first reliable evidence of genetic susceptibility to schizophrenia, within a stretch of DNA on human chromosome 13. The association of DNA with the susceptibility to the disease, reported by a Johns Hopkins-led international team, is the first such linkage to meet stringent statistical standards.

"Finding an actual gene for schizophrenia susceptibility will be like finding a particular house in a large city," said genetic epidemiologist Ann Pulver, who led the study. "But we've found the city. It's a first step, and an exceedingly important one."

The study, reported in this month's Nature Genetics, also suggests that different genes may be responsible for the disease in different families.

Most experts agree schizophrenia is a condition influenced by both genes and environment. In studies of identical twins, for example, where only one twin develops schizophrenia, the other twin has a 46 percent chance of having the disorder. That's higher than the 1 percent rate for the general population but not the near 100 percent expected if genes are the only cause. "It's not the case that if you have the gene, you have the disease," Pulver said. "The genetic effect is one of susceptibility to schizophrenia."

Unlike such inherited disorders as sickle cell anemia, which stems from mutation in a single gene, susceptibility to schizophrenia involves more than one gene, Pulver said, as well as environmental factors. In the new study, the researchers took and evaluated blood samples from 54 patients diagnosed with either schizophrenia or schizoaffective disorder, a type of schizophrenia with elements of depression, mania or both. Researchers also took and evaluated samples from patients' extended families. They extracted blood cell DNA and scanned it with molecular probes, looking for particular sequences of DNA that were more likely to appear in those with the mental illness than those without it. By noting where these markers lay on chromosomes, the researchers further narrowed the address for the susceptibility genes. A second study of 51 more families verified the first results.

The research team also found evidence for susceptibility on chromosomes 8 and 22, though neither had the statistical strength of the chromosome 13 area.

Other labs have reported such "linkages" in the past, on chromosomes 5 and 6. "But there's been a failure to reach high statistical significance," Pulver said, in part because the targeted groups of schizophrenic patients were too diverse genetically. The likelihood of the linkage found on chromosome 13 being due to chance alone, Pulver said, is about two in 100,000.

Many studies show blood relatives of schizophrenia patients are at risk for several personality disorders as well as for schizophrenia, Pulver said. A second part of the study suggests different genes may come into play with different types of the disorders. Using descriptions of all the family members in the study, the researchers formed two subgroups: one where at least one family member had a schizophrenia-like personality disorder and another where a family member had a mood disorder with hallucinations and/or delusions.

Then they re-examined the data, focusing on chromosomes 13, 8 and 22. The results showed that families in the study with the schizophrenic-like personality disorders were more likely to have genetic ties to chromosomes 8 and 13, whereas those leaning toward the mood disorder were missing ties to chromosome 8.

"We'd like to see these results repeated," said Pulver, who's planning new genetic studies on the varied forms of the disease.

This study was funded by grants from the National Institute of Mental Health and from Novartis Pharmaceuticals and from donations by individuals. Co-researchers from Hopkins were Paula S. Wolyniec, Gerald Nestadt, Mary Thornquist, Gail Ullrich, John McGrath, Laura Kasch, Malgorzata Lamacz, Virginia K. Lasseter, Karin Neufeld, Marion G.Thomas, Karen L. Swartz and Barton Childs.