Schizophrenia linked for first time to chromosome region in study led by Stanford scientists

Stanford University School of Medicine scientists have played a major role in an international effort that has shown, for the first time, that modern genetic technologies can solve the riddle of how gene variations lead to schizophrenia.

Researchers at Stanford and 14 other institutions carried out a study of common DNA variations throughout the genome, and then combined forces with two independent studies to complete a pooled analysis of 27,000 individuals. The largest genetic differences between the study participants with and without schizophrenia were found on a stretch of chromosome 6 containing numerous genes associated with immune response (and some with other roles). This raises the possibility that immune function plays a role in schizophrenia.

Stanford's Jianxin Shi, PhD, and Douglas Levinson, MD, are first and second authors of one of three linked papers to be published online together in Nature on July 1. Their paper reports on the Molecular Genetics of Schizophrenia Project. This undertaking implicated a region of the human genome not previously suspected as a risk factor for schizophrenia. That finding was bolstered by another of the simultaneously published papers, which showed an even stronger association when the number of subjects was increased to almost 48,000, and identified significant association in two additional genes. The third paper shows that there are likely to be many common gene variations, perhaps hundreds or more, that have small effects in the risk of schizophrenia.

Taken together, "the papers present the first highly significant findings of gene regions associated with schizophrenia risk," said Levinson, professor of psychiatry and behavioral sciences, director of that department's Program on the Genetics of Brain Function, and the Walter E. Nichols, MD, Professor in the School of Medicine.

It is already known that schizophrenia — which strikes close to one in every 100 people — has a very strong genetic component, probably accounting for at least 80 percent of risk for this disease. However, unlike sickle-cell anemia or Huntington's disease, in which a defect at a single genetic location is responsible, most cases of schizophrenia are believed to involve interactions among a multitude of genes, with a variant of any single gene contributing only a tiny bit to a person's risk.

"That makes it hard to tease out, in a statistically significant way, any of these schizophrenia-associated genes," said Levinson. But it is feasible with very large numbers of subjects, he said. Finding genes involved in a multigenic trait can, at least in theory, be accomplished by means of so-called genome-wide association studies, in which DNA variations are measured in two large groups of people, one with a common pathology and the other without it.

To achieve the needed sample size, data from three independent studies were pooled and analyzed in a special way that corrected for differences in how those disparate studies were designed and run. Such a methodology is called a meta-analysis. Shi, a research scientist in Levinson's laboratory, designed and performed the meta-analysis on the resulting pooled-subject group, some 8,000 individuals with schizophrenia and 19,000 normal controls of European ancestry. (Restricting the study population to people of similar ancestry excludes numerous non-disease-related genetic differences that would otherwise be observed, Shi said.)