Increased burden of rare genetic variations found in schizophrenia

People with schizophrenia bear an "increased burden" of rare deletions and duplications of genetic material, genome-wide, say researchers supported in part by the National Institute of Mental Health (NIMH), a component of the National Institutes of Health (NIH). "Although many of us have these changes in our genetic material, they are about 15 percent more frequent in people with schizophrenia," explained Pamela Sklar, M.D., Ph.D., of Harvard University and the Stanley Center for Psychiatric Research. "We also discovered two large areas of chromosomal deletions that confer a great deal of risk for schizophrenia and confirm involvement of a third previously reported area."

Sklar and colleagues in the International Schizophrenia Consortium team, representing 11 research institutes worldwide, report on the largest study of its kind to date, online July 30, 2008, in the journal Nature.

"By implicating two previously unknown sites, this study triples the number of genomic areas definitely linked to schizophrenia," said NIMH Director R Thomas Insel, M.D. "It also confirms in a large sample that unraveling the secrets of rare structural genetic variation may hold promise for improved diagnosis, treatment and prevention of such neuro-developmental disorders."

Although recent smaller studies had identified such structural genetic glitches in schizophrenia, this genome-wide association study is the first large enough to detect weak signals that might otherwise be drowned out amid a din of statistical noise. Genetic factors are thought to account for 73 to 90 percent of schizophrenia, but most of these have so far eluded detection.

In search of rare illness-linked genetic variations, Sklar and colleagues scanned the genomes of 3,391 schizophrenia cases and 3,181 controls in a European sample.

The cases showed a subtle, but statistically significant increased number of such variations, which were found in 13.1 percent of cases and 10.4 percent of controls. Variations affected 1.41-fold more genes in people with schizophrenia, who also had a 1.45-fold higher prevalence of the rarest glitches – those that occurred only once.

The large sample also allowed the researchers to pinpoint previously undiscovered chromosomal locations associated with schizophrenia. An area on Chromosome 15 harbored deletions in 9 cases and no controls, while an area on Chromosome 1 had deletions in 10 cases and only one control.

"This tells us that variations in both of these areas are very potent risk factors for schizophrenia," said Sklar.

The researchers also confirmed in 13 cases a previously-reported association between schizophrenia and a deletion on chromosome 22 known to cause velo-cardio-facial syndrome. Other suspect sites identified were on Chromosomes 12 and 16 and in genes relevant to neural development and growth.

Exactly how the subtly increased number of structural variations in schizophrenia might translate into illness remains to be discovered, say the researchers.

The same sites of deletions on Chromosomes 1 and 15 reported by Sklar and colleagues, as well as an additional area on Chromosome 15, are also implicated in schizophrenia by another large study published online the same day in Nature by another international group of researchers supported in part by NIMH.

The International Schizophrenia Consortium is composed of researchers at: Cardiff University, Karolinska Institute/University of North Carolina at Chapel Hill, Trinity College Dublin, University College London, University of Aberdeen, University of Edinburgh, Queensland Institute of Medical Research, University of Southern California, Massachusetts General Hospital, Stanley Center for Psychiatric Research and Broad Institute of MIT and Harvard.

Source: NIH/National Institute of Mental Health