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Results from the first genome-wide study assessing common genetic variation in schizophrenia show that the disease is caused, at least in part, by large, rare structural changes in DNA referred to as copy number variants - not the tiny, single letter alterations known as "snips" that scientists have pursued for years.

The findings, published February 6 in the open-access journal PLoS Genetics, support the "need for a sharp turn in the direction of schizophrenia genetics research," says David Goldstein, PhD, senior author of the study and director of the Center for Human Genome Variation at the Duke Institute for Genome Sciences & Policy.

Schizophrenia is one of the most common psychiatric disorders in the world, and it tends to run in families. But scientists have been hard-pressed to come up with any significant genetic links. Over the past two decades, dozens of possible genes and single nucleotide polymorphisms (SNPs or "snips") have been identified as possible candidates, but the current study dismisses all of them.

"The literature is replete with dozens of genes and SNPs identified as associated with schizophrenia," says Anna Need, PhD, a postdoctoral associate in the Center for Human Genome Variation and lead author of the study. "But we systematically retested all the leading candidates and concluded that most, if not all of them, are false positives."

So how could so many studies be so wrong?

Need says earlier research was undoubtedly done in good faith, but she believes the studies were too small to properly assess the role of SNPs.

Goldstein and Need worked with more than a dozen other geneticists in scanning the genome of schizophrenia patients and healthy controls for SNPs and copy number variants (CNVs). While none of the previously heralded SNPs appeared significant in schizophrenia, several CNVs emerged as potentially causative.

Copy number variants are common throughout the genome, usually appearing as deletions or duplications of significant stretches of DNA. They come in all sizes, but Goldstein says it is the largest deletions - those over two million bases long - that appear only in people with schizophrenia, and may be unique and causative in those individuals.

"We were fortunate to have an ongoing study in which we were assessing the cognitive abilities of healthy volunteers. When we looked for these extra-large deletions in more than 1500 participants, we didn't find any deletions larger than 1.5 million bases in them," says Need.

In schizophrenia patients, however, researchers found eight deletions larger than two million bases.

Of the eight deletions, four had been identified earlier as associated with schizophrenia and two were new, one at a genetic region referred to as 8p22 on chromosome 8 and one at 16p13.11-p12.4, a range of chromosome 16. Interestingly, one of the two newly-identified CNVs deletes a gene that interacts with DISC1, a gene that has already been shown to cause psychiatric illness in one family.

While CNVs have been previously implicated in schizophrenia and other psychiatric conditions, the Duke researchers are the first to argue that the rarity of extremely large deletions suggest they are indeed pathogenic, at least in a small number of patients.

"What this means is that if we are going to make real headway in assessing genetic links to schizophrenia, we will have to sequence the entire genome of each schizophrenia patient," says Goldstein. "That is a tremendous amount of work, but it is the only way we will be able to find these extremely rare variations."

The research team at Duke has already begun that work using next-generation sequencing technologies developed by co-lead author Dongliang Ge. The project is designed to identify genetic variables that may explain why some patients respond to therapy and others do not.

Additional colleagues from Duke who participated in the study include co-lead author Michael Weale, Jessica Maia, Sheng Feng, Erin Heinzen, Kevin Shianna, Woohyun Yoon, Warren Strittmatter, Joseph McEvoy, Richard Keefe and Allen Roses.