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Study Finds Rare, Large CNVs in Schizophrenia Cases

NEW YORK (GenomeWeb News) – Large, rare deletions and duplications may account for as much — or more — of the genetic risk for schizophrenia than SNPs and smaller CNVs, according to a new study appearing online today in PLoS Genetics.

An international team of investigators led by Duke University researcher David Goldstein genotyped hundreds of individuals with and without schizophrenia and followed up by assessing data on thousands of individuals from four independent cohorts. But their results failed to support the findings of several studies, leading the team to argue that many SNPs, candidate genes, and CNVs implicated in schizophrenia in the past may have been false positives.

"The literature is replete with dozens of genes and SNPs identified as associated with schizophrenia," lead author Anna Need, a post-doctoral associate at Duke University's Institute for Genome Sciences, said in a statement. "[W]e systematically retested all the leading candidates and concluded that most, if not all of them, are false positives."

When the researchers turned their attention from SNPs to CNVs they detected deletions and duplications in both individuals with schizophrenia and controls. But only rare large CNVs, bigger than two million bases, were exclusive to those with schizophrenia.

Despite the high heritability of schizophrenia, understanding the genetics of this neuropsychiatric disease has proven challenging for researchers. Previous studies have implicated a variety of SNPs, genes, and common and rare CNVs in the condition.

For the latest study Goldstein and his team genotyped 871 individuals with schizophrenia and 863 without. They then tested the top SNPs in four independent cohorts. Although they found several SNPs in those with schizophrenia, none of them reached genome-wide significance or could be definitively implicated in the disease. Their analyses also could not validate SNPs identified in other schizophrenia studies.

Based on their data and sample size, the researchers suggested that it's unlikely that common SNPs alone explain schizophrenia risk.

"While our sample size is not large enough to identify risk factors of small effect in the genome-wide context, we have introduced an approach for assessing whether our negative results are consistent with a model in which common SNPs explain most of the heritability in schizophrenia," the authors explained. "While this analysis shows that we cannot rule out such a possibility, it would require a large number of SNPs and an implausible genetic model."

The researchers subsequently turned their attention to structural variants, first looking for CNVs in data from three cohorts of individuals of European descent from Munich, Germany, (422 cases, 381 controls), Aberdeen, Scotland, (441 cases, 439 controls), and the US (150 cases and 264 controls). The team also looked at 60 cases and 64 control individuals of African descent.

While the researchers detected smaller deletions and duplications in both cases and controls, they found that only rare, large CNVs were exclusive to individuals with schizophrenia. They identified eight deletions larger than two million base pairs in those with schizophrenia, but none in the control group. The deletions were also absent in an additional 1,378 controls.

The schizophrenia-specific deletions affected chromosomes 22q11.2 and 1q21.1, regions previously linked to schizophrenia, as well as regions on chromosomes 16 and 8 that have not been previously associated with the disease.

In contrast, though, the researchers found little data supporting the notion that individuals with schizophrenia carry higher than usual levels of rare CNVs that are 100 kilobases or larger — an idea proposed last year. Even so, they did detect some CNVs in and around some genes shown to have structural variation in past schizophrenia studies — including APBA2, NRXN1, EFCAB2, and KIF26B.

Based on their results, the researchers speculated that cataloguing all of the rare genetic changes associated with schizophrenia could help define common pathways associated with schizophrenia or subtypes of the disease.

Still, the researchers noted that schizophrenia risk likely goes beyond structural variation alone. And, they suggest, different schizophrenia patients likely have distinct genomic causes for their conditions — including both CNVs and rare SNPs.

"What this means is that if we are going to make any real headway in assessing genetic links to schizophrenia, we will have to sequence the entire genome of each schizophrenia patient," Goldstein, director of Duke's Institute for Genome Sciences & Policy Center for Human Genome Variation, said in a statement. "That is a tremendous amount of work, but it is the only way we will be able to find these extremely rare variations."

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