NEW YORK (GenomeWeb News) – Genetic variation in specific parts of the genome as well as genome-wide increases in rare copy number variants both play a role in schizophrenia, new research suggests.
In three papers appearing today — two in the online version of Nature and a third in Nature Genetics — international research teams used genome-wide approaches to define SNPs and copy number variants associated with schizophrenia. Taken together, the studies indicate that rare changes in chromosomal structure — particularly deletions and duplications — are more common in those with schizophrenia than in the general population. Each study also defined specific loci that heighten schizophrenia risk.
“This work opens up an entirely new way to think about schizophrenia and eventually will suggest new avenues for researching effective therapies for the sake of patients and families suffering from this terrible disorder,” Pamela Sklar, a researcher at the Broad Institute’s Stanley Center for Psychiatric Research who led one of the studies, said in a statement.
Schizophrenia is a mental condition afflicting roughly one percent of the population. It is characterized by delusions, hallucinations, and other social and cognitive defects. Although the majority of cases appear to have a genetic component, the precise causes and heritability patterns are largely unknown.
For the first paper, the International Schizophrenia Consortium, a collaborative group formed in 2006 involving researchers from 11 research institutions in Europe, the UK, and the US, looked for structural variants that bumped up schizophrenia risk. To do this, the team used high-density microarrays to analyze DNA from 3,391 individuals with schizophrenia and 3,181 of their unaffected relatives.
Their results suggest that those with schizophrenia are more likely to have the rarest genetic changes. Such CNVs were nearly one-and-a-half times more common in those with schizophrenia. Of these, larger deletions, shorter duplications, and variants affecting genes seemed to have the most pronounced effects.
The results are consistent with smaller studies published earlier this year, linking schizophrenia with rare mutations across the genome. And, based on such results, the authors of the latest research suggested that schizophrenia — and potentially other neuropsychiatric conditions — are “genomic disorders,” involving both genome-wide variants and specific risk loci.
The team also fingered specific CNVs around chromosomes 1 and 15 that significantly increased schizophrenia risk. Consistent with findings published in the International Review of Neurobiology in 2006, the team also detected a schizophrenia risk variant on chromosome 22.
“We now have strong and replicated evidence that individuals with schizophrenia have a greater burden of structural variation across their genomes,” the authors wrote. “Our data show that CNVs in at least three loci act as strong risk factors for schizophrenia in a minority of individuals.”
A second, independent study, conducted by researchers at Iceland’s DeCode Genetics and collaborators in Europe, China, and the US, not only confirmed the schizophrenia risk associated with these chromosome 1 and 15 deletions but also identified an additional risk variant on chromosome 15.
For that study, the researchers first identified dozens of rare, spontaneous CNVs in unaffected individuals by analyzing nearly 10,000 parent-to-offspring genetic transmissions to find CNVs that were present in children but not either parent.
They detected 66 new, spontaneous copy number variants, which they then tested for schizophrenia association in 1,433 individuals with schizophrenia and 33,250 unaffected controls. Finally, they validated their results in another group of 3,285 individuals with schizophrenia and 7,951 controls.
Their work suggested that the three deletions — two on chromosome 15 and one on chromosome 1 — increased schizophrenia risk by between three and 15 times.
Even so, CNVs appear to explain only a fraction of the schizophrenia’s overall genetic risk, the authors conceded. That means further analysis will be needed to understand how these and other variants contribute to schizophrenia.
“CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia,” the authors wrote. “To determine diagnostic and treatment implications it is also important to study the CNVs conferring risk with respect to drug response, disease progression, and symptomatology.”
In a third paper, published online today in Nature Genetics, an international team of researchers led by Cardiff University psychological medicine researcher Michael Owen tested a dozen loci identified through genome-wide association studies on 479 individuals with schizophrenia and 2,937 controls as well as a larger replication dataset. That work revealed three risk loci on chromosomes 2, 11, and 16, with the strongest of these mapping to a region on chromosome 2 near a gene called ZNF804A.