Researchers in the U.S. and U.K. reveal genetic commonalities in schizophrenia and bipolar disorder
CARDIFF, Wales—Studies in the United States and abroad are taking an in-depth look at schizophrenia and bipolar disorder. A study being conducted by British researchers from the MRC Centre for Neuropsychiatric Genetics and Genomics at Cardiff University have revealed thousand of genetic contributions to schizophrenia and bipolar disorder, while in the U.S., a trio of genome-wide studies—collectively the largest to date—have pinpointed a vast array of genetic variations that cumulatively may account for at least one-third of the genetic risk for schizophrenia.
Scientists from the MRC Centre for Neuropsychiatric Genetics and Genomics at Cardiff University, working as part of an international research team, have discovered that most of the genetic basis of schizophrenia comes from the accumulation of small effects from thousands of common genetic variants. Many of these genetic effects are also shared by individuals with bipolar disorder.
In a novel use of genome chip data, the International Schizophrenia Consortium (ISC) found thousands of genetic variants had small influences separately but together make a strong impact on a person's risk for developing schizophrenia and bipolar disorder, in a report published online July 1 by the journal Nature.
"The very large number of genetic contributions surprised us initially yet we observed the same pattern across multiple samples, making us confident that we were measuring something real and relevant," says Michael O'Donovan, professor of psychiatric genetics at the MRC Centre for Neuropsychiatric Genetics and Genomics.
Schizophrenia is a common, chronic and often devastating brain disorder characterized by persistent delusions and hallucinations. It affects about 1 person in 100 and usually strikes in late adolescence or early adulthood.
Despite the availability of effective treatments, the course of the illness is usually chronic and response to treatments is often limited, leading to prolonged disability and personal suffering. Family history, which signifies genetic inheritance, is a strong risk factor for schizophrenia and bipolar disorder. Last year, the ISC found that rare chromosomal deletions and duplications of all types elevate risk of developing schizophrenia.
Formed in 2006, the ISC is led by senior researchers from 11 institutes in Europe and the USA. Crucial to the success of the project was the willingness of consortium groups to pool DNA resources that have taken them years to collect, totaling 3,391 individuals with schizophrenia and 3,181 related individuals without the disorder.
The investigators used new genomic technologies and novel analytical techniques. Based upon the theoretical models of consortium members Drs. Naomi Wray and Peter Visscher (Queensland Institute of Medical Research, Brisbane, Australia), the consortium tested hundreds of thousands of genetic variants to find those more common in patients with schizophrenia than in people without the disorder.
They then went on to test a subset of about 30,000 of these variants in additional people with schizophrenia and also in people with bipolar disorder. The critical finding was that the same large group of genetic variants was found in the new samples of schizophrenia patients, even when they were collected by many different investigators and tested in different laboratories.
Surprisingly, this group of schizophrenia-related variants was also more common in people with bipolar disorder. These results are at odds with the orthodoxy in psychiatry that the two disorders are distinct. The finding was relatively specific to psychiatric disorders rather than general illness, since the variants were not found in excess in people with a range of other diseases such as diabetes and heart disease.
"Over the past year, using techniques designed to study common DNA changes, psychiatric disease geneticists have detected more statistically compelling findings than in the previous 100 years," says Eric Lander, founding director of consortium partner The Broad Institute, and a member of the President Obama's Council of Advisors on Science and Technology.
"If some of the same genetic risks underlie schizophrenia and bipolar disorder, perhaps these disorders originate from some common vulnerability in brain development. Of course the big question then is how some people develop schizophrenia and others develop bipolar disorder," adds Dr. Thomas Insel, director of the National Institute for Mental Health (NIMH), which partially funded the Cardiff study.
One of the studies being conducted in the United States traced schizophrenia and bipolar disorder, in part, to the same chromosomal neighborhoods.
"These new results recommend a fresh look at our diagnostic categories," Insel says. "If some of the same genetic risks underlie schizophrenia and bipolar disorder, perhaps these disorders originate from some common vulnerability in brain development."
Three schizophrenia genetics research consortia, are also each funded in part by NIMH, report separately on their genome-wide association studies online in July in the journal Nature.
However, the SGENE, the ISC and Molecular Genetics of Schizophrenia (MGS) consortia shared their results—making possible meta-analyses of a combined sample totaling 8,014 cases and 19,090 controls.
All three studies implicate an area of Chromosome 6, which is known to harbor genes involved in immunity and controlling how and when genes turn on and off. This hotspot of association might help to explain how environmental factors affect risk for schizophrenia. For example, there are hints of autoimmune involvement in schizophrenia, such as evidence that offspring of mothers with influenza while pregnant have a higher risk of developing the illness.
"Our study was unique in employing a new way of detecting the molecular signatures of genetic variations with very small effects on potential schizophrenia risk," explained Dr. Pamela Sklar, of Harvard University and the Stanley Center for Psychiatric Research, who co-led the ISC team with Harvard's Dr. Shaun Purcell.
"Individually, these common variants' effects do not all rise to statistical significance, but cumulatively they play a major role, accounting for at least one-third—and probably much more—of disease risk," says Purcell.
Among sites showing the strongest associations with schizophrenia was a suspect area on Chromosome 22 and more than 450 variations in the suspect area on Chromosome 6. Statistical simulations confirmed that the findings could not have been accounted for by a handful of common gene variants with large effect or just rare variants. This involvement of many common gene variants suggests that schizophrenia in different people might ultimately be traceable to distinct disease processes, say the researchers.
Sklar adds there was substantial overlap in the genetic risk for schizophrenia and bipolar disorder that was specific to mental disorders.
"We saw no association between the suspect gene variants and half a dozen common non-psychiatric disorders," he says.
Still, most of the genetic contribution to schizophrenia, which is estimated to be at least 70 percent heritable, remains unknown.
"Until this discovery, we could explain just a few percent of this contribution; now we have more than 30 percent accounted for," says Dr. Thomas Lehner, chief of NIMH's Genomics Research branch. "The new findings tell us that many of these secrets have been hidden in complex neural networks, providing hints about where to look for the still elusive—and substantial—remaining genetic contribution."
The MGS consortium pinpointed an association between schizophrenia and genes in the Chromosome 6 region that code for cellular components that control when genes turn on and off. For example, one of the strongest associations was seen in the vicinity of genes for proteins called histones that slap a molecular clamp on a gene's turning on in response to the environment. Genetically rooted variation in the functioning of such regulatory mechanisms could help to explain the environmental component repeatedly implicated in schizophrenia risk.
The MGS study also found an association between schizophrenia and a genetic variation on Chromosome 1, which has been implicated in multiple sclerosis, an autoimmune disorder.
"Our study results spotlight the importance not only of genes, but also the little-known DNA sequences between genes that control their expression," adds Dr. Pablo Gejman, of the NorthShore University HealthSystem Research Institute, in Evanston, Ill., who led the MGS consortium team. "Advances in biotechnology, statistics, population genetics, and psychiatry, in combination with the ability to recruit large samples, made the new findings possible."
The SGENE consortium study pinpointed a site of variation in the suspect Chromosome 6 region that could implicate processes related to immunity and infection. It also found significant evidence of association with variation on Chromosomes 11 and 18 that could help account for the thinking and memory deficits of schizophrenia.
The new findings could eventually lead to multi-gene signatures or biomarkers for severe mental disorders. As more is learned about the implicated gene pathways, it may be possible to sort out what's shared by, or unique to, schizophrenia and bipolar disorder, the researchers say.