A multi-national group of investigators, including a scientist at the University of North Carolina at Chapel Hill, has discovered that nearly a third of the genetic basis of schizophrenia may be attributed to the cumulative actions of thousands of common genetic variants. The effects of each of these genetic changes, innocuous on its own, add up to a significant risk for developing both schizophrenia and bipolar disorder.

The finding, published online July 1, 2009, in the journal Nature, suggests that schizophrenia is much more complex than previously thought, and can arise not only from both rare genetic variants but also from a significant number of common ones.

“This is an enormous first for our field,” said co-author Patrick Sullivan, M.D., Ray M. Hayworth and Family Distinguished Professor of Psychiatry in the department of genetics at the UNC School of Medicine. “You could say that we now have the outline of the puzzle, and we just need to take all of these pieces that we have identified and see how they fit them together.”

Schizophrenia is a chronic and often devastating mental illness that affects one person in every 100 in the course of their lives. Scientists have long recognized that the disease which can run in families — has a strong genetic component. However, only recently have they begun to pinpoint the exact spots in our genetic material that contribute to the illness. Last year, the International Schizophrenia Consortium found that rare chromosomal structural variants elevate the risk of developing schizophrenia.

In this study, Sullivan and other investigators in the Consortium used “genechip” technology to identify 30,000 genetic variants (single nucleotide polymorphisms or “SNPs”) that were more common in 3,000 individuals with schizophrenia than in 3,000 comparison subjects without schizophrenia. This pattern was found in three separate samples of individuals with schizophrenia and two samples with bipolar disorder indicating a previously unrecognized overlap between the two diseases. These risk variants were not present in patients with other non-psychiatric diseases, such as hypertension or diabetes.

“While our study finds a surprising number of genetic effects, we fully expect that future work will assemble them into meaningful pathways that will teach us about the biology of schizophrenia and bipolar disorder,” says senior author Pamela Sklar, MD, PhD, associate director of the Department of Psychiatry and Center for Human Genetic Research at Massachusetts General Hospital (MGH) and a senior associate member of the Broad Institute of MIT and Harvard.

The researchers are also investigating how genes and environment interact to cause the disease. One additional finding of their study was the identification of the human leukocyte antigen (HLA) locus as a possible risk factor. Because this region plays an important role in immune response to infection, it could suggest that exposure to an infectious agent increases risk of developing psychiatric disease.

Funding for the studies led at UNC came from the National Institutes of Mental Health, the Sylvan C. Herman Foundation and the Stanley Medical Research Institute.

In addition to those from UNC, the consortium includes investigators from the University of Aberdeen, Cardiff University, University of Edinburgh, Karolinska Institutet, Massachusetts General Hospital, the Queensland Institute of Medical Research, University of Southern California, Stanley Center for Psychiatric Research at the Broad Institute of Harvard and MIT, Trinity College Dublin and University College London.

Source: University of North Carolina

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A trio of genome-wide studies - collectively the largest to date - has pinpointed a vast array of genetic variation that cumulatively may account for at least one third of the genetic risk for schizophrenia. One of the studies traced schizophrenia and bipolar disorder, in part, to the same chromosomal neighborhoods.

“These new results recommend a fresh look at our diagnostic categories,” said Thomas R. Insel, M.D., director of the National Institute of Mental Health (NIMH), part of the National Institutes of Health. “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, each funded in part by NIMH, report separately on their genome-wide association studies online July 1, 2009, in the journal Nature. However, the SGENE, International Schizophrenia (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 (6p22.1), 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 Pamela Sklar, M.D., Ph.D., of Harvard University and the Stanley Center for Psychiatric Research, who co-led the ISC team with Harvard’s Shaun Purcell, Ph.D.

“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,” said 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.

“There was substantial overlap in the genetic risk for schizophrenia and bipolar disorder that was specific to mental disorders,” added Sklar. “We saw no association between the suspect gene variants and half a dozen common non-psychiatric disorders.”

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,” said Thomas Lehner, Ph.D., MPH, 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 (1p22.1) 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,” said Pablo Gejman, M.D., of the NorthShore University HealthSystem Research Institute, of 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.

References:
Jianxin S, et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. July 1, 2009, Nature


Stefansson H, et al. Common variants conferring risk of schizophrenia. July 1, 2009, Nature


Purcell SM, et al. Common polygenic variation contributes to risk of schizophrenia that overlaps with bipolar disorder. July 1, 2009, Nature

Source:
Jules Asher

NIH/National Institute of Mental Health

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