A multi-national group of investigators 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.
Schizophrenia and bipolar disorder share genetic roots that appear to be specific to serious mental disorders, and are not shared by non-psychiatric illnesses. Bars representing different study samples show that the same genetic variations that account for risk in both mental disorders account for virtually none of the risk for coronary artery disease (CAD), Crohn’s disease (CD), hypertension (HT), rheumatoid arthritis (RA), or Type 1 (T1D) or Type 2 (T2D) 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.
Genetic Details of the Findings
Three schizophrenia genetics research consortia reported separately on their genome-wide association studies. 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.
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.
Still, most of the genetic contribution to schizophrenia, which is estimated to be at least 70 percent heritable, remains unknown.
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.
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.
Source: University of North Carolina