Schizophrenia – Suspected Common Genetic Variants Soar From 30 to 108
According to an article published online in the journal Nature (21 July 2014), the largest genomic dragnet of any psychiatric disorder to date has unmasked 108 chromosomal sites harboring inherited variations in the genetic code linked to schizophrenia, 83 of which had not been previously reported. By contrast, the skyline of such suspect variants associated with the disorder contained only 5 significant peaks in 2011. The newfound genomic signals are not simply random sites of variation, but converge around pathways underlying the workings of processes involved in the disorder, such as communication between brain cells, learning and memory, cellular ion channels, immune function and a key medication target. The publication comes out of The Schizophrenia Working Group of the Psychiatric Genomic Consortium (PGC) report on its genome-wide analysis of nearly 37,000 cases and more than 113,000 controls. The NIMH-supported PGC represents more than 500 investigators at more than 80 research institutions in 25 countries.
According to the NIH, while the suspect variation identified so far only explains about 3.5% of the risk for schizophrenia, these results warrant exploring whether using such data to calculate an individual’s risk for developing the disorder might someday be useful in screening for preventive interventions. The NIH added that even based on these early predictors, people who score in the top 10% of risk may be up to 20-fold more prone to developing schizophrenia.
Prior to the new study, schizophrenia genome-wide studies had identified only about 30 common gene variants associated with the disorder. Sample sizes in these studies were individually too small to detect many of the subtle effects on risk exerted by such widely shared versions of genes. The PGC investigators sought to maximize statistical power by re-analyzing not just published results, but all available raw data, published and unpublished. Their findings of 108 illness-associated genomic locations were winnowed from an initial pool of about 9.5 million variants.
A comparison of the combined study data with findings in an independent sample of cases and controls suggest that considerably more such associations of this type are likely to be uncovered with larger sample sizes. There was an association confirmed with variation in the gene that codes for a receptor for the brain chemical messenger dopamine, which is known to be the target for antipsychotic medications used to treat schizophrenia. Yet evidence from the study supports the view that most variants associated with schizophrenia appear to exert their effects via the turning on and off of genes rather than through coding for proteins. The study also found a notable overlap between protein-related functions of some linked common variants and rare variants associated with schizophrenia in other studies. These included genes involved in communication between neurons via the chemical messenger glutamate, learning and memory, and the machinery controlling the influx of calcium into cells.
Among the strongest associations detected, as in in previous genome-wide genetic studies, was for variation in tissues involved in immune system function. Although the significance of this connection for the illness process remains a mystery, epidemiologic evidence has long hinted at possible immune system involvement in schizophrenia. Findings confirm that it’s possible to develop risk profile scores based on schizophrenia-associated variants that may be useful in research — but for now aren’t ready to be used clinically as a predictive test. The authors noted that the associated variations detected in the study may not themselves be the source of risk for schizophrenia, rather, they may be signals indicating the presence of disease-causing variation nearby in a chromosomal region.
Follow-up studies are being designed to pinpoint the specific sequences and genes that confer risk. The PGC is also typing genes in hundreds of thousands of people worldwide to enlarge the sample size, in hopes of detecting more genetic variation associated with mental disorders. Successful integration of data from several GWAS studies suggests that this approach would likely be transferrable to similar studies of other disorders, say the researchers.