In the largest genomic dragnet of any psychiatric disorder to date, researchers have unmasked 108 chromosomal sites harboring inherited variations in the genetic code linked to schizophrenia, of which 83 have never been previously reported. The study was funded by the National Institute of Mental Health (NIMH), a part of the National Institutes of Health (NIH).
The Schizophrenia Working Group of the Psychiatric Genomic Consortium (PGC), which consists of more than 500 investigators at over 80 research institutions, recently reported on its genome-wide analysis of nearly 37,000 cases and more than 113,000 controls in the journal Nature. The newly discovered genomic signals are not just random sites of variation, but move around pathways involving certain processes involved in the disorder such as communication between brain cells, learning and memory, cellular ion channels, immune function, and a key medication target.
Prior to the new study, only about 30 common gene variants associated with the disorder were identified due to small sample sizes. The PGC investigators found 108 illness-associated genomic locations from an initial pool of about 9.5 million variants.
Researchers confirmed an association with variation in the gene that codes for a receptor for the brain chemical messenger dopamine. However, 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 were for variation in tissues involved in immune system function. Although the significance of this connection for the illness process remains unknown, epidemiologic evidence has long hinted at possible immune system involvement in schizophrenia.
These findings confirm that it may be possible to develop risk profile scores based on schizophrenia-associated variants that may be useful in research in the future. Currently, researchers are following up with studies designed to pinpoint the specific sequences and genes that indicate 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.
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