Schizophrenia, a debilitating psychiatric disorder that affects approximately 1 out of every 100 people worldwide, is characterized by hallucinations, paranoia, and a breakdown of thought processes, and often emerges in the teens and early 20s. Its lifetime impact on individuals and society is high, both in terms of years of healthy life lost to disability and in terms of financial cost, with studies estimating the cost of schizophrenia at over $60 billion annually in the U.S. alone.
Despite the pressing need for treatment, medications currently on the market treat only one of the symptoms of the disorder (psychosis), and do not address the debilitating cognitive symptoms of schizophrenia. In part, treatment options are limited because the biological mechanisms underlying schizophrenia have not been understood. The sole drug target for existing treatments was found serendipitously, and no medications with fundamentally new mechanisms of action have been developed since the 1950s.
In the genomics era, research has focused on the genetic underpinnings of schizophrenia because of the disorder’s high heritability. Previous studies have revealed the complexity of the disease (with evidence suggesting that it is caused by the combined effects of many genes), and roughly two dozen genomic regions have been found to be associated with the disorder. The new study confirms those earlier findings, and expands our understanding of the genetic basis of schizophrenia and its underlying biology.
In the genome-wide association study (GWAS) published in Nature, the authors looked at over 80,000 genetic samples from schizophrenia patients and healthy volunteers and found 108 specific locations in the human genome associated with risk for schizophrenia. Eighty-three of those loci had not previously been linked to the disorder.
The study implicates genes expressed in brain tissue, particularly those related to neuronal and synaptic function. These include genes that are active in pathways controlling synaptic plasticity – a function essential to learning and memory – and pathways governing postsynaptic activity, such as voltage-gated calcium channels, which are involved in signaling between cells in the brain.
Additionally, the researchers found a smaller number of genes associated with schizophrenia that are active in the immune system, a discovery that offers some support for a previously hypothesized link between schizophrenia and immunological processes. The study also found an association between the disorder and the region of the genome that holds DRD2 – the gene that produces the dopamine receptor targeted by all approved medications for schizophrenia – suggesting that other loci uncovered in the study may point to additional therapeutic targets.
The study is the result of several years of work by the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC, http://pgc.unc.edu), an international, multi-institutional collaboration founded in 2007 to conduct broad-scale analyses of genetic data for psychiatric disease. A total of 55 datasets from more than 40 different contributors were needed to conduct the analysis. The 80,000 samples used in this study represent all of the genotyped datasets for schizophrenia that the consortium has amassed to date. The PGC is currently genotyping new samples to further study schizophrenia and additional psychiatric diseases, including autism and bipolar disorder.
Text: Veronica Meade-Kelly, Broad Institute
Original publication: Schizophrenia Working Group of the Psychiatric Genomics Consortium. “Biological insights from 108 schizophrenia-associated genetic loci.”