The biology behind schizophrenia
02 August 2014
University of California, Los Angeles (UCLA), researchers were part of a multinational effort that has identified more than 100 locations in the human genome associated with the risk of developing schizophrenia.
The study, the largest genomic study published on any psychiatric disorder to date, provides important new insights about the biological causes of schizophrenia, and it could lead to new approaches to treatment. The report was published in the 22 July online edition of the journal Nature.
"As recently as five years ago, we still lacked proof that mental disorders had a genetic basis," says Dr Nelson Freimer, a UCLA professor of psychiatry and director of the UCLA Center for Neurobehavioral Genetics, who was part of the study. "This work now demonstrates unequivocally that at least 100 distinct genes contribute to schizophrenia. By providing the strongest evidence to date for the biological underpinnings of mental illness, this study is of historic importance."
Schizophrenia, a debilitating psychiatric disorder that affects approximately 1 per cent of the world's population, is characterised by hallucinations, paranoia and a breakdown of thought processes, and it 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 that schizophrenia costs over $60 billion annually in the US alone.
Despite the pressing need for treatment, there have been few innovations in drugs to treat schizophrenia for more than 60 years - in part because the disease's underlying biological mechanisms have not been understood.
Current medications treat only the psychosis that is one of its symptoms but do not address its debilitating cognitive symptoms.
Since the dawn of genomic medicine in the early 2000s, schizophrenia research has focused on the disorder's genetic underpinnings, because it is so frequently hereditary. Previous studies have suggested that it is caused by the combined effects of many genes, and roughly two dozen locations of the chromosome have been found to be associated with the disorder.
The new study confirms those earlier findings and sheds new light on schizophrenia's genetic basis and underlying biology.
"These results firmly show a biological basis of schizophrenia, which should remove some of the remaining stigma that still surrounds the disease," said Roel Ophoff, a professor of human genetics and psychiatry at the UCLA Semel Institute for Neuroscience and Human Behavior who also contributed to the study. "It is remarkable to observe that the genetic architecture of schizophrenia is very similar to that of other heritable human diseases and traits. Our ability to detect genetic risk factors on this massive scale, which is providing a wealth of information, should give us hope to develop new treatments for schizophrenia."
The authors analysed more than 80,000 genetic samples from people with and without schizophrenia. They identified 108 specific locations in the human genome associated with risk for schizophrenia, 83 of which had not previously been linked to the disorder.
The study implicates genes expressed in brain tissue, particularly those related to neuron and synapse function. Among them are genes active in the pathways that control the ability for neuronal synapses to change - a function essential to learning and memory.
Additionally, the researchers found a small 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 a gene called DRD2, which produces the dopamine receptor targeted by all approved medications for schizophrenia. That finding suggests that other locations uncovered in the study may be targets for new therapies.
"By studying the genome, we are getting a better handle on the genetic variations that are making people vulnerable to psychiatric disease," says Dr Tom Insel, director of the National Institute of Mental Health, which helped fund the study. "Through the wonders of genomic technology, we are in a period in which, for the first time, we are beginning to understand many of the players at the molecular and cellular level."
The study was conducted over several years by the Schizophrenia Working Group of the Psychiatric Genomics Consortium; it included 55 datasets from more than 40 different contributors, including Ophoff and Freimer, who genotyped their samples at UCLA. Ophoff was one of the founding principal investigators of the international collaboration, which was founded in 2007 to conduct broad-scale analyses of genetic data for psychiatric disease.
The PGC is currently genotyping new samples to further study schizophrenia, autism, bipolar disorder and other psychiatric diseases.
Core funding for the Consortium comes from the National Institute of Mental Health, along with numerous grants from governmental and charitable organizations, as well as philanthropic donations.
Rita Cantor, a UCLA professor of human genetics, was also an author on the paper.