Researchers from UNC’s School of Medicine, working with scores of institutions from around the world, have helped identify more than 100 locations in the human genome associated with the risk of developing schizophrenia.
Findings from the effort, described as the largest genomic study published on any psychiatric disorder to date, point to biological mechanisms and pathways that may underlie schizophrenia. In turn, this could lead to new approaches to treating a disorder that has seen little progress in drug development in more than 60 years. The findings were published online this week in Nature.
“This paper is a landmark,” said Dr. Patrick Sullivan, a co-author of the study and a Distinguished Professor of genetics and psychiatry at UNC. Sullivan also directs UNC’s Center for Psychiatric Genomics.
“We have never before had such a profound and important look into the inner workings of schizophrenia,” Sullivan said.
Schizophrenia is a debilitating psychiatric disorder affecting about 1 out of every 100 people worldwide. It is characterized by hallucinations, paranoia and a breakdown of thought processes; when it emerges, it tends to afflict people in their 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. It is estimated that the annual cost of schizophrenia is more than $60 billion in the U.S. alone.
Despite a 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.
This new study confirms those earlier findings and expands researchers’ understanding of the genetic basis of schizophrenia and its underlying biology.
“By studying the genome, we are getting a better handle on the genetic variations that are making people vulnerable to psychiatric disease,” said 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.”
In the genomewide association study published in Nature, the authors looked at more than 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.
“In just a few short years, by analyzing tens of thousands of samples, our consortium has moved from identifying only a handful of loci associated with schizophrenia to finding so many that we can see patterns among them,” said first author Stephan Ripke, a scientist at the Broad Institute’s Stanley Center for Psychiatric Research and the Analytic and Translational Genetics Unit at Massachusetts General Hospital. “We can group them into identifiable pathways — which genes are known to work together to perform specific functions in the brain. This is helping us to understand the biology of schizophrenia.”
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.
The researchers also 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. And the study 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 molecular pathways identified in the study represent the most promising targets for therapeutics found in over 50 years,” said the paper’s senior author Michael O’Donovan, deputy director of the Institute of Psychological Medicine and Clinical Neurosciences at Cardiff University School of Medicine. “We now have new biological mechanisms that we and fellow researchers can explore as we attempt to develop new treatments.”
The study is the result of several years of work by the Schizophrenia Working Group of the Psychiatric Genomics Consortium, an international, multi-institutional collaboration founded in 2007 to conduct broad-scale analyses of genetic data for psychiatric disease.
The 80,000 samples used in this study represent all of the genotyped datasets for schizophrenia that the consortium has amassed to date. The Psychiatric Genomics Consortium is genotyping new samples to further study schizophrenia and additional psychiatric diseases, including autism and bipolar disorder.
Core funding for the Psychiatric Genomics Consortium comes from the U.S. National Institute of Mental Health, numerous grants from governmental and charitable organizations as well as philanthropic donations.