Evidence continues to accumulate regarding genetic factors involved in the development of schizophrenia, a debilitating psychiatric disorder. UCLA researchers were involved in a multinational project that has identified more than 100 locations in the human genome associated with the risk of developing schizophrenia. The new information may lead to new treatments for the disorder. The findings were published online on July 22 in the journal Nature.
The authors note that their study is the largest genomic study published on any psychiatric disorder to date; furthermore, it provides important new insights regarding the biological causes of schizophrenia. “As recently as five years ago, we still lacked proof that mental disorders had a genetic basis,” explained study member Dr. Nelson Freimer, a UCLA professor of psychiatry and director of the UCLA Center for Neurobehavioral Genetics. He added, “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 is a devastating psychiatric disorder, which affects approximately 1% of the world’s population. It is characterized by hallucinations, paranoia, and a breakdown of thought processes; it usually develops during adolescence and the early 20s. Its lifetime impact on affected individuals and society is significant, both in terms of years of healthy life lost to disability and in terms of financial cost; studies estimate that schizophrenia costs more than $60 billion annually in the US alone.
An urgent need for new treatments exist; however, for more than 60 years, innovative treatments have not appeared. This is due in part to the fact that the disorder’s underlying biological mechanisms have not been clarified. Current medications merely treat the psychosis, which is one of its symptoms; however, they do not improve the debilitating cognitive symptoms. Since genomic medicine first emerged in the early 2000s, schizophrenia research has focused on the disease’s underlying genetics, because it is so frequently hereditary. Previous research has suggested that it is caused by the combined effects of a number of genes; approximately, two dozen locations of the chromosome have been found to be associated with schizophrenia.
The new study confirms the findings from previous genomic studies and provides new insight into the disorder’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,” explained study member Roel Ophoff, PhD, a professor of human genetics and psychiatry at the UCLA Semel Institute for Neuroscience and Human Behavior. He added, “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.”
For the study, the investigators analyzed more than 80,000 genetic samples from individuals with and without schizophrenia. They identified 108 specific locations in the human genome associated with s risk for schizophrenia, 83 of which had not previously been linked to the disorder. The study associates genes expressed in brain tissue, particularly those related to neuron and synapse function, to schizophrenia. Among them are genes active in the pathways that control the ability for neuronal synapses to change, which is a function essential to learning and memory.
In addition, the investigators found a small number of genes associated with schizophrenia that are active in the immune system; this discovery offers some support for a previously theorized link between schizophrenia and immunologic processes. The study also found an association between schizophrenia and the region of the genome that holds a gene known as DRD2, which produces the dopamine receptor targeted by all approved medications for schizophrenia. That finding suggests that other locations discovered 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,” noted Dr. Tom Insel, director of the National Institute of Mental Health, which helped fund the study. He added, “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 took several years to complete and was conducted by the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC); it included 55 datasets from more than 40 different contributors, including Drs. Ophoff and Freimer, who genotyped their samples at UCLA. Dr. 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.