Using a recently developed technology for analysing DNA, scientists have found dozens of genes and two major biological pathways that are likely to be involved in the development of schizophrenia. The work provides important new information about how schizophrenia originates and could lead to better treatments in the future.
The study, which was carried out by the David Geffen School of Medicine at UCLA, is also likely to have an impact beyond schizophrenia research because it demonstrates a general and potentially powerful new strategy for illuminating the mechanisms of human disease.
Schizophrenia is a chronic, disabling mental illness whose symptoms can include hallucinations, delusions and cognitive problems. The illness afflicts about 1 per cent of the human population. Because the causes of schizophrenia are poorly understood, current medications can help diminish the symptoms but do not cure the disorder.
"This work provides a road map for understanding how common genetic variation associated with a complex disease affects specific genes and pathways," said principal investigator Dr. Daniel Geschwind, Professor of Neurology and Psychiatry at UCLA.
The genetic nature of schizophrenia has been known for some time as it often runs in families. A large genome-wide association study of people with schizophrenia, published in 2014, linked the disorder to small DNA variations at more than 100 distinct locations on the human genome. However, most of those locations lie outside of actual genes, so their roles in schizophrenia have been unclear. Genome-wide study analyses of other major diseases have come up with similarly puzzling results.
In some cases, the non-gene locations identified in these studies have turned out to be what are known as "regulatory regions," which serve to enhance or repress the activity of genes lying near them on the genome. But many of these disease-linked locations have no obvious gene target nearby on the genome.
Chromosome confirmation capture
One possibility is that these mysterious disease-linked locations are also regulatory regions that target genes lying relatively far away on the genome. They could do this if they are brought physically close to those "distant" genes by the complex twisting and looping that DNA undergoes when packaged into a chromosome, just as two opposite ends of a rope can end up close together when the rope is coiled.
To investigate that possibility, Dr Geschwind and his team used a relatively new, high-resolution version of a technology called "chromosome conformation capture," which chemically marks and then maps the locations where loops of chromosomal DNA come into contact.
Because each cell type in the body can have subtly different 3-D chromosome structures, the researchers applied the technique to immature human brain cells from the cortex, the large region across the top of the brain that handles higher cognitive tasks. Schizophrenia is believed to be a disorder of abnormal cortical development.
The mapping revealed that most of the schizophrenia-linked sites from the 2014 study contact known genes during brain development. Many of these are genes that already have been linked to schizophrenia in previous studies. Others had been suspected of involvement, for example because their level of activity in schizophrenics is known to be abnormal in the cortex.
The genes newly linked to schizophrenia in the study include several for brain cell receptors that are activated by the neurotransmitter acetylcholine, implying that variations in the functions of these receptors can help bring about schizophrenia.
"There's a lot of clinical and pharmacologic data suggesting that changes in acetylcholine signalling in the brain can worsen schizophrenia symptoms, but until now there's been no genetic evidence that it can help cause the disorder," Dr Geschwind said.
The analysis also pointed for the first time to several genes that are involved in the early-life burst of brain cell production that gives rise to the cerebral cortex of humans.
In all, the researchers identified several hundred genes that may be abnormally regulated in schizophrenia but had not been linked to the disorder before. In further experiments and analyses of two dozen of those genes, they found additional evidence of abnormal regulation in schizophrenia.
More effective treatments possible in future
As further studies clarify the roles of these genes in schizophrenia, scientists will get a more complete picture of how the disorder develops and persists, and should then be able to develop more effective treatments.
"In the near term we're using the findings from this study to help us understand schizophrenia better, but we're also planning to apply this same strategy to identify key genes in the development of autism and other neurodevelopmental disorders," Dr Geschwind said.
The study is published online in the journal Nature.