A team including researchers from UCLA and UNSW has made a major advance in understanding the biology of schizophrenia using 3D chromosome-mapping, a new technology for analysing DNA.
The scientists found dozens of genes and two major biological pathways that are likely involved in the development of the disorder but had not been uncovered in previous genetic studies of schizophrenia.
The work provides important new information about how schizophrenia originates and points the way to more detailed studies – and possibly better treatments in the future.
Schizophrenia is a chronic, disabling mental illness whose symptoms can include hallucinations, delusions and cognitive problems. The illness afflicts about 1 percent of the human population — more than 50 million people worldwide. Because the causes of schizophrenia are poorly understood, current medications can help diminish the symptoms but do not cure the disorder.
The study, which is published online in the journal Nature, is 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 has long been known to be highly genetic; 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.
“The fascinating property of these regulatory regions is that they can regulate target genes located at very large distances away," says UNSW’s Dr Irina Voineagu, whose laboratory contributed to the study.
"In turn, this means that we can’t directly infer which gene is targeted by a given regulatory region, which makes it difficult to put genetic association data into biological context."
To link genes to their regulatory regions, the team led by UCLA’s Professor Daniel Geschwind 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 3D 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 results confirmed what many suspected, that the regulatory regions rarely target the nearest gene. But more importantly, identifying the links between genes and distal regulatory regions allows us to begin to decipher the biological meaning of genetic associations,” says Dr Voineagu.
The mapping revealed that most of the more than 100 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 people with schizophrenia 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.
In principle, the 3D chromosome-mapping technology can be used to make sense of gene association data for any disease involving genetic risk.
The UNSW team included Dr Irina Voineagu and Gavin Sutton from the School of Biotechnology and Biomolecular Sciences.