The astonishing frontiers that have opened over the past decade or so with the completion of the human genome project and the development of new genotyping technologies are leading to a deeper understanding of the brain and the potential for new treatments for disorders. Professor Sham Pak-chung, Suen Chi-Sun Professor in Clinical Science and Chair Professor of Psychiatric Genomics, has been at the forefront of this research.
He participated in an international consortium that in 2014 reported on the largest molecular genetic study of schizophrenia or any psychiatric disorder, a genome-wide association study (GWAS) involving 36,989 schizophrenia patients and 113,075 controls. The researchers were able to detect 108 genetic loci (positions on a chromosome) associated with schizophrenia, a disease for which there currently are no biomarkers or diagnostic tests.
“We have known for a long time that psychiatric disorders are likely to be complex and involve multiple genes, but we didn’t really have a good idea of how complex they are. It was only with the GWAS that we have been able to get answers,” Professor Sham said.
They also showed that the associations were not random but converged on genes expressed in certain tissues and cellular types. Schizophrenia was associated with proteins involved in synaptic function – synapses are the connections that allow neurons in the brain to communicate with each other – as well as certain neurotransmitters. While it was previously known that the neurotransmitter dopamine played a part, the research also identified glutamate and gamma-aminobutyric acid as important, suggesting possible new targets for treatments.
Professor Sham said the findings also supported the idea that schizophrenia may have origins early in life, long before the onset of clinical symptoms, and perhaps even before birth.
The strongest schizophrenia-associated locus was found to contain a gene important in brain development. Normally, the process involves both creating and pruning back neurons to establish properly functioning neuronal networks.
“But in animals, if this gene is excessively activated or expressed, it can lead to too much pruning of neurons. Indeed, one of the consistent differences in the brains of patients with schizophrenia is that there is a reduction in brain volume,” Professor Sham said. Interestingly, they also found evidence of an overlap between genes associated with schizophrenia and those with mutations responsible for intellectual disability.
“We now have a number of new leads into the molecular changes associated with schizophrenia although there is still a long way to go before we have a detailed understanding of the mechanisms.”
Taking that understanding forward, Professor Sham and his colleagues have also been investigating the impact of genetic variations on gene expression (or activity). They gathered evidence from GWASs about the gene expressions of seven psychiatric disorders, including schizophrenia, and compared this with the changes in gene expressions produced by thousands of drugs that have gone through clinical or pre-clinical trials. These drugs may not be in use for various reasons or may be used for other purposes, but the research showed that some of these drugs may reverse the gene expression changes seen in psychiatric disorders. Promisingly, some anti-psychotic drugs showed up as a potential match for schizophrenia and some anti-psychotics and anti-depressants for bipolar disorder. “It would be much easier to use existing drugs than to try to develop new ones,” he said.
In yet another study, Professor Sham has also started looking at the genetic origins of major depression with Professor Tatia Lee Mei-chun, May Professor in Neuropsychology and Chair Professor of Psychology. They recently obtained access to the UK Biobank, which has genetic data from half a million people. They are comparing the data with brain images of 10,000 people of that group, as well as detailed health and lifestyle information drawn from questionnaires, to see how these factors interact with each other and influence the risk of depression.
Professor Sham is also Co-Director, with Professor Lee, of HKU’s State Key Laboratory of Brain and Cognitive Sciences, whose members are producing other insights on brain and mental health. For example, work by Professor Lee has shown how the brain changes in response to psychological stimulation such as meditation. Professor So Kwok-fai, Jessie Ho Professor in Neuroscience and Chair Professor of Anatomy, has shown how physical exercise may mitigate the effects of depression by reversing the reduction in neurogenesis in the hippocampus, thus enabling more new neurons to be created. And Professor Eric Chen Yu-hai, Chi-Li Pao Foundation Professor in Psychiatry, and his group have demonstrated the value of early intervention in improving the outcome of patients with psychosis.
“Our overall strategy is to improve brain health and mental well-being by creating models that can integrate brain imaging, genetics, biomarkers and human behaviour,” Professor Sham said.
THE ROOTS OF DISORDER
Genetic variations that affect the structure and function of the brain are helping scientists better understand the mechanisms of brain disorders, such as schizophrenia and major depression.
We now have a number of new leads into the molecular changes associated with schizophrenia although there is still a long way to go before we have a detailed understanding of the mechanisms.
Professor Sham Pak-chung