Medical

Major mental illnesses share gene activity

CNRI/Science

Despite mental illness affecting one out of every six adults, the underlying knowledge about most neuropsychiatric disorders remains unclear.

For a long time now, scientists have been aware that genes influence mental illness. In 2013, the Psychiatric Genomics Consortium discovered that people with autism, schizophrenia, bipolar disorder, depression, and attention-deficit hyperactivity disorder ‘frequently share certain DNA variations’.

Scientists are still not sure how genetic variants interact with environmental and epigenetic risks, even though there has been remarkable success in identifying important factors that increase major neuropsychiatric diseases. What makes this particularly difficult is that there is not a single laboratory blood test, brain scan, or medical analysis, which helps doctors distinguish between, for example, bipolar disorder and depression. Disorders such as these are the most prevalent and disabling and therefore, poignantly contribute to the global disease burden.

In order to solve this problem, a team of researchers from the University of California, Los Angeles (UCLA) analysed earlier studies dedicated to gene-expression in the cerebral cortex (the brain’s folded outer layer). A large-scale analysis of 700 post-mortem brains has been carried out and has revealed distinctive molecular traces. The samples were taken from 50 individuals with documented autism, 159 with schizophrenia, 94 with bipolar disorder, 87 with depression, 17 with alcoholism, and 293 without any record of mental illness. To provide a supplementary control group, samples were taken from 197 post-mortem brains belonging to patients with inflammatory bowel disease, to exclude general disease processes shared by non-central nervous system conditions.

Following this meta-analysis, the group led by Dan Geschwind, a neurologist and neuroscientist at UCLA, noted that ‘five major psychiatric disorders have patterns of gene activity that often overlap but also vary in disease-specific, and sometimes counterintuitive, ways’. This moved the scientists to suggest that their findings might someday lead to ‘diagnostic tests and novel therapies’.

In order to determine how variants associated to the disease may influence different biological processes, the research team looked into whether any modules were associated with genetic susceptibility for a particular disorder or even cognitive or behavioural traits.

Previous research had suggested that the genetic risk factors for major depression and alcoholism were similar. Nevertheless, no correlation in gene activity patterns existed between alcoholism and the other four disorders studied in this investigation.

In summary, the collected data helped scientists to characterise major neuropsychiatric disorders. Therefore, they are capable of identifying genetic variants. For instance, autism was linked to overactive microglia (a subset of brain immune cells that protect against inflammation), which gives the opportunity for potential antibiotics to help keep these cells in a resting state in adults with autism. Kenneth Kendler, a psychiatric geneticist at Virginia Commonwealth University in Richmond, declared that ‘this work is changing fundamental views about the nature of psychiatric illness’.

The researchers also found that ‘many genes in the cerebral cortex are active in both schizophrenia and autism – but are far more active in autism’. This suggests that gene overexpression might be crucial in exhibiting autism’s symptoms. On the other hand, genes linked to neuronal firing were turned down in schizophrenia, autism and bipolar disorder. This suggests that brain cell communication changes play a role in these conditions.

Moreover, the results revealed that certain psychiatric diseases are more similar on a biological level than what would be expected based on the characteristic symptoms they exhibit. For example, it seems logical to think that bipolar disorder and depression, which are commonly considered as ‘mood disorders’, would have similar underlying pathophysiology. The genomic data, however, showed that bipolar disorder had little resemblance to depression.

Furthermore, the study progressed to identifying cell type-specific patterns for autism, bipolar disorder and schizophrenia. This provides an ‘organisational pathological framework for future investigation of the mechanisms underlying specific gene- and isoform-level transcriptomic alterations in psychiatric disease’.

A conclusion may be drawn that the natural progression of the study, according to the researchers, focuses on the gene expression from single cells rather than the large brain areas examined so far. As stated by Jordan Smoller, a psychiatric geneticist at Harvard Medical School, this holds the potential to allow scientists to ‘zero in on specific cell types driving the disorders’.

‘We’re beginning to see the bits of the puzzle starting to slowly get clearer.’

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