Common Gene Sets Disrupted in Major Psychiatric Disorders

The measurement of gene expression in postmortem brain is an important tool for understanding the pathogenesis of serious psychiatric disorders such as schizophrenia, bipolar disorder and major depression.

The commonly affected genes sets, identified with ribonucleic acid (RNA) sequencing methods, engage in making proteins, controlling brain cell communications and mounting an immune system response. The major molecular deficits associated with psychiatric disease would affect the entire brain, and such deficits may be shared across disorders.

Scientists at Johns Hopkins School of Medicine (Baltimore, MD, USA) collected 100 tissue samples from donor brains gathered by the Stanley Medical Research Institute's Array Collection (SMRI, Kensington, MD, USA). All samples were from the hippocampus, the seahorse-shaped part of the brain important for memory and spatial navigation. Thirty-five brains were from people with schizophrenia, 33 were from people with bipolar disorder and 32 were controls without a mental disorder. Of the total brain samples from both the hippocampus and the orbitofrontal cortex, 57 were from women and 100 were from men. All but seven samples were from Caucasians, and the donors' ages ranged from 19 to 68 at the time of death.

The team extracted and sequenced the messenger ribonucleic acid (mRNA) - genetic material that function as the blueprints created from DNA and used as guides by cells to build proteins - from the tissue. The investigators report that each sample from the hippocampus produced on average 154 million sequenced bits of RNA and 140 million sequences for each brain sample from the orbitofrontal cortex. They then aligned the sequences from each sample with a fully sequenced human genome (version 19) and counted the number of times a sequence matched up to each individual gene. In all, 21,861 genes were represented in the hippocampus tissues, and 20,711 were represented in the orbitofrontal cortex region tissues.

The scientists identified genes that make either more or less mRNA in individuals with mental disorders than in individuals without a mental disorder. They then compared the list of genes affected in each disorder to lists of genes grouped by their function in the cell, and identified which groups contained a disproportionate number of genes with either increased or decreased mRNA in individuals with schizophrenia, bipolar disorder and major depression. The team reports that out of a total of 1,070 gene sets, 13 of these groups changed in common ways among all three mental disorders. Ribosomal genes are overexpressed while genes involved in neuronal processes, GABAergic signaling, endocytosis and antigen processing have predominantly decreased expression in affected individuals compared to controls without a psychiatric disorder.

Sarven Sabunciyan, PhD, an assistant professor of pediatrics and a senior author of the study said, “Although there isn't a clear reason why the brains of people with these mental disorders would have more of the protein production machinery, we think our findings suggest that it's a fruitful line of investigation to pursue. We now plans to study these changes in induced pluripotent stem cells derived from patients, which also show an increase in ribosomal gene expression.” The study was published on September 13, 2016, in the journal Translational Psychiatry.

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