Functional Genomics of Bipolar Disorder

National Institute Of Mental Health

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Abstract

NCT00001174 Genetic Risk for Mental Illness and Brain Function Even though we know mental illnesses like bipolar disorder, schizophrenia, and depression are partly inherited and linked to certain genes, we still don’t fully understand how these genes affect brain function—especially in specific brain cells like neurons and astrocytes. Studying Brain Tissue in People with Bipolar Disorder and Related Mental Illnesses We focus these studies on a part of the brain called the subgenual anterior cingulate cortex (sgACC), which is involved in emotion and mental health. Using brain samples from 200 people (some with mental illness, some without), we looked at the degree to which genes are turned on or off in donors with a mental health diagnosis. We found small differences in gene activity between people with and without mental illness, but bigger differences when we looked at individual gene versions (called transcripts). Some of these differences were linked to common genetic variants that seem to play a bigger role in mental illness than expected. We are now using novel technology that allows us to directly measure transcripts, some of which have not been previously found in the brain. These studies will allow us to get a more complete picture of gene regulation in BD and other mental illnesses. Medication Effects on Gene Activity Previous studies found many genes behave differently in people with mental illness, but it’s unclear whether that’s due to the illness itself or the medications they were taking. To address this question, we looked at brain samples from people with schizophrenia who had or hadn’t taken antipsychotic drugs. The drugs—especially newer ones—did change gene activity. We also studied brain tissue from animals treated with these drugs and saw similar effects. However, the types of brain cells didn’t change much due to the drugs. This means medications can influence gene expression in the brain, making it difficult to separating medication effects from those that are part of the underlying biology of mental illness. To avoid this problem, we are now studying how medications affect brain cells that are grown in the laboratory. We are testing how medications commonly used to treat BD —lithium and valproic acid (VPA)—affect brain cells made from stem cells donated by people with BD or no mental illness. VPA caused many gene changes, and both drugs influenced a key signaling pathway called Notch. This shows how stem cell models can help us understand how medications work. This information may help us find new treatments. Stem Cell Models of Mental Illness We’ve also created stem cell lines from over 95 people to study how their genes affect brain cells grown in the laboratory. These cells are tested using imaging, electrical activity, and gene analysis. This helps us see how patient’s cells differ from healthy ones and how treatments might help. We’re also using gene editing to test whether (and how) specific mutations cause problems in brain cells. A Better Way to Analyze Gene Expression Data Traditional methods haven’t matched gene expression patterns with known risk genes very well. So, we used a new technique called GRCCA that adjusts for outside influences like drug use. This method found gene changes linked specifically to schizophrenia, not to bipolar disorder, depression, or drug use. It also matched known schizophrenia risk genes, helping us build a clearer picture of how the illness affects the brain. Studying High-Risk Genetic Variants We’re looking at people with known high-risk genetic changes (called copy number variants or CNVs), which are linked to BD and other mental illnesses. Brain cells with these CNVs show changes in gene activity and problems with growth, communication, and development. Astrocytes (support cells in the brain) from healthy donors helped fix these problems, while astrocytes from CNV carriers made things worse. These studies are helping to understand how CNVs disrupt brain development and how astrocytes may contribute to mental illness. Single-Cell Brain Analysis of CNVs To understand how CNVs influence gene expression in brain tissue, we studied brain samples donated by 13 people with a high-risk CNV and compared them to samples from people without any of these CNVs. We looked at gene activity in 9 types of brain cells. As expected, genes in the CNV regions were changed, but many other genes were also changed, both up and down. People with deletions (a missing piece of DNA) had more gene changes than those with duplications (a piece of DNA that appears twice). These changes were linked to stress, energy use, and brain communication—similar to what we saw in lab-grown cells. Why This Matters Together, these studies aim to discover how genetic risk factors affect the brain and contribute to mental illness. If successful, this research will advance the goal developing better ways to diagnose and treat conditions like bipolar disorder, schizophrenia, and depression. In the coming year, we will study more samples so that we can be sure that the differences we’ve seen so are reproducible.