Biological Pathways for Common Psych Disorders Identified

Pauline Anderson

January 26, 2015

New biological mechanisms involved in schizophrenia, bipolar disorder, and major depressive disorder (MDD) have been identified.

The research implicates pathways related to histone methylation (molecular changes affecting proteins associated with DNA molecules) and immune and neuronal signaling.

The results suggest that psychiatric disorders share more of a genetic basis than previously recognized, joint lead author Colm O'Dushlaine, PhD, manager, Statistical Genetics, Regeneron Pharmaceuticals Genetics Center, Tarrytown, New York, formerly of the Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, told Medscape Medical News.

The study was published online January 19 in Nature Neuroscience.

A "Big Deal"

Genome-wide association studies have identified multiple genetic associations with psychiatric disorders. It is estimated, for example, that there is about a 30% genetic overlap between bipolar disorder and schizophrenia. However, the underlying biological mechanisms have been unclear.

The findings provide additional understanding about common pathways, information that could have important implications for diagnosis and treatment.

Although the results are preliminary, to Dr O'Dushlaine, they are "a big deal." "It's the largest study to date; it includes the most comprehensive set of pathways; and it spans multiple different psychiatric disorders," he said.

"I think it puts things into a biological context" that researchers can now further interpret to provide additional insights, he added.

For the study, a team of researchers from the University of California, Los Angeles, King's College, London, United Kingdom, and dozens of other investigators from around the world accessed data from more than 60,000 participants in the Psychiatric Genomic Consortium. The participants included those with schizophrenia, bipolar disorder, MDD, autism spectrum disorder, and attention- deficit/hyperactivity disorder, as well as healthy individuals.

From an initial compiled set of 19,752 pathways across five gene set databases, researchers restricted downstream analyses to the 4949 pathways of size 10-200 genes.

According to Dr O'Dushlaine, biological pathways represent DNA "packaging" that contain clusters of genes that are coexpressed and may turn on at a certain time in development or in response to environmental factors.

Top Pathway for Bipolar Disorder

The research team's disease-specific pathway analysis found that the top pathway for bipolar disorder is histone H3-K4 methylation. For schizophrenia, it is postsynaptic density; and for MDD, protein phosphatase type 2A regulator activity was the top pathway.

Because these disorders overlap, the researchers also carried out analyses across disorders, sort of aggregating the signals across pathways, said Dr O'Dushlaine. For example, he explained, in bipolar disorder, the genetic association might be at the start of a pathway and schizophrenia at the end of that same pathway.

This analysis showed that histone H3-K4 methylation and histone methylation were the top two ranked pathways, suggesting that dysregulation of the genes involved in histone methylation is a common etiologic mechanism for certain psychiatric disorders.

"It looks like it's bipolar and schizophrenia that seem to be driving that signal," said Dr O'Dushlaine. "Maybe the DNA isn't being packaged or folded nicely enough, and it's unwinding left, right, and center, so you're getting all these side products of genes being expressed that are interfering with the endogenous mechanisms."

According to the authors, histone methylation mechanisms play a role in the coordination of complex cognitive processes such as long-term memory and in conditions from addiction to schizophrenia to neurodegeneration. Histone pathways have previously been studied in cancer and with regard to the immune pathway in infectious disease.

Schizophrenia and bipolar disorder seemed to also be strongly associated with the pathway related to cell-cell junction organization. And schizophrenia appeared to signal highly in the pathways related to postsynaptic density, B cell activation, and signal release.

"Our results suggest that histone methylation appears to play a more prominent role in bipolar disorder and that synapse- and post-synapse-related processes are more strongly implicated in the etiology of schizophrenia," the authors write.

The researchers also found evidence for associations with immune pathways, reinforcing other research suggesting a role for the inflammatory system in psychiatric illnesses. Dr O'Dushlaine pointed out that one of the top signals in schizophrenia is the MHC (major histocompatibility complex) locus, which is "a huge immune branch" involving many genes.

"It looks like immune genes do have a role" in mental illnesses, but because that area of the genome is so large, it will take a lot of work to "disentangle" it, he said.

Treatment Implications

The researchers also noted the role of calcium channel activity. This is "one of the strongest emerging pathways" involved in bipolar disorder, although it does not seem to be "a theme" across all disorders, according to Dr O'Dushlaine.

One of the next steps for researchers is to take these identified pathways, create experimental models, and knock out genes that have been implicated, he said.

The new information could eventually help inform individualized treatment approaches. For example, said Dr O'Dushlaine, if a patient does not have any histone methylation involvement of interest, a drug targeting this area may not be of much use.

Or it might be a matter of varying the dose of a particular drug.

"There's this idea of drug repurposing," he said. "There might be a drug that's highly efficacious for schizophrenia that works on, say, the H3-K4 mechanism. Maybe we could target those same deficits in bipolar using the same drug."

The aim is to create finely tuned, focused therapeutics, added Dr O'Dushlaine. "The idea here is to design drugs that are genetically informed instead of a drug that just happens to work for whatever reason. It works because it's targeting a deficit."

Asked which psychiatric disorder might see the fastest advances in terms of targeted gene-based treatments, Dr O'Dushlaine speculated it would be schizophrenia.

"We know of a few hundred genes now that are strongly and significantly associated with schizophrenia. That's more than we know are involved in bipolar and significantly more than for depression."

The new results, together with what functional biologists and others are learning with cell models of mutations of interest, should move the field further forward, added Dr O'Dushlaine.

"Layering all what we know about the genetic variants onto a kind of scaffold of pathways will allow us to look at this in a focused way," he said. "Pathways are the bridge between the macrobiology of the structures of the cell and the underlying genetics are the blueprints."

Terrific Study

Commenting on the study for Medscape Medical News, Turhan Canli, PhD, associate professor of psychology and radiology, director of SCAN (Social, Cognitive, and Affective Neuroscience) Center, and senior fellow, Center for Medical Humanities, Compassionate Care, and Bioethics, Stony Brook University, New York, said it was "terrific" for several reasons.

First, by pooling data in a consortium-based approach, researchers were able to look at information from "a staggeringly large dataset," said Dr Canli.

Researchers used several methods of analysis, each with different weaknesses, strengths, and statistical assumptions, but they only counted those results that proved significant across all methods. "That means that the results are very robust, because they always 'won,' regardless of which analysis method they used," said Dr Canli.

The data confirm certain things researchers already knew, for example, the involvement of postsynaptic membrane proteins in schizophrenia. "This is always reassuring to see," said Dr Canli.

But the data also point to new discoveries, primarily the overlap across schizophrenia, bipolar disorder, and MDD of histone methylation. "This process may represent one way in which the environment may 'reprogram' genes," commented Dr Canli.

He added that given recent interest in the topic, he found it "intriguing" that the analysis implicated both immune processes and infectious disease processes in psychopathology.

Dr O'Dushlaine and Dr Canli report no relevant financial relationships.

Nat Neurosci. Published online Jan 19, 2015. Abstract

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