Making sense out of the biological matrix of bipolar disorder

Reports new study in Biological Psychiatry

2012-08-20

(Press-News.org) Philadelphia, PA, August 20, 2012 – The more that we understand the brain, the more complex it becomes. The same can be said about the genetics and neurobiology of psychiatric disorders. For "Mendelian" disorders, like Huntington disease, mutation of a single gene predictably produces a single clinical disorder, following relatively simple genetic principals. Compared to Mendelian disorders, understanding bipolar disorder has been extremely challenging. Its biology is not well understood and its genetics are complex.

In a new paper, Dr. Inti Pedroso and colleagues utilize an integrative approach to probe the biology of bipolar disorder. They combined the results of three genome-wide association studies, which examined the association of common gene variants with bipolar disorder throughout the genome, and a study of gene expression patterns in post-mortem brain tissue from people who had been diagnosed with bipolar disorder. The findings were analyzed within the context of how brain proteins relate to each other based on the Human Protein Reference Database protein-protein interaction network.

"None of our research approaches provides us with sufficient information, by itself, to understand the neurobiology of psychiatric disorders. This innovative paper wrestles with this challenge in a creative way that helps us to move forward in thinking about the neurobiology of bipolar disorder," commented Dr. John Krystal, Editor of Biological Psychiatry.

Dr. Pedroso explained, "We combined information about genetic variation from thousands of cases and controls with brain gene expression data and information from protein databases to identify networks of genes and proteins in the brain that are key in the development of bipolar disorder."

The analysis resulted in the ability to define risk gene variants that were deemed functional, by virtue of the association with changes in gene expression levels, and to group these functional gene variants in biologically meaningful pathways.

The results implicated genes involved in several neural signaling pathways, including the Notch and Wnt signaling pathways. These pathways are key processes in neurotransmission and brain development and these findings indicate they are also likely to be involved in causing this severe disorder. The authors noted that three features stand out among these genes: i) they localized to the human postsynaptic density, which is crucial for neuronal function; ii) their mouse knockouts present altered behavioral phenotypes; and iii) some are known targets of the pharmacological treatments for bipolar disorder.

Dr. Gerome Breen, senior author on the study and Senior Lecturer at King's College London Institute of Psychiatry, said, "Our study provides some of the first evidence to show the biochemical and developmental processes involved in causing risk for developing this life-long and costly illness. We have highlighted potential new avenues for new drug treatments and intervention."

### The article is "Common Genetic Variants and Gene-Expression Changes Associated with Bipolar Disorder Are Over-Represented in Brain Signaling Pathway Genes" by Inti Pedroso, Anbarasu Lourdusamy, Marcella Rietschel, Markus M. Nöthen, Sven Cichon, Peter McGuffin, Ammar Al-Chalabi, Michael R. Barnes, and Gerome Breen (doi: 10.1016/j.biopsych.2011.12.031). The article appears in Biological Psychiatry, Volume 72, Issue 4 (August 15, 2012), published by Elsevier.

Notes for editors Full text of the article is available to credentialed journalists upon request; contact Rhiannon Bugno at +1 214 648 0880 or Biol.Psych@utsouthwestern.edu. Journalists wishing to interview the authors may contact Seil Collins at +44 0207 848 5377 or seil.collins@kcl.ac.uk.

The authors' affiliations, and disclosures of financial and conflicts of interests are available in the article.

John H. Krystal, M.D., is Chairman of the Department of Psychiatry at the Yale University School of Medicine and a research psychiatrist at the VA Connecticut Healthcare System. His disclosures of financial and conflicts of interests are available here.

About Biological Psychiatry Biological Psychiatry is the official journal of the Society of Biological Psychiatry, whose purpose is to promote excellence in scientific research and education in fields that investigate the nature, causes, mechanisms and treatments of disorders of thought, emotion, or behavior. In accord with this mission, this peer-reviewed, rapid-publication, international journal publishes both basic and clinical contributions from all disciplines and research areas relevant to the pathophysiology and treatment of major psychiatric disorders.

The journal publishes novel results of original research which represent an important new lead or significant impact on the field, particularly those addressing genetic and environmental risk factors, neural circuitry and neurochemistry, and important new therapeutic approaches. Reviews and commentaries that focus on topics of current research and interest are also encouraged.

Biological Psychiatry is one of the most selective and highly cited journals in the field of psychiatric neuroscience. It is ranked 5th out of 129 Psychiatry titles and 16th out of 243 Neurosciences titles in the Journal Citations Reports® published by Thomson Reuters. The 2011 Impact Factor score for Biological Psychiatry is 8.283.

About Elsevier Elsevier is a world-leading provider of scientific, technical and medical information products and services. The company works in partnership with the global science and health communities to publish more than 2,000 journals, including The Lancet and Cell, and close to 20,000 book titles, including major reference works from Mosby and Saunders. Elsevier's online solutions include ScienceDirect, Scopus, Reaxys, ClinicalKey and Mosby's Nursing Suite, which enhance the productivity of science and health professionals, and the SciVal suite and MEDai's Pinpoint Review, which help research and health care institutions deliver better outcomes more cost-effectively.

A global business headquartered in Amsterdam, Elsevier employs 7,000 people worldwide. The company is part of Reed Elsevier Group PLC, a world-leading publisher and information provider, which is jointly owned by Reed Elsevier PLC and Reed Elsevier NV. The ticker symbols are REN (Euronext Amsterdam), REL (London Stock Exchange), RUK and ENL (New York Stock Exchange).

Media contact Rhiannon Bugno
Editorial Office, Biological Psychiatry
+1 214 648 0880
biol.psych@utsouthwestern.edu

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Making sense out of the biological matrix of bipolar disorder

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