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NIMH: Genetic Roots of Bipolar Disorder found


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http://www.nimh.nih.gov/press/mcmahon-bipolar-genetics.cfm

Genetic Roots of Bipolar Disorder Revealed by First Genome-Wide Study of Illness

Targeting enzyme produced by a specific gene may lead to better medications

The likelihood of developing bipolar disorder depends in part on the combined, small effects of variations in many different genes in the brain, none of which is powerful enough to cause the disease by itself, a new study shows. However, targeting the enzyme produced by one of these genes could lead to development of new, more effective medications. The research was conducted by scientists at the National Institutes of Health's National Institute of Mental Health (NIMH), with others from the Universities of Heidelberg and Bonn and a number of U.S. facilities collaborating in a major project called the NIMH Genetics Initiative.

...

One of the genes the researchers correlated with the disorder, DGKH, is active in a biochemical pathway through which lithium is thought to exert its therapeutic effects. The gene produces an enzyme (diacylglycerol kinase eta) that functions at a point closer to the root of the lithium-sensitive pathway than does the protein that lithium is thought to target. Scientists can now try to develop more effective medications by focusing on new compounds that act on the DGKH enzyme or regulate how much of the enzyme is produced. The DGKH gene is on chromosome 13.

Several other genes detected in the study produce proteins involved in this and other biochemical pathways thought to play a role in bipolar disorder. Understanding the effects that variations of these genes have on brain-cell function could lead to explanations of how they contribute to the condition and how it might be better prevented or treated.

"Treatments that target just a few of these genes or the proteins they make could yield substantial benefits for patients. Lithium is still the primary treatment for bipolar disorder, but DGKH is a promising target for new treatments that might be more effective and better tolerated," McMahon said.

The finding was enabled by recent genetics technology that allows researchers to scan, in a single experiment, thousands of genes for variations. Everyone has the same genes, but variations in them influence whether or not a person gets a specific disease. In this study, researchers compared variations found in the scans of 413 adults who had bipolar disorder with variations found in the scans of 563 healthy adults.

By pooling the genetic material of the adults with bipolar disorder, the U.S. researchers were able to scan the entire group at a small fraction of the cost of scanning each person's material individually. The genetic material of the healthy group was pooled and scanned separately, again at a fraction of the cost of individual scans. The researchers then zeroed in on the gene variations that occurred more often in the people with bipolar disorder and examined them individually.

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Wow, this represents TWO major advances. The use of pooled genetic material for faster cheaper surveys, and the detection of the eta gene.

Ehygon, any new treatment does not necessarily depend on previous response to lithium. As stated, this new recpetor is below the level of where lithium is believed to work. So, ideally any new drug will be working more directly with better effectiveness and fewer side effects. Also this in no way represents the end of all work on genetic sites for bipolar disorder. No doubt the found numerous others in this study, which they will be looking into as well. This was just the strongest connnection.

a.m.

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Related:

http://www.medicinenet.com/script/main/art...rticlekey=79889

TUESDAY, March 20 (HealthDay News) -- A gene involved in regulating circadian rhythms -- daily rhythms, including the wake/sleep cycle -- may also play a central role in the manic phase of bipolar disorder.

Mice with a particular mutation in the CLOCK gene, which is central in regulating circadian rhythms, displayed behavior very similar to manic behavior in humans. Given lithium, a drug used to treat bipolar disorder, the mice returned to many of their normal behaviors.

The findings could serve as a launching point for further research into bipolar disorder, whose mechanisms continue to elude scientists.

"It gives us a really nice model of mania to be able to study how mania develops and how the treatments for mania work, because a lot of the actions of mood stabilizers have been a mystery," said Colleen McClung, study senior author and assistant professor of psychiatry at the University of Texas Southwestern Medical Center at Dallas. "Bipolar has been difficult to study."

David J. Earnest, a professor of neuroscience and experimental therapeutics at Texas A&M Health Science Center College of Medicine, added: "It really does provide something beyond an associative or correlative observation that circadian rhythms are disturbed when patients are experiencing bipolar disorder. In this animal model, this mutation in the CLOCK gene produces behavioral patterns which are very similar to bipolar disorder."

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This paper seems ground-breaking... enzymes aren't the first things you think of when you think of genes and molecules in mental illness.

This, along with various research hypotheses of lithium changing around neurotransmitter uptake should help us form a good basis for both detection and appropriate treatment of bipolar disorder.

And, ehygon, who knows, maybe the reason you didn't respond to lithium was because you had a genetic issue similar to the one in the paper! ;)

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Anyone have the energy to rephrase or shorten that down for me?

I know what enzymes, pathways, genes, chromosomes and proteins are... it's just that I can't put it together in my head.

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Anyone have the energy to rephrase or shorten that down for me?

I know what enzymes, pathways, genes, chromosomes and proteins are... it's just that I can't put it together in my head.

Dittos.

My brain is so scattered lately I can't concentrate for shit.

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I'm gonna put on my asbestos suit and try this...

*Before we start, a very brief primer [n.B. - for those of you in biology, pun not intended] about what the hell molecular biology is about: First, a gene is a sequence of DNA that ultimately has the code for a protein, which is a useful molecule in the body. Different sequences of DNA will result in different proteins -- there are infinite possibilities. We have millions upon millions of DNA sequences in our bodies, which code for a large number of unique proteins. The "pathways" they discuss are chemical/protein reactions that happen in a certain order. For example, serotonin sticking to a serotonin receptor causes other things to happen afterwards, and this series of events is called a "pathway". That's about all I'll try to explain for the basics.

Now for Article 1:

1) We all have this "DGKH" gene, which codes for a protein called "diacylglycerol kinase eta"... I'm not sure what this thing does, I haven't been able to find any references to it other than this paper.

2) Nonetheless, these researchers found that being bipolar was correlated to having altered sequences of this DGKH gene (compared to "normal" people with "normal" DGKH sequences -- your interpretation of "normal" may vary). An altered (mutated) DNA sequence generally leads to a protein molecule with altered function.

3) These researchers feel that lithium has a more significant effect on the DGKH protein and its after-effects (pathway), as compared to what researchers previously thought lithium had an effect on -- at least judging by what happens in the clinic! (I assume that's what they base this assumption on - other biologists, I need input here!)

4) Therefore, these researchers hypothesize, the DGKH protein could potentially make a good "target" to treat bipolar -- in other words, it's possible that researchers could develop a drug that can allow an altered DGKH protein molecule to function more normally, as if it were a non-mutant. Which in theory could make us bipolars more normal. Whether this is good or not, is up to you...

4b) #4 is an ideal scenario, and it's more likely that researchers will develop drugs that alter the DGKH protein's function -- mutated or otherwise, and that these treatments might "normal"ize our neuronal function by dorking around with the DGKH protein.

This is all theoretical at this point, but this kind of research is one of the starters for developing new treatments for disorders.

[Explanation of the second article coming up in another reply, when I feel like it]

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okay.

Article #2 seems (I think) a bit simpler.

1) Mice that have an alteration in the gene (and therefore the protein) CLOCK show altered circadian rhythms. They also happen to show bipolar-like behavior (at least the mania).

2) Giving these mice lithium relieves their bipolar symptoms (at least the mania issues).

3) Therefore, could altering the function of CLOCK (using some sort of drug) help treat bipolar...? Bipolar humans (who perhaps have weird 'CLOCKs', we don't know yet) could be treated with drugs that alter what the CLOCK protein does... after all, mice with screwy CLOCKs also act manic, and respond to lithium.

That's my 0:02 opinion on the subject...

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