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Bipolar Genetics
(revised 6/2004)

Why is there bipolar disorder at all?  Why didn't evolution "select it out"?  

(You don't believe in evolution? Here's some brief help with that)

Ten to twenty thousand years ago humans were still strongly affected by evolutionary selection. Only highly "fit" individuals could survive and prosper.  If they did prosper, they could help their children survive and reproduce.  So genes that created increased "fitness" would be preserved, and amplified: more children with these genes would survive to reproduce -- and prosper enough to help their children survive, and so forth.  

The opposite is also true: genes that decreased "fitness" -- the ability to survive and prosper -- would be reduced in every generation, as the humans with those genes struggled and failed to reproduce, or their children struggled without prosperous parents to help them.  

Severe bipolar disorder clearly reduces "fitness".  In bipolar I, an individual who has delusions that his wife is unfaithful and kills her, loses her support for their children and his opportunity to reproduce (to put the matter in blunt evolutionary terms).  Becoming "manic" and giving away all one's grain because of a belief that more can easily be harvested, when actually it's all been harvested already -- this too would decrease survival and reproduction of the individual and probably his children.  

So why wasn't the "gene", or genes, for bipolar disorder eliminated by evolution many thousands of years ago?  Surprisingly, there are numerous genes that appear to decrease an individual's reproductive success yet still have not disappeared.  The most common explanation for this puzzle is that the gene causes some change that in small doses provides increased fitness, and only with a "large dose" of this gene, and its effects, does the individual function less well than average.  

One of the classic examples of this is "sickle cell anemia".  When an individual gets two copies of the gene that causes this condition, she has a crippling anemia and will die young.  However, if she gets only one copy of this gene, and a normal gene from her other parent, she can actually have increased survival success.  If she lives in an area with lots of malaria, she will have a lower risk contracting this lethal infection (her red blood cells contract into a sickle shape in which the malaria bug cannot survive -- but only some of her cells do this, because half of them are being governed by a "normal" gene, so she doesn't get the crippling effect of many cells doing this at once).  

The bipolar geneticists are thinking this same kind of thing has happened in bipolar disorder.  There must be some advantage that getting a "small dose" of bipolar genes provides.  And that's not too hard to imagine.  What is a person like in a manic phase?  What if you could have just a little of that?  For example: 

Gene Gene Effect Just a little Too much
A Connect unrelated ideas Creativity Tangential, disorganized
B Seek novelty Fascinated by change, curious Jumping from project to project
C Take risks Courageous Bad judgment about harm
D Be aware of others' opinions Socially polished Anxious, suspicious, paranoid
E High energy level Very productive Can't stop, slow down
Racing thoughts
Unable to focus
Scattered activity

If there are multiple genes that cause bipolar symptoms, then having a few was probably a good thing, in terms of one's reproductive success 10,000 years ago.  Later,  human evolution became dominated by social selection:  those who rose up the social ladder, or started there by being born of social leader, were more reproductively successful.  This pattern has been diminished in the last several hundred years as more and more humans are able to reproduce regardless of their position in the social hierarchy.  But until then, a genetic selection process probably still had major effects on bipolar gene "frequency" -- how many individuals, in the total population, carried one or more genes that in large doses cause illness.  

So our model looks like this: 

Having a few too many genes begins to decrease reproductive success, because the behaviors they cause are becoming too extreme -- in other words, a person with that many genes is becoming "symptomatic".  If you get a few more genes than that, you may have so many symptoms that you cannot function well.  This is what we regard as "mental illness".   

What are the genes involved? (revised August 2003)

Great progress has been made even since Dr. Kelsoe first reported the chromosome 22 connection.  They have found, on that chromosome, the gene for a molecule called GRK-3.  Among other things, GRK-3 is involved in turning off the effects of CRF,  which is the brain molecule that starts the entire anxiety response.  Imagine: if someone's brain couldn't turn off the anxiety generator very well, that would be pretty disastrous (see the summary essay on anxiety as a bipolar symptom if you want more on this connection).  

This latest work, published in May 2003 by Dr. Kelsoe's group,Barrett represents one of the biggest advances in psychiatry ever seen, in my opinion.  If this result holds up (we should wait for the repeat studies to get completely excited), we will have watched a research group go from a disorder; to a chromosome; to a gene; to a specific gene region; to the specific difference in that region in some patients with bipolar disorder; to an understanding of how that gene is performing differently in those individuals (in this case, the region ends up directing the production of less GRK3 in these people, which may -- to early to say yet on this part -- be why some people with bipolar disorder seem more susceptible to stress effects).  The only remaining step to make this sequence of discoveries complete -- after repeating the work, to become more certain of the initial finding -- is to determine if the GRK3 difference really leads to a difference in CRF in these people.  

We already know that CRF is directly implicated in mood disorders.  There are several companies trying to make CRF blockers for use as medications (here's an example).  We may be nearing the development of one of the first psychiatric medications based directly on an understanding of the problem the medication is designed to address. That is a very exciting possibility, as up to now every medication we use has been borrowed from another purpose, or discovered accidentally or by blind trial and error.  Here are the current projects of the UCSD genetics research team, including their work on GRK3 and CRF.  For yet more detail than their site offers, here's a bit more on GRK3 and anxiety.     

Don't forget: you may be able to actually participate in this genetic research if you have a brother or sister who also has symptoms.  Go to the UCSD Genetics Research website to learn more and sign up. 

 

 

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