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Chapter 1: The Genetic Basis of Bipolar Disorder

Summary:
Whereas 10 years ago it was hoped that a single gene for bipolar disorder might be found, it is now clear that many genes are involved.  Indeed, the diagram below tells this story well, and our task in this chapter is to explain that diagram.  In the process we will examine a few particular genes which are best understood in terms of their roles in bipolar disorder.

Bipolar Disorder        Shared Genes            Schizophrenia

Link to Chapter 2


The master diagram

Of course this is not the end of the story about the genetics of bipolar disorder, but it represents a very good beginning.  

Don't worry, I won't snow you with too much basic biology.  But you do remember, you knew this once: there are 23 human chromosomes; 22 pairs, one of each from mom and dad, plus the X and the Y sex chromosomes -- unless you have two X's and no Y, in which case you have more genetic material overall and therefore more responsibility to save the planet (that's the female of the species, guys).

At least one psychiatric illness is caused by a single gene: Huntington's disease.  But so far, nothing else in psychiatry has proved to be that simple.  And unfortunately, bipolar disorder seems to be an opposite story, in which many genes are involved.  Worse yet, it appears that any given individual can have one of many different combinations of these genes, so that there are many different bipolar disorders, quite literally.  

The gene diagram below  illustrates this theme well. In the left column are represented genes known to be associated with bipolar disorder. Actually, these are not individual genes, but rather positions on the various chromosomes.  At these positions are found particular gene sequences which appear to differ in people with bipolar disorder.  In the right column are chromosome positions known to be associated with schizophrenia.  In the middle column are chromosome positions in which particular genetic sequences are associated with symptoms shared by both conditions, such as delusions, hallucinations, and abnormal thought processes (as you probably know from reading elsewhere on this website, these are symptoms of Bipolar I, not Bipolar II.  The latter shares some of the genes of Bipolar I, but clearly not all of them, because it does not share these psychosis genes at all).

Bipolar Disorder        Shared Genes            Schizophrenia

As you can see, any given individual (shown here by the black ellipticals circles) could have one of many different combinations of genes.  You would expect that different combinations would produce different manifestations.  And that is the current thinking on why there appeared to be so many different variations of bipolar disorder. You can see in this diagram that some of those variations share genes with schizophrenia.  For example, someone who had several genes from the left column, but one or two from the middle column, might have symptoms that look a bit more like someone with schizophrenia than someone whose bipolar disorder was associated with genes from the left-hand column only. in other words, the genes in the left column represent relatively "pure" bipolar disorder.  

With my apologies both to you and to the researchers who originally created this diagram, I confess that I have lost the reference for this picture.  However, it is at least three years old now and so quite out of date.  A more up-to-date list of genes associated with particular conditions is shown below.  In this table, we are looking at individual genes, not positions on a chromosome.  In other words, the table below shows a very precise location of gene differences in people with these conditions.  Indeed, in the third column of the table you see that an exact difference in the DNA sequence is known for these particular genes. Don't worry, you don't need to understand any of the details.  The point is to show off how well some of these gene differences are now understood. You could substitute the genes shown in purple below into the left-hand column of the black and white diagram above for a more up-to-date picture. 

Gene
Name
Variant
Effects
SERT
Serotonin Transporter
Gene length polymorphism
Depression, anxiety, alcohol
COMT
Catechol-O-methyltransferase
Val-158-met
Intelligence, BP, schizophrenia
DRD4
Dopamine receptor D4
48 base pair repeat
ADHD
DRD4
Dopamine receptor D4
120 base pair insertion/deletion
ADHD
DAT
Dopamine transporter
Base pair repeat
Schizophrenia
BDNF
Brain derived neurotrophic factor
Val-66-met
BP, cognitive performance
MAO
Monoamine oxidase
Promoter region base pair repeat
BP, cognitive performance
ApoE
Cholesterol transport system
Epsilon E4 allele
Alzheimers, late-life cognitive performance

Particular genes

As I have watched this story unfold, two genes in particular have been particularly striking: one because it seems central to the story, and the other because it represents such an advance in our understanding.  They are not shown in the table above because their exact gene sequence difference has not been determined yet. 

GSK3-Beta 
Glycogen synthase kinase 3-beta  is an enzyme which appears repeatedly at the crossroads between pathways associated with mood problems.  Exactly how it works in creating mood symptoms is not yet known.  But many of the known treatments for mood disorders work through pathways that pass through this enzymatic step, as shown in the following diagram (note the pink rectangle in the lower left-hand corner):

If you read all the way through this story about what causes bipolar disorder, you are going to run into this enzyme again in the section on the biological clock.  Recently it was discovered that lithium works by inhibiting GSK3-beta and thereby restoring normal cycling of the biological clock.  (Lithium works in other ways as well, but this may be one of the most important).

Link to Chapter 2: Brain differences