GENETICS AND MANIC DEPRESSION - Dr Brien Riley

Introduction

This is an enormously complex area of research. Psychiatric traits are different from normal medical traits in many ways. They rely on the individual to report symptoms and there are very few ways to test for differences between people in terms of their biochemical or biological make-up.

What we have is two very closely related but different depressive conditions; major depression and Manic Depression. It is also quite possible that these two conditions are related to schizophrenia and perhaps to psychiatric disorders as a whole. You need to imagine a set of three interlocking circles each of which have elements in common with each of the other two, elements in common across all three and elements which are separated and specific to each of them. That I think is the solution and what we are dealing with.

What is a gene?

What I am about to discuss are psychiatric disorders as a field related to bipolar disorder which is the 'trade' name for manic depression. I think it is important to have an idea of what a gene actually is - and to start with something that I think many people find very confusing. The standard metaphor for this has always been a language written in four letters using very long words. It is a good metaphor but it leaves some of the things that are quite easy to understand, unexplained. So, I am going to try a new metaphor - the metaphor of a road. Imagine a very long single road extending in a line in either direction. There are areas along this road that are built-up into a high street with very heavy traffic and a lot of buildings and things happening around; and there are areas in between where not very much happens which are quite empty and desolate. These areas are separated by regions that are empty but which still contain landmarks and useful information for people such as myself. There are also spaced out along this road stop and go-lights to control the flow of traffic and, most importantly for the illnesses which we are talking about, parking places of various sizes particularly in the built up areas specific to the vehicles that are supposed to be parked there. Normally in classical genetic research what people have looked for are things that resemble very large potholes in the road, things that actually prevent the flow of traffic along the road completely.

What genes do?

What genes do is make people's protein, and proteins are the essence of all living creatures. You can get a very good idea of what a protein is compared to say a rock or air just by feeling the palm of your hand; there is a texture to proteins which is unmistakable - it is the texture of living tissue. They represent most of the important functional elements of the body. DNA, like the genes themselves can be considered as an arterial main road along which this business of making proteins progresses.

Genetics

The origin of genetics began about 110 years ago, with a monk named Gregor Mendel who discovered by looking at peas that offspring carry characteristics from their parents. He also saw (and this perhaps is even more important) that these traits could dominate one another, they could mix or they could be masked. So; red and white flowers would produce all red flowers from the first generation but white flowers would reappear in the second generation as one trait is masked by another trait.

DNA

It was another 70 years before Watson and Crick unravelled the chemical structure of the DNA molecule. It is an enormously complicated chemical substance with a double helix - two mirror-image strands which run in opposite directions, linked all the way along their length and twisting three-dimensionally in space. This molecule carries the information from which proteins are made and all the information required for the development and life of the organism.

Family Studies

There are three critical pieces of research that need to be done in order to establish whether or not a trait is genetic. The first of these are family studies, and they ask the question; does a disease cluster in families? This is very important and it has often been noted by doctors in the past that certain families had more than their share of people who were ill with a particular disease. But while a significant finding there is not sufficient to demonstrate that a trait is genetic.

Twin Studies

The second source of research is twin studies, and these ask the question; how genetic is this disease? The answer to this question is a quantity called the concordance, which is the number of twins who are either both ill or both healthy and it is this quantity that allows us to assess what the impact from both genetic factors and the environment is in the development of an illness. In a simple trait the concordance will be 100% for twins, so all identical twins will either share the trait or not share the trait.

Adoption Studies

Finally there are adoption studies and these are critical because if the disease or any other trait is strictly caused by the environment then in family-shared environments the family resemblance will be present even if the trait is not genetic. So we need to know whether the trait and its clustering in families is related strictly to genetics, or whether there is an environmental component. And here adoption studies can help us study children who have been adopted away from their family and the answer to the question; do they resemble their adopted family? - If yes then we see an environmental component. But if the answer is that they resemble their biological family? - then the evidence is quite strong for a genetic component.

Comparative Data

Our research team has produced some comparative data on Manic Depression and simple depression. Simple depression is much more common than manic depression - about 1% of the population will suffer from Bipolar Disorder and approximately 5% of the population will suffer from depression at some point in their lives. If someone is related to a patient with bipolar disorder, their risk of developing Bipolar Disorder themselves is increased six-fold and their risk of major depression is increased by slightly more than twice. Thus, being related to someone with Bipolar Disorder increases greatly your risk of suffering not only from bipolar disorder, but also from depression. For people who are related to individuals with depression only the increase in risk is approximately three times for each of them - from ~0.8% to ~2.6% for bipolar disorder and from ~5% to ~15% for depression. This tells us two fairly important things: first that there is some relation between the causes of these two diseases, because risk for both is increased by being related to a patient with either of them. It also tells us that there are elements that are necessary for manic depression which are not necessary for simple depression. What this means is that Bipolar Disorder is a complex condition.

In twin studies of this condition it has been shown that identical twins seem both to have Bipolar Disorder between 70 - 80% of the time, and this indicates that this trait is highly genetic and that approximately three-quarters of the liability for manic depression is contained within the genes with the remaining 25% being an effect of the environment, life events and other issues within the individual's life. Twin studies also allow us to parcel out these three elements i.e. genetic elements; shared environment between the two individuals; and non-shared environment. What can be seen is that for manic depressive illness, 86% of the liability to this trait is estimated to arise from genetic material, and only about 7% each from the common and non-shared environment. If this is compared to Major Affective Disorder (which is depression alone) we can see that this appears to be approximately 50% versus 30% for environment and 18% for things which are different between related individuals.

Complex traits: (a) Generally
We now return to the idea of a complex trait and this is probably the most important thing to understand about research into psychiatric illnesses and the genetic components of them. There are many illnesses (the words illness and trait can be used interchangeably) which do not follow the pattern that Gregor Mendel observed for peas i.e. they are not simple and straightforward - and these are called complex traits. In classical genetic illnesses usually only one gene is involved and either something happens to that gene that resembles a very large pothole in the road that we were discussing earlier, or the loss or a bridge somewhere along the road causes the gene to cease to function. This is clearly not the case with psychiatric illnesses. These illnesses involve more than one gene and also involve non-genetic causes including life events, biological environment, and psychological and social environment. In other words there are many things that come together to create the liability in the individual.

(b) In Schizophrenia

In Schizophrenia for example, a certain kind of analysis suggests that there are three or four genes involved, when even three or four elements makes for a problem of staggering complexity. However, these illnesses are worth pursuing and worth researching because they affect so many people. Bipolar Disorder and Schizophrenia each affect about 1 in 125 people, so ten times as many people will suffer from Manic Depression and Schizophrenia as will suffer from Cystic Fibrosis. Therefore any progress in this field is going to affect a great number of people, the estimates are 500 000 at any one time affected with schizophrenia or with manic depression in the U.K. It is important to realise that the elements that cause these illnesses are very common and - reverting to the road image - rather than representing complete failure in the road network itself, what they represent is part of the normal variation that is present in all of us - e.g. some of us have brown hair or blonde hair, blues eyes, green eyes, and this same kind of variation is likely to be responsible for these illnesses.

(c) In Manic Depression

In the research work that has been carried out on Manic Depression, there have been several very encouraging results; the top two in particular on chromosome 21 and chromosome 4. Although these findings have been replicated, no gene has yet been identified in either loccation. Moving to that level will allow us to develop better therapy, and better preventative measures and to determine people who are at particular levels of risk. There are so far no major susceptibility factors which have been identified, but there are a number of apparently moderate or minor susceptibility factors in four locations: two on chromosome 18, one possibly on chromosome12 and one on the X chromosome which may contribute to this illness. These have, unfortunately, not been replicated as yet and they also are not linked to an actual gene; so these are still very open-ended findings for the moment.

What are we looking for?

The question is: what do we actually look for when we are doing this kind of work? Fragments of DNA are analysed which consist of repeated sets of the letter TG. These repetitive pieces of DNA are very useful. Going back to the road again they tend to be in the desolate wastelands between the built-up regions of the DNA and they vary from person to person. By finding out the size of the short stretch of Ts and Gs in an individual we can tell which of their two parents they have inherited it from. We can then begin to associate particular sizes of the stretch of DNA with the trait. These are not responsible for causing the illness themselves, but, if for example just off the bottom of this stretch of DNA there is a gene which is related to the condition, then this little piece of DNA will tend to be inherited with the condition as well; and it is this that we look for - finding pieces of anonymous DNA like this which tend to segregate with disease tell us that we are somewhere close to the actual location of a gene which is involved in the cause of the illness.

The Seratonin transporter

Finally, I would like to mention some research which David Collier and our research group are doing on the seratonin transporter and its possible role in both depression and Manic Depression. The brain, as an organ, is a network of cells which are almost connected but not quite - there are tiny gaps in between them. These cells need to be able to communicate with each other and with other cells a long distance away. And in order to be able to communicate they need a method of crossing this tiny gap between them. The method that all living creatures have evolved is to spray a tiny amount of a chemical from the end of the cell before the gap which is called the synapse - across the gap to the beginning of the next cell, and it is by this process that the communication network is completed. One such chemical is called seratonin and has been a focus of interest in both depression and Manic Depression. Seratonin is known to be involved in moods, appetites, sleep and reaction to pain and there are several other biochemical studies that suggest that there are differences in people who are depressed or who have Manic Depression compared with normal individuals. There is a protein in the body whose sole function is to move around in the gap between to two nerve cells, re-collect the seratonin and return it to the first cell for re-use. This protein is known as the seratonin transporter. In order to examine and determine whether there is a genetic relationship between this gene and depression in people and possibly the therapeutic elements, genetic work was undertaken by colleagues in our department.

What the team has found is that there is a strong association between one size of a piece of DNA and liability to Manic Depression. This is a particularly significant result for a number of reasons. It is the first gene-specific strong, positive result that has been found in this field and it is a great step-forward actually to find a gene that appears to have a real change and a real difference between individuals that are ill and individuals who are not ill. And I believe that this will ultimately move our understanding of this condition forward by a huge degree. Unfortunately, the piece of DNA that my colleagues looked at can be shown not to be the causal element itself, although it shows that it is very close to whatever the causal element is. We are currently trying to find this causal element in this piece of DNA, and although this result can be regarded as preliminary it is still very exiting.

What the Institute is doing:

Studying the factors which predispose to bipolar illness, and assessing the value of a range of different drug and psychological treatments as well as better alternatives to ECT for depression.