week_of_science: genetic linkage and psychosis

People went, on the whole, crazy. The riots and rallies in my city resulted in buses burnt, people hurt, the usual sad story. I wondered about the genetic basis of psychosis. As a matter of curiosity , I decided to look into the genetic basis of insanity. What I found was interesting insights into a couple of diseases that I am very interested in.

Everybody knows that DNA is the blueprint of life. It contains, coded as a sequence of chemical elements, all the information that one needs for life. It would not be straying TOO far from the truth to say that genes – sections of DNA – determine most of our characteristics. At least, predisposition towards certain characteristics.

It is well known that the genes linked to insanity (which by itself is a broad term, and cannot simply be used as I have here) have not been identified. In fact, there are so many implicated (alongside a number of other variables such as environmental factors) that it is generally accepted that a simple solution does not exist. I ‘know’ this, having somehow absorbed it by university-atmosphere-osmosis. The question I asked myself, therefore, was: is there some sort of proof of this complexity?

You could see disease as a state of abnormality. This abnormality comes, presumably, from changes in the DNA – small variations or polymorphisms that code for, say, the natural colour of your hair. It is generally accepted that DNA variation is due to the effect of one or more genes. It is relatively simple to detect a single gene that controls a feature. You just scan the genome of a (large) bunch of people who either have the trait or don’t. If you see a variation that is consistent in all of them: for example, if gene X is expressed in all individuals with condition Y, and not otherwise, then you can conclude that gene X controls character Y. In the case of multiple genes exerting an effect, the procedure is a bit more complicated, but in effect, you can detect a similar pattern. Genes X, Y and Z must be active, and gene A and B must not, in order for a condition L to be true. These studies are called genetic linkage studies, and the basic laws of genetics were derived by Mendel using them to study a pea plant. Luckily for him, there were no environmental factors controlling the characters he was studying. This process is infinitely more complicated when you are studying predisposition towards a disease rather than the occurrence of the disease itself, because if a person without the disease has a predisposition, how do you know? You study his family, that’s how.

You could take a pair of identical twins, who have the same DNA and hence exactly the same predisposition. If one carries the disease and the other does not, then you could conclude that there are some external factors affecting the disease. A trigger, perhaps. Timothy J. Crow in his paper* asserts that changes underlying psychosis are epigenetic : which basically means that DNA sequence does not change, but something in the whole big genetic machinery does. Where does one see genetic machinery? In gene regulation – for example, although all the cells in your body contain the genes to produce insulin, only the Islets of Langerhaans do. It usually refers to the modification of the DNA (methylation, acetylation of histones etc) without changing the sequence of DNA.

Crow’s argument is that several large scale studies have come up with rather discordant results: while one predicts one set of gene loci associated with schizophrenia, another comes up with a different set. A study of genetic linkages over a larger dataset actually weakens, and in a particular case, refutes, the results obtained by a smaller study. Basically, no one has been able to come up with a consistent set of genes that could code for the predisposition towards schizophrenia or bipolar disorder. The experiment when repeated on different scales wind up with different results. So, obviously, these are not valid. Given that there is no conclusive evidence for a multi -gene system, his hypothesis is that there is a single gene or set of genes that code for this disorder. Further, since the X chromosome is not considered in any of the genetic linkage studies, he figures that the genes might be present on both the sex chromosomes. He reasons that there is a strong connection between sex and onset of disease, and thus, if the variation is epigenetic, it is likely to occur during meiosis.His theory is that the disease-state is somehow epigenetically triggered, which is why it is not detected by genetic linkage studies.

To me, his most startling argument is the connection of language and the disease. Given that identical twins have a 40-50% chance of having the same disease state, there must be some other factor that accounts for the difference. He notices that monozygotic or identical twins have different handedness – one left handed and the other right handed and that this asymmetric genetic bias is due to the development of celebral dominance. This is also essential for the development of language. It is known that primates are not left-or-right handed (called directional asymmetry), nor, he says, do they have the faculty of language. He further claims that the symptoms of psychosis are linked to language, be it hallucination, disturbance of thought processes or delusion.Epigenetic factors contribute powerfully for individual differences in the asymmetrical development of the human brain (unique to us). Thus, he links language,epigenetic control, and predisposition to psychosis.

He concludes that that the variation that codes for psychosis is actually on the sex chromosome, is epigenetically controlled and is related to hemispheric dominance for language. I, for one, cannot see how he arrives at that last without first confirming that other primates do not suffer from schizophrenia. Because he shows no proof outside logic, and we know that the communicative property (A give B, B gives C, implies A gives C) is not true in many biological situations.

* Timothy J Crow 2007 How and Why Genetic Linkage Has Not Solved the Problem of Psychois: Review and Hypothesis; Am J. Psychiatry 164:1

Disclaimer: This is neither a thorough review of the subject, nor have I covered all the aspects involved in such a subject. I’m only trying to demonstrate how far we have come, and how much further we have to go. I am not an expert in this field, and am only going to explain some basic concepts in this post.

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5 responses to “week_of_science: genetic linkage and psychosis

  1. You just scan the genome of a (large) bunch of people who either have the trait or don’t. If you see a variation that is consistent in all of them: for example, if gene X is expressed in all individuals with condition Y, and not otherwise, then you can conclude that gene X controls character Y

    just a quibble: what you’re describing is a genetic association study
    http://www.gnxp.com/blog/2006/07/linkage-versus-association-mini-primer.php

    the problem with linkage studies for finding genes involved in complex disease is that the design has low statistical power to find causal alleles of moderate frequency and moderate penetrance. large-scale association studies will likely be more fruitful, and they’ve only recently come online.

    epigenetics does certainly play a role in schizophrenia
    http://hmg.oxfordjournals.org/cgi/content/abstract/15/21/3132?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=schizophrenia&searchid=1&FIRSTINDEX=10&sortspec=date&resourcetype=HWCIT

    but it’s also likely that variation in epigenetic signals has a genetic component. from what you’ve presented, Crow’s argument seems somwhat unsophiticated–before you rule out genetic factors, you have to ask: if there are genetic factors, will our approaches have detcted them? In this case, the answer is likely no, so new approaches are needed (and are being developed).

  2. p-ter:
    Thanks! It’s good to learn. He used “linkage studies”, so I did too. Will try to do better next time.

    I have over-simplified in an attempt to not scare off my non-biology lurker friends. Crow’s argument seems to have quite a few deficiencies, but the advantage I found in his paper is that (I hope) after reading that post, if one reads a paper, it should be more or less manageable. And if they read your comment and your post following, it should help more. 😀

    There are always advances, but what I tried to do here was to take a paper that I found interesting, and present it so that the educated layman has some sense of what sort of studies are happening.
    Obviously, I need to get a good deal better at this. Thanks for dropping by.

  3. A tifr lab dealing with adult neurogenesis has already made an entry into investigating this epigenetic aspect of neurobiology.

    I am certainly excited about it. An epigenetic change being something which can be acquired non-genetically, say as a response to neurobiological experience is essentially a much subtler change to one’s genome than a full blown genetic change. A more dynamic and reversible way of modulating gene expression.

    Look out for maternal separation experiments in mice.

  4. Slightly off the subject maybe, and we all understand some keen gardeners can be lectured by lots of people to be environmentally friendly. However it is also important that you think about people cost. E.G., a few makes of rotovators may be manufactured with child labor in Asia. So PLEASE consider where your rotovator is coming from when you buy. A cultivator manufactured in the US may not be the cheapest, however it’s a very fundamental decision.

  5. Very awesome article! Honest!

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