November 17, 2005

Another gene linked to Schizophrenia (PDE4B)

Scientists move forward understanding of schizophrenia

A Scots-led medical research team has identified a new gene linked to major mental illness that links back to a previously discovered gene known to increase the risk of schizophrenia and depression. Scientists from the Universities of Edinburgh and Glasgow, together with scientists from the pharmaceutical company Merck, Sharp & Dohme Limited, report the discovery of the second gene, phosphodiesterase 4B (PDE4B) in the prestigious journal Science today (17 November). Their discoveries could lead to the eventual development of new drugs to treat mental health problems.

In 2000, researchers at the University of Edinburgh identified a gene they called Disrupted in Schizophrenia 1 (DISC1), which was found to increase the chances of people developing schizophrenia, bipolar disorder (manic depression) and major clinical depression.

Now, new research by the two Universities and by scientists from the pharmaceutical company Merck Sharpe and Dohme reveals that damage to the gene PDE4B is also seen to increase the risk of developing mental illness. PDE4B was already known to play an important role in how the brain thinks and builds memories, but had not previously been linked to mental disorder. In addition, researchers have discovered that DISC1 acts as a regulator for PDE4B, creating a 'pathway' between the two genes.

Professor David Porteous at the University of Edinburgh said: "This is another important breakthrough in our still limited understanding of major mental illness. It is the result of a long term research commitment to use the tools of genetics to better understand the root causes of mental disorder.

"This has been a fantastic combined effort. The collaboration between the Universities of Edinburgh and of Glasgow, jointly with our research colleagues at Merck Sharpe and Dohme has really made this happen.

"It is now clear that the DISC1 gene plays an important role in the risk of developing schizophrenia or bipolar affective disorder. The new genetic link we have made to PDE4B and how that links back to DISC1 sheds much needed light on these debilitating disorders. It also suggests a new way of thinking about developing better and effective medicines."

Professor Miles Houslay of the University of Glasgow said: "Over the past few years we've been working hard to help in the development of medicines for treating asthma and chronic obstructive pulmonary disease by inhibiting very similar enzymes to PDE4B. It has been so exciting to work together with the Edinburgh and Merck groups in finding this new link between the gene coding for PDE4B and schizophrenia. This new research has the potential for developing novel ways of diagnosing and treating this debilitating disease."

Peter Hutson, the Neuroscience Research Centre, Merck Sharp & Dohme, said: "Mental illness remains a scourge of society. Our insights into the important role that the proteins PDE4B and DISC1 may play in the mis-function of the brain that leads to schizophrenia will lead our thinking in the development of new treatments for this disorder"

For More information see BBC News Story: Mental illness genetic risk found


Genetics is indeed the Science of Small Discoveries! Leading schizophrenia researchers, like Daniel Weinberger and Robin Murray, now realize that the known schizophrenia genes are no more than susceptibility genes, that (at most) double one's risk of developing the disorder. This weak effect, although necessary, can also be seen in identical twins of schizophrenia cases, who have less than a 50% risk of developing the disorder.
The pure phenotype of schizophrenia, driven solely by these weak causative genes, is often seen in the poorer nations, as a mild, self-limiting psychosis in young adults. The outcome of such purely genetic schizophrenia is far better than in the West, with 50% of cases recovered within 2 years, and 64% symptom-free within 5 years of onset--without any drug treatment. Only 10% of Western cases enjoy a full natural recovery.
These striking international differences, discovered by WHO surveys, have a compelling nutritional explanation: the fatty Western diet, which causes heart disease and diabetes, also causes a marked increase in these diseases in the families of schizophrenia patients. Fatty maternal diet causes lifelong anxiety disorder in the offspring, which severely aggravates any psychosis genes harboured by the latter. In addition, the offspring of fat-eating mothers frequently eat a fatty diet themselves, which will independently cause diabetes, and also convert anxiety to depression. Although we need to know what schizophrenia genes do, a complete understanding of the disease depends much more on understanding the role--especially in Western cases--of prenatally acquired anxiety disorder, and the added role of personal fatty diet.

Posted by: Dr Robert Peers at November 21, 2005 03:37 AM

Dr. Peers,

Your comments are interesting - but I've never seen much data that supports your claims. In fact, quite the opposite:

Just last week a genetics researcher who is publishing his research in the American Journal of Medical Genetics stated that " a paper accepted by the American Journal of Medical Genetics, where we show a five times greater risk of schizophrenia in people who carry a certain version of the gene DISC1" (see the Oct. 28th news story on this site for more information) - so - here we have a geneticist stating that a mutation in this one gene confers 500% greater risk for schizophrenia. I've also talked with Daniel Weinburger - and he has suggested that they believe its likely additive - so if you have a mutated DISC1 gene, your risk could be increased by 500% and if you also have a specific version of the COMT gene, it could increase your risk by an additional significant percent (I don't have the exact number in front of me.)

Additionally - we saw in research that came out on October 24th of this year from Stanford University (again, I spoke with the researchers) - they are saying that if you have the 22q11.2 microdeletion in your DNA your risk of schizophrenia goes from 1% to 33% (or 33 times increased risk from this one gene mutation). So again - your claim that genetic mutations can "(at most) double one's risk of developing the disorder" seems wildly innacurate.

With regard to the WHO studies - I'm only familiar with a single WHO study in the area you speak, and since I've travelled extensively in Africa, India and other lesser developed countries - I would be skeptical of the validity of a single study done in these very poor countries who may not have the same standards of measurement for schizophrenia (and for definitions of recovery). Are you relying for your statement entirely on that single WHO study on incidence and recovery related to schizophrenia?

On the fish oil side - early researchs suggests that it looks "interesting" and at least one researcher (Dr. Peet at Shefield University) is very optimistic - but on the contrary side we have a link to a Cochrane review of this topic (under the "schizophrenia treatments" link on the home page - and they say that while it looks interesting there not enough proof to suggest making any definite claims regarding fish oil and schizophrenia. So, again - we'd like to see some larger double blind research studies done by well-recognized professional organization that specifically support the claims you're making, or are you just conjecturing that its your theory/belief that this could be beneficial?.

Perhaps you can provide some scientific journal references that back up your claims?

Best regards,

Posted by: szadmin at November 21, 2005 10:09 AM

Help! I could not get my return comment accepted yesterday, due to some problem with a security number. Am I supposed to keep a record of the first 6-digit code number, and use only that number for subsequent posts? And what is the meaning of "Remember me?"--does that mean I should not enter any 6-digit code number in later posts? Would somebody please e-mail me with exact instructions on how to get my posts accepted through your system?

Posted by: Dr Robert Peers at November 22, 2005 06:44 PM

Wow! What a challenge! I thank you for being a very good Devil's Advocate, expressing deep doubts about everything I say! This is in the true spirit of Science. Now, can I defend my various claims, and do I have credible support from published data? I believe so. To answer, point by point:

1. I am no expert on scz genes, or on how strongly they increase disease risk: my claim that, in general, they are surprisingly weak, is based on comments made by Robin Murray and Dan Weinberger, who now expect greater effects from gene combinations, and not much from individual genes.
It remains to be seen, whether such gene combinations occur at all often in scz--I must say I am doubtful, since there are strong non-genetic factors (anxiety and fatty diet) that seem quite sufficient to precipitate scz in the presence of even one weak predisposing gene.
Murray and Weinberger have clearly not considered these extra factors, so are clinging to the untenable assumption that scz is a purely genetic disorder, that they will be saved by mysterious gene combinations.
If some stronger gene is found, I can accept that, but I cannot accept the chromosome 22q11.2 deletion as a representative scz genetic fault, because is this not the cause of a rare syndrome (velo-cardio-facial syndrome), that incidentally includes scz? It is not fair to include this lesion.

Overshadowing all genetic research in scz, there is good presumptive evidence that most scz genes are weak--except in (theoretical)combination. I refer to the historical rise in prevalence of insanity (confined to the fat-eating Western industrial nations) after 1800, and the rarity of descriptions of typical scz before that time (E Hare, E F Torrey). In addition, the very low pairwise concordance for scz in identical twins (30%) does not support the assertion that scz genes have powerful effects!
Finally, it is obvious that scz researchers who have not noticed co-morbid added anxiety in most Western cases, or considered any role at all for nutrition, are forced to rely on strong genes (or imaginary combinations of weak ones)

2. About those WHO studies (the International Pilot Study of Schizophrenia, 1973, the 2-year and 5-year follow-up studies, and the Determinants of Severe Mental Disorder study): strict diagnostic criteria were used in all countries involved, and the far better outcome in Third World nations is now widely accepted, although rarely mentioned by psychiatrists, who remain unable to explain this fascinating difference.

If you have any doubts about the WHO's methodology, I suggest you write to the study authors, Prof Norman Sartorius in Geneva, or Prof Assen Jablensky, in Perth, Australia. Both are extremely intelligent and scientifically rigorous epidemiology researchers, well acquainted with the challenges of defining scz and scz recovery in poorer nations. It was pioneer scz researcher Emil Kraepelin who, on noticing apparently milder scz in Javanese in 1906, along with an absence of manic depression, first suggested that international comparisons be made on psychosis prevalence and presentation.

The WHO's four studies (not one), commencing in 1973, have now given us the Holy Grail of all epidemiological research--a probable nutritional and intergenerational cause of the aggravated scz syndrome that we see in the West, that often presents as "Stressophrenia".

A striking example of intergenerational nutritional effects on scz incidence is the very high scz rate in second-generation West Indies immigrants born and raised in fat-laden London. Back in Trinidad and Tobago, not much scz is seen.

Posted by: Dr Robert Peers at November 22, 2005 08:10 PM

Dr. Peers,

I would be interested in seeing your fully referenced explanation. Thanks! ("PS Regarding my hard-won discovery, that fatty maternal diet is indeed the direct cause of the anxiety disorder affecting 20-30% of Western people, plus a majority of Western scz cases, I would be pleased to provide a fully referenced explanation, if you would care to see it.")

Posted by: Bob Chang at April 27, 2006 10:53 AM

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