![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 14 of 14. This is the beginning of the thread.
Posted by Larry Hoover on January 17, 2009, at 20:19:46
There's a new way of looking at genetic influences upon illnesses. How is it that two people with the same genes, such as identical twins, often have one member ill while the other is healthy, even though the disorder is considered to be genetically linked? The answer is non-genetic changes to DNA, modifications superimposed on the genes, called epigenetics. Epi- means "in addition to".
I remember when I was 11, and we were being taught about the development of a human being from one fertilized ovum. One cell was the source of all the different tissues in the body. But we were also taught that nerve cells reproduced to form other nerve cells. Muscle cells begat muscle, and so on. There was an inherent paradox in that. How did cell types differentiate, if they could only reproduce copies of themselves? It turns out that the differentiation is mediated by epigenetic factors, i.e. genes are switched on or off.
Flying in the face of standard genetic theory, epigenetic changes leading to adaptation of a parent to his or her environment can be passed along in germ cells to their progeny. So, it is possible that not only genes, but gene regulation is heritable.
http://biology.mcgill.ca/undergrad/c524a/articles2007/Chandler_Cell128.pdf
A recent paper out of North America's only lab studying epigenetic influences on mental illness offers some insight into epigenetic changes and psychosis in bipolar disorder and schizophrenia.
I wouldn't be surprised to discover that kindling, the idea that recurrence of mental illness becomes more likely the more times it occurs, is actually an epigenetic phenomenon. Or that PTSD is an epigenetic phenomenon.
We're only just scratching the surface on the subject so far, but seeking purely genetic factors for disease may have to take a back seat to epigenetics.
Lar
Posted by SLS on January 17, 2009, at 20:58:53
In reply to Epigenetics and mental illness, posted by Larry Hoover on January 17, 2009, at 20:19:46
If you think about it, most cases of mental illness are epigenetic. The reason I say this is because there are always psychosocial environmental stressors and the resultant response in gene activity that creates changes in psychodynamics. Even the environment and events in the womb can be differential between identical twins. If the system is contemporaneously vulnerable to dysregulation with the exposure to these environmental stresses, gene activity - expression or non-expression - changes inappropriately. The native blueprints for checks and balances are disregarded.
- Scott
Posted by Phillipa on January 17, 2009, at 23:34:08
In reply to Re: Epigenetics and mental illness, posted by SLS on January 17, 2009, at 20:58:53
Like skin cancer sun damages skin and ages skin makes it more suseptible to skin cancer cause the epigenes have been altered like the lung and smoking ages the lung. So what a mother ingests during preganacy can alter the child am I even close? Phillipa
Posted by linkadge on January 18, 2009, at 8:29:37
In reply to Epigenetics and mental illness, posted by Larry Hoover on January 17, 2009, at 20:19:46
I also read that certain mood related epigenic changes can be reversed by HDAC inhibitors like valproate. Valproate has only *some* adjunctive efficacy in schizophrenia and *some* adjunctive efficacy in depression however.
Also, don't agents like SAMe increase DNA methylation, yet it is an effective antidepressant for some people.
Linkadge
Posted by Larry Hoover on January 19, 2009, at 8:03:27
In reply to Re: Epigenetics and mental illness, posted by SLS on January 17, 2009, at 20:58:53
> If you think about it, most cases of mental illness are epigenetic. The reason I say this is because there are always psychosocial environmental stressors and the resultant response in gene activity that creates changes in psychodynamics. Even the environment and events in the womb can be differential between identical twins. If the system is contemporaneously vulnerable to dysregulation with the exposure to these environmental stresses, gene activity - expression or non-expression - changes inappropriately. The native blueprints for checks and balances are disregarded.
>
>
> - ScottI agree with you, Scott. I was trying to make a case for purely epigenetic phenomena associated with mental illness.
Up until now, vast effort and expense have been invested into finding genes associated with e.g. schizophrenia, or bipolar. There's a thread just up the page about this very subject. The problem I see is that these sorts of linkage analyses might help narrow down the biochemistry of etiology of the disorder, but the studies invariably turn up far more people with the unusual gene form who don't have overt symptoms than those who do. As well, frequently there's a majority who suffer from the disorder who don't have the gene, either. So, false positives and false negatives coming out the woohoo.
Getting back to your point, I would summarize to say that genes define the upper and lower bounds of physical expression of some trait, while environment determines where in that range the trait is expressed. And, the latter can change over time.
I'm beginning to suspect that these unusual genes that may confer additional risk of developing these mental conditions may actually, and coincidentally, happen to mimic the more common epigenetic changes that mediate the development of the disorder in the majority of cases. If this is the case, and we figure out how to re-regulate these genes, the idea of cure becomes at least a theoretical possibility.
Lar
Posted by Larry Hoover on January 19, 2009, at 8:06:48
In reply to Re: Epigenetics and mental illness, posted by Phillipa on January 17, 2009, at 23:34:08
> Like skin cancer sun damages skin and ages skin makes it more suseptible to skin cancer cause the epigenes have been altered like the lung and smoking ages the lung.
I believe you've picked examples of genetic injury leading to e.g. cancer. Not to say that epigenetic changes don't also occur, but gene mutations are found in both situations.
> So what a mother ingests during preganacy can alter the child am I even close? Phillipa
Yes, what the mother ingests influences the child's development. Some, or maybe most of that effect would be epigenetic.
Lar
Posted by Larry Hoover on January 19, 2009, at 8:16:02
In reply to Re: Epigenetics and mental illness, posted by linkadge on January 18, 2009, at 8:29:37
> I also read that certain mood related epigenic changes can be reversed by HDAC inhibitors like valproate. Valproate has only *some* adjunctive efficacy in schizophrenia and *some* adjunctive efficacy in depression however.
You're way ahead of me on mechanisms, linkage. I had to look this up. The thing is, HDAC is suppressive of gene transcriptional activity generally, rather than specific to individual gene loci. I don't think we can generalize. At least, not yet.
> Also, don't agents like SAMe increase DNA methylation, yet it is an effective antidepressant for some people.
>
> LinkadgeMethylation of a suppressor gene would increase the expression of another.
What I'm trying to say is that methylation and histone acetylation and other biochemical changes are regulators of gene expression, assuredly. I don't know that general up- or down-regulation of these processes can lead to predictable outcomes. Yet.
Lar
Posted by SLS on January 19, 2009, at 13:16:59
In reply to Re: Epigenetics and mental illness » SLS, posted by Larry Hoover on January 19, 2009, at 8:03:27
> Getting back to your point, I would summarize to say that genes define the upper and lower bounds of physical expression of some trait, while environment determines where in that range the trait is expressed. And, the latter can change over time.
Wow. I really like that.
- Scott
Posted by Larry Hoover on January 19, 2009, at 14:13:29
In reply to Epigenetics and mental illness, posted by Larry Hoover on January 17, 2009, at 20:19:46
This was just published yesterday. I have never ever seen such a small P value.
Lar
Nature Genetics
Published online: 18 January 2009 | doi:10.1038/ng.286
DNA methylation profiles in monozygotic and dizygotic twins
Zachary A Kaminsky1,2, Thomas Tang1, Sun-Chong Wang1,3, Carolyn Ptak1,2, Gabriel H T Oh1,2, Albert H C Wong1,2, Laura A Feldcamp1,2, Carl Virtanen4, Jonas Halfvarson5,6, Curt Tysk5,6, Allan F McRae7, Peter M Visscher7, Grant W Montgomery7, Irving I Gottesman8, Nicholas G Martin7 & Art Petronis1,2
Top of pageTwin studies have provided the basis for genetic and epidemiological studies in human complex traits1, 2. As epigenetic factors can contribute to phenotypic outcomes, we conducted a DNA methylation analysis in white blood cells (WBC), buccal epithelial cells and gut biopsies of 114 monozygotic (MZ) twins as well as WBC and buccal epithelial cells of 80 dizygotic (DZ) twins using 12K CpG island microarrays3, 4. Here we provide the first annotation of epigenetic metastability of 6,000 unique genomic regions in MZ twins. An intraclass correlation (ICC)-based comparison of matched MZ and DZ twins showed significantly higher epigenetic difference in buccal cells of DZ co-twins (P = 1.2 x 10^-294). Although such higher epigenetic discordance in DZ twins can result from DNA sequence differences, our in silico SNP analyses and animal studies favor the hypothesis that it is due to epigenomic differences in the zygotes, suggesting that molecular mechanisms of heritability may not be limited to DNA sequence differences.
Posted by diego on January 19, 2009, at 19:49:08
In reply to Re: Epigenetics and mental illness » Larry Hoover, posted by SLS on January 19, 2009, at 13:16:59
Then there's Gregory Cochran's infectious disease model.
You guys ever heard of that?
Plausible...
Posted by Elanor Roosevelt on January 28, 2009, at 22:07:32
In reply to Re: Epigenetics and mental illness » Larry Hoover, posted by SLS on January 19, 2009, at 13:16:59
> > Getting back to your point, I would summarize to say that genes define the upper and lower bounds of physical expression of some trait, while environment determines where in that range the trait is expressed. And, the latter can change over time.
>
> Wow. I really like that.
>
>
> - Scottyes Scott, quite well put
the genetics are in place but can be effected by negative or positive environmental stimulithe things i do that mimic my father amaze me
not just the alcoholism and the whacko brain chemistryrecently i have been waking in the night and find myself holding on to a plank on my headboard--took a while to remember i used to see my dad do that--an attempt to keep oneself from falling up i think
Posted by antigua3 on January 29, 2009, at 10:33:44
In reply to Epigenetics and mental illness, posted by Larry Hoover on January 17, 2009, at 20:19:46
I would have to question that PTSD is an epigenetic phenomenon. I just don't see it. Maybe based on our genetics, my children might be more likely to have PTSD if something damaging happens to them, but I don't think epigenetics would be a predictor that something would happen to them to result in PTSD.
Or maybe I'm not understanding. PTSD is related to an event(s) that occur and that seems to me to be an environmental/social factor rather than genetics.
antigua
Posted by Larry Hoover on January 29, 2009, at 11:31:44
In reply to Re: Epigenetics and mental illness » Larry Hoover, posted by antigua3 on January 29, 2009, at 10:33:44
A person has the same genes before and after the event that triggers PTSD. Epigenetics says that the genes are working differently than they were before. It's like switches are thrown. The body reacts in a different but stable physiological pattern to new stimuli. Some genes are more active than they were, and some less so. The kind of change I'm talking about appears to be at least semi-permanent. And, bizarre as it may sound, these non-genetic gene regulatory changes can be passed down to the next generation(s).
Lar
Posted by antigua3 on February 1, 2009, at 13:19:48
In reply to Re: Epigenetics and mental illness » antigua3, posted by Larry Hoover on January 29, 2009, at 11:31:44
OK, I get it now.
Thanks,
antigua
This is the end of the thread.
Psycho-Babble Medication | Extras | FAQ
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.org
Script revised: February 4, 2008
URL: http://www.dr-bob.org/cgi-bin/pb/mget.pl
Copyright 2006-17 Robert Hsiung.
Owned and operated by Dr. Bob LLC and not the University of Chicago.