From what I have seen re: PTSD studies and twin data, heritability is given as 50%. But that is not in fact the case. We know from general population genetic studies that about 20% of a population is susceptible to PTSD and yet only 1/2 those are affected.

OTOH in high stress war zones reports of the % of troops affected runs in the 20 to 25% range. About what you would expect if 100% of the susceptible get enough stress.

Twin studies do not in fact control for environment. As far as I can tell.

I’m sure it can be done (or done better), but that is currently not the case. IMO. I only know this because the study of PTSD is a hobby of mine. So I’m not deeply conversant with the general field of genetics and heritability.

Is that really the right way to look at all this?

Some have noted that all the complexities of genetic interactions have not yet been teased out. Throw in the environment and there are a LOT more threads to untangle.

I think that would provide a clear example of diversity that was once advantageous but has become deleterious in recent times.

Haven’t also claims been made about genetic morphs related to Alzheimer’s that they protect the brain from the consequences of starvation early in development?

And of course there’s good old Sickle Cell Anemia, which exists as a side effect of selection pressures for a trait which is quite advantageous… if there are endemic problems with malaria in your area, which thankfully is no longer the case for most of us.

If you try to get around this by lumping together many families and performing linkage analyses across all of them (which has been done many times) then you dilute real signals if heterogeneity is high.

As it happens, linkage analyses for schizophrenia have identified a large number of loci, but not had the power to get down to specific genes. The inference that all these signals are false positives is an assumption (many probably are but many may be real).

Re the common versus rare dichotomy, the question is which mutations are most important and most likely to get us to the underlying biology? I favour focusing on the ones of large effect, because these can be more accurately said to be “causal” (in the sense that if the person did not have that mutation they would most likely not have the condition). As detailed in the paper referred to above, I absolutely expect an important role for modifiers of these mutations, common or rare, and for oligogenic interactions.

Finally, re selection, you are remaking the balancing selection argument – this requires evidence. Yes, some traits may change in advantageousness in different contexts or over time – this has not been demonstrated for deleterious diseases, especially early-onset ones with demonstrable, negative (current) effects on fitness. I find those claims inherently implausible – that is just an opinion, but the point is that without some evidence to bolster such claims, they should not simply be accepted.

I find it very strange that people are so married to the idea that genetic architecture has to be either “common SNP” or “rare variant”. Why can’t we have some diseases of each type, and some diseases with a combination of these architectures for the very same disease? I expect that when everything shakes out, that is exactly what we’re going to have…common SNPs creating phenotypes that predispose individuals to have particular phenotypes (in particular environments), with the occasional strong effect from a rare variant rising to the forefront.

And to address your argument about selection, that was a non-starter…selection isn’t something that works in just one direction or at just one strength. It’s a force that has variable directionality and variable force. If you haven’t become familiar with Wright’s shifting balance theory, you should.

the problem may be the following
1. many diseases are essentially a constellation of signs and symptoms. they well be a final common destination of a number of paths

2. we in medical science and biology are using mathematical / statistical techniques from the linear ( 2 dimensional ) space to explore complex phenomena. i.e. our mathematics is not capable (as yet?) of making any sense out of phenomena.

3. I think kjmtchl might be right that SOME syndromes may be the result of rare variants producing similar phenotypes in a Mendelian fashion. But this does not address the fact that some disorders may be related to gene regulation and not to a mendelian form of gene expression. And some may work in the Falconer type model. why cannot all of the above be the correct response?

4. stable systems generally will have negative feedback loops tending to bring the system from temporary instability to stability. the more complex the system the more complex the feedback loops and the inter-relationships and interplay between them, and the more difficult it is to predict the end result.

“the evidence for genetic mechanisms playing a major role is overwhelming.”

That’s probably true for ALL disease including infectious disease.

Scientists pinpoint flu gene
http://www.telegraph.co.uk/health/3538487/Scientists-pinpoint-flu-gene.html

“An unlucky combination of “vulnerable” genes could explain why some people recover from the flu overnight and others struggle to shake off the virus for weeks.”

“My initial response is that the abstracts I read are inferring causation from correlation.”

That sounds like 99.999% of the abstracts I’ve read concerning heredity and disease.

Anyway according to the study on US military personnel symptoms occurred after infection with Toxoplasma.

Toxoplasma Infection Increases Risk Of Schizophrenia, Study Suggests
http://www.sciencedaily.com/releases/2008/01/080116123517.htm

“Researchers found that of the 180 study subjects diagnosed with schizophrenia, 7 percent had been infected with toxoplasma prior to their diagnosis, compared to 5 percent among the 532 healthy recruits. Thus, people exposed to toxoplasma had a 24 percent higher risk of developing schizophrenia.”

“Our findings reveal the strongest association we’ve seen yet between infection with this very common parasite and the subsequent development of schizophrenia,” says Robert Yolken, M. D., a neurovirologist at Hopkins Children’s who was among those conducting the analysis.

Previous studies have reported on the link between schizophrenia and the presence of toxoplasma antibodies, which are evidence of past infection, but this is the first study to show that infection with the parasite can precede the initial onset of symptoms and subsequent diagnosis with schizophrenia, Yolken says.

Because the U.S. military routinely tests its active personnel for toxoplasma, among other infectious agents, and stores blood samples in a central repository, researchers were able to determine the time line between infection and a diagnosis of schizophrenia.

“Many schizophrenia patients show shrinkage in parts of their cerebral cortex, and Flegr thinks the protozoan may be to blame for that. He hands me a recently published paper on the topic that he co-authored with colleagues at Charles University, including a psychiatrist named Jiri Horacek. Twelve of 44 schizophrenia patients who underwent MRI scans, the team found, had reduced gray matter in the brain—and the decrease occurred almost exclusively in those who tested positive for T. gondii. After reading the abstract, I must look stunned, because Flegr smiles and says, “Jiri had the same response. I don’t think he believed it could be true.” When I later speak with Horacek, he admits to having been skeptical about Flegr’s theory at the outset. When they merged the MRI results with the infection data, however, he went from being a doubter to being a believer. “I was amazed at how pronounced the effect was,” he says. “To me that suggests the parasite may trigger schizophrenia in genetically susceptible people.”

How Your Cat Is Making You Crazy
http://www.theatlantic.com/magazine/archive/2012/03/how-your-cat-is-making-you-crazy/8873/

“I’d say 75 percent of cases of schizophrenia are associated with infectious agents, and Toxo would be involved in a significant subset of those.”

This seems to imply that in each pathway, there is complete segregation of the components into those that produce qualitative vs. quantitative behavior.

Imagine an enzyme where a particular mutation causes a complete loss of function–i.e. the enzyme fails to catalyze the reaction at all, or so little that the improvement over the uncatalyzed reaction has no physiological relevance. Then it seems logical that other mutations of the same enzyme, even possibly at the same amino acid position, may have milder effects on function, giving less extreme phenotypes that still seem “normal”, just perturbed.

And this view doesn’t even take into account that qualitative changes in behavior need not necessarily arise from complete absence of any one component or interaction, even if they often do. Often, a combination of parameters will determine whether, e.g., a negative feedback is strong enough to keep a system stable.

Besides, haven’t you, or others, argued on this blog that rare variants also contribute substantially to “normal” phenotypes, i.e. things like personality types that are not considered diseases?