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beowulf888's avatar

Fascinating article!

Do you have links to any studies that support the validity of polygenic liability threshold models? I found a couple of studies up on Google Scholar where the authors claimed a PLT model couldn't explain the data (a paper on sex differences in autism rates, and a paper on heart disease, CVD, and Type II diabetes in Korean populations). In the pro-PLT model camp, I found a meta-study that implied that PLT model worked for the observed data for 8 psychiatric disorders.

How controversial is this model? I'm inclined to believe it, though, but I'd like to see more pro-PLT model studies to fully buy into it.

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Federico Soto del Alba's avatar

Not really useful comments, but, I get the intuitive impression the rarer a disease is the more genes are involved in polygenic disorders. I get the feeling there is a sort of diffusion of "liability" distributed among several, perhaps hundreds of genes with different prevalences in the population, and different probabilities by their lonesome to increase the probability of having a disease, making estimations of likelihood from several of the sources in the comments unreliable. Two sources I really have no idea what they are!. I just picture the interactions changing probabilities in uncanny ways, uugggh!.

Like the estimations are somehow fitted on the data, instead of the data making the estimation. And with a lot of simplifications. Good thing I never considered being a Clinical Geneticist...

And it might seem esoteric stated as such, but although I am not sure, I am confident if we were to add up all diseases in a closed population, the estimates would lead us to conclude all members of said closed population should not be alive!, let alone healthy, from those sources of "estimation" data.

And if pedigree is the weakest it can point into my strong confidence: real vast world data won´t match the predictions.

Just 1 in 200 having two Genetic Diseases really does not reflect the World as I see it, and it comes from the WHO...

Which makes me question the reliability of so many mutations used for diagnosis described in many genetic disorders: dozens, hundreds of mutation for a given condition. Some, or many without a causal mechanism, well enough established of course.

And molecular mechanism are subject to all the problems for them to be published and known, so, double...

But, it seems I am missing a view of how these things move from monogenic diseases, to bigenic, trigenic, tetragenic, etc...

It could be illuminating. And it can start a fad: Oh, I have a quadgene disease...

Then something missing from the comments is somewhat of an understatement: the environment.

Having an environmentally independent threshold does really not work for the most common polygenic diseases: Hypertension, Diabetes, Obesity, Hypercholesterolemia, Coronary Artery Disease, Chronic Pulmonary Obstructive Disease and Stroke.

Let alone Cancer... and Occupational Diseases...

All of those are predominantly Modern Living diseases, even if Atherosclerosis seems to be there in other not that "modern" societies. But surely, limb amputations for chronic arterial insufficiency must be rare in those places: just the exercise, which is the best treatment for it...

I think such is an important point: for the most common polygenic diseases, the environment is determinant.

or am I wrong on those? :)

Then the really bad issue is Psychiatric Diseases: that´s hocus pocus. Those are not Diseases, there is not Neuropathology to them, and estimates of heritability and prevalence/incidence in the Population are just crazy: Some places have over 50% of depressed women.

Some have 30% of kids with Autism, etc.

And shifting from the steadiest of them all in the past: Schizophrenia, to Bipolar disorder, now with a 1% Prevalence is nuts. Bipolar disease used to be 1 in 1,000 to 1 in 10,000 disease, and it took decades of depression turning into a first maniac episode to be diagnosed. It was called Bipolar for a reason, and cycling took years, and most people really did not have many maniac florid episodes.

As such, either it is not the same disease, or a lot of the now called diseased are not sick at all.

Because all Diseases models needs to be History Resistant: they need to explain the past too.

Specially in Genetics!, right? :P

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