Sorry, links got lost somehow! See annotated post here: http://wiringthebrain.blogspot.com/2012/04/robustness-and-fragility-in-neural.html

Thanks for that. That is exactly what I think is the major mode of robustness here - distributed robustness of the system as opposed to redundancy of parts. Thanks for the refs. Kevin

Rosko, you hit on a really interesting and, I think, crucial question. If mutations in so many different genes can result in autism (or schizophrenia or epilepsy), then the question shifts to why those particular phenotypes emerge. This is not just down to a general degradation of brain systems nor to the specific primary effects of each mutation on any particular brain system. It is a property of the system itself, that when disturbed in various ways, it tends to gravitate towards particular pathophysiological states. What the chain of events is that leads from any specific mutation to the eventual phenotype is not clear (though it can be investigated directly in animal models). What is clear is that, for the vast majority of cases, we will not be able to predict the phenotype accurately even from full genome sequences, given that even monozygotic twins show a wide range of phenotypic expression. This is a neurodevelopmental question - you cannot relate genotype to phenotype directly. The genotype is expressed through the processes of development - these may channel the system into particular states (typically functioning in most cases, but specific pathologic states in others). And these processes are intrinsically noisy, contributing substantially to phenotypic variance.

DR01D: "Research that looks for correlations between heredity and illness becomes less impressive by the day"??? How a report on the discovery of four new genes in which mutations cause autism leads you to that conclusion is baffling.

Well, you're right, I overstated the case with respect to these specific discoveries, though the fact that NTNG1 mutations have previously been found (multiple independent times) in Rett syndrome makes that finding pretty strong. The others look strong from these three papers but time will tell. More generally, we already know of over a hundred separate genetic conditions caused by mutations in either single genes or by copy number variants that can cause autism (see, for example: Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Betancur C. Brain Res. 2011 Mar 22;1380:42-77). They do not always result in the symptoms of autism (as in Fragile X syndrome for example, where autistic symptoms are common but not universal), but, in the cases where the individual does have autism, the evidence that the specific mutation is causing those symptoms is extremely strong (i.e., the most reasonable and probable inference is that if they did not have the mutation they would not have autism). In contrast, previous associations with common SNPs, which supposedly contribute only a tiny increase in risk alone but a large effect in aggregate, have not held up over time. In my opinion, that is because that model of the genetic architecture of illness is not correct - that does not imply (at all) that the illness is not primarily genetic.

I also don't find associations with increased risk in the range of 10% very convincing (e.g., expressed as natural frequencies, from an average population risk of say 1% to an increased risk of 1.1%). Many GWAS results are actually less than that, which is why it is very hard to interpret what they mean in an individual. In contrast, the risks associated with mutations in genes like FMR1, MeCP2, PTEN and many many others now identified are huge - ten, twenty, thirty-fold. Any of these mutations is thankfully rare, but that does not bear on the magnitude of the effect in the individuals who carry them. It just means we have a long way still to go to account for all or even a majority of cases.

Regarding the idea that many diseases represent the extreme end of a normal distribution, it is clear that where the line is drawn, in terms of who gets a clinical diagnosis, can be blurry. What I am arguing against is the assumption that the genetics of a trait like sociability, for example, is the same as the genetics of a symptom like social withdrawal. There can be a normal distribution of a trait and deviations from that distribution that are caused by different mechanisms. I argue that you need some major insult to get a serious phenotype - not just an accumulation of very small variants, because the system has to deal with that kind of variation all the time. For example, at the ends of the normal distribution of height you don't get dwarfism or giantism suddenly appearing (say in breedings of quite short or quite tall people) - these major effects on phenotype are caused by single mutations. Same for mental retardation or intellectual disability - the genetics of these conditions are not the same as the genetics of IQ. The point is that the genetics of how a system varies is not necessarily the same as the genetics of how the system fails. (And, in my view, should not be expected to be the same). Re height itself, the normal distribution could be caused all by common variation - there is no evolutionary reason why that should not be the case. But it could also involve a lot more rare and unique mutations that have larger effects in individuals than all their SNPs combined.

Joe, why is the idea that complex diseases are caused by different rare, partially penetrant mutations in different genes in every individual a "very special model"? (Obviously not different genes in every individual but possibly mutations in any of hundreds or maybe even thousands of different genes). That is exactly the architecture of mental retardation, inherited blindness, inherited deafness, epilepsy and many other conditions defined by surface symptoms. We already know that mental retardation can be caused by mutations in any of a large number of different genes and so nobody would think of doing a population-based study lumping all cases together. We are now learning that the same is true for autism and schizophrenia. Treating them as unitary disorders is an assumption that I argue is not supported.

I would argue that common diseases are caused by effectively Mendelian alleles in many cases - we now know of many examples, especially for autism and schizophrenia. We still have to explain incomplete penetrance, but that is dependent on phenotypic definition - are we looking for penetrance for one specific diagnostic category, for psychiatric illness more generally, for some neurobiological or behavioural endophenotype? We should expect there to be genetic interactions with other mutations in the background - ones that either have an effect alone or that act only as modifiers. What I argue against is the model that very very large numbers of common variants could cause disease without some major mutation being present - one that you could say is "causal". (Like an FMR1 or a MeCP2 mutation in someone with autistic symptoms - even though those mutations don't always result in autism, if you find one in a patient so affected, most clinicians would be happy to say that if the person didn't have that mutation, the most probably would not have autism). Re the SZ GWAS, it's not so easy to say what they are picking up. Clearly they find a number of SNPs that are significantly associated (statistically) but with almost negligible effect on risk. Those signals could be caused by common or linked rare variants - it is not possible to distinguish. Claims that they prove a large polygenic effect in SZ caused by thousands of common variants are not justified. (For more on this, see the article referred to in the post).

DR01D, there is a link between maternal infection and schizophrenia in the offspring (a statistical link, that is - not a huge effect at the population level, but enough to warrant understanding how maternal infection can affect neural development in utero). As far as I know there is no evidence for a link with infection in patients themselves. I would be interested to know what you base that claim on, especially as the evidence for substantial heritability is very very solid and consistent.

There do seem to be some interesting links in the literature between toxoplasma infection and risk of schizophrenia. To be honest, I have not read enough of that literature to be able to evaluate it. My initial response is that the abstracts I read are inferring causation from correlation. It seems quite plausible that having schizophrenia would make you more likely to engage in behaviour that could lead to toxoplasma infection. In fact, at least one study suggests that is the explanation for the statistical link: http://www.ncbi.nlm.nih.gov/pubmed/20608474 (simply greater contact with cats in people with SZ). I am not discounting the possibility of a real causal link, but it doesn't seem to have been demonstrated in any conclusive way. I certainly would not accept, fro the kind of study you cite above, your claim that this kind of infection is the major cause of SZ - the evidence for genetic mechanisms playing a major role is overwhelming.

There are certainly a few well-known examples of balancing selection. That does not mean it is a widespread mechanism - there is no evidence that it is. My point is that simply invoking it does not get you off the hook if you are proposing that common variants predispose to highly deleterious disease - you have to provide some evidence that it actually pertains and the negative effects on fitness are so large for disorders like autism and schizophrenia that the balancing selection would have to be correspondingly (and implausibly) large in the opposite direction.

Ria, thanks for your comments. Your argument that linkage studies would have found rare variants of major effect, if they indeed exist, is a popular one, but flawed for several reasons, especially for psychiatric disorders. For linkage studies to work (to actually get down to identifying specific genes) you need big families with multiple affected individuals and you need to map the phenotype correctly. It is rare to find such families for psychiatric disorders (partly because they are so deleterious), especially under the mistaken notion that they should "breed true" - i.e., that there should be distinct mutations causing schizophrenia versus bipolar disorder versus autism, for example. We now know that the etiology is overlapping. Also, overall penetrance (for some psychological or neurobiological phenotype) tends to be higher than that for mental illness (generally), which is higher than that for any specific diagnostic category. Performing linkage based only on the latter phenotype is therefore not likely to work. 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.

It is certainly quite plausible that some mutations may increase risk to environmental triggers or that their effects may be modified by environmental factors (or vice versa). Many disorders, especially neurodevelopmental ones, may even be directly phenocopied by environmental insults. However, in terms of accounting for the missing heritability, these are not likely to be important, as they should not contribute to the measure of heritability - they should either be controlled for in twin studies or contribute to the non-genetic sources of variance.

I understand his argument in using the phrase - I just don't agree with it, because it can be so easily misinterpreted. And you will see in the YouTube clip that Dawkins does go to some lengths to construct possible scenarios to explain the persistence of "genes for homosexuality". My argument is that that phrase itself tends to put one in the frame of mind of considering the purpose, rather than the function of a gene or the effect of its mutation. In this particular instance (which is all I am referring to) he is explicitly discussing why these genetic variants might have been selected for.

I think your proposed solution works well actually: “Scientists have discovered a genetic defect that leads to X” - that might be modified sometimes to "associated/linked with X", depending on how strong an effect it is. For general traits, you might say: “Scientists have discovered a genetic variant that affects X". Not very exciting prose, but accurate, and if you don't say precisely what you mean, people will infer things you didn't intend. (Sometimes they do that even when you have said precisely what you meant!)

DR01D, thanks for your comments. I would argue strongly with your statement that the latest research strongly suggests an environmental trigger. I know of no such evidence. The study on epigenetics that you refer to does not speak to this issue. It shows some differences in DNA methylation across the genome in cells from patients with autism versus controls. DNA methylation is a means of gene regulation that is carried out by proteins encoded in the genome - it is part of the genetic programme of differentiation and development. It is also part of the dynamic response to environmental factors and experience. So, seeing epigenetic differences does not necessarily implicate environmental factors - this could be just an expression of underlying genetic differences and altered developmental trajectories. (Epigenetic does not mean environmental or "not genetic"). And to your second point, I wholeheartedly agree - as with many other psychiatric disorders, even ones with fairly late onset like schizophrenia, all the evidence suggests the initial insults are in early (prenatal) neurodevelopment

Yes, it's not surprising really that the things we recognise as "traits" are by definition, something fairly permanent and unchangeable. (Unlike attitudes, beliefs, skills, etc., as you say). The hardware-software analogy may be valid, to a point anyway. I like to think of traits as the system settings and the skills, beliefs, etc. as the content.

Personally, I find that spending too much time trying to partition variance precisely is a waste of time, as these figures are not biological constants but highly population-specific. The question is, biologically, what do these values mean? Gene x environment correlations are usually presented as two-hit models - the environmental factor only has an effect on people who are genetically vulnerable, for example. If the genes themselves are influencing the environment that people have, then that should show up as a genetic influence.

Chuck, I mean (and said) trying to calculate the figures *precisely* is a waste of time. Showing a trait is heritable is indeed very useful and behavioural genetics has shown this convincingly. That has been backed up by the discovery of many individual genetic variants that strongly influence behavioural traits. And showing that a trait can be in some way affected by experience is also useful. Calculating exactly what the percentages are in various populations doesn't really help much - they are always going to be very rough estimates anyway. What I was trying to do here was show that experience can be affected by genetics, in individuals, in ways that tend to amplify initial differences. Whether such an effect can be discerned in mathematical estimates of heritability is another matter and it doesn't bear on whether the effect actually happens - it depends on the design of the study.

It is funny how people read into things. The post I wrote is specifically about how experience can alter the brain. The point I was making was that it tends not to overcome innate preferences because the innate wiring tends to shape the experience, leading people to select ones that reinforce or amplify them. How you go from that, to thinking that beating your agreeable child will not have any consequences is beyond me.

Gabriel, You are ascribing opinions to me that I have not stated and do not hold. I try not to insinuate anything - I try to mean precisely what I say. For example, I said "Our environment does not just shape us - we shape it". Note the word "just" in that sentence - it is included for a reason. I do not as you claim say the environment has no effect on us. Quite the opposite in fact - I tried to make it very clear that brain development involves an intimate interaction with the environment and our patterns of experience. The point of the post is that our innate preferences will tend to shape that experience. Again, I use the phrase "tend to" very deliberately, to (try to) make sure that anyone who reads the post carefully will realise I am NOT excluding environmental effects! And I also specifically do not refer to extreme environmental factors or experiences like neglect or abuse _ I absolutely agree that these can have very large effects. You are arguing against positions that you only imagine I hold.

Gabriel - first, thank you for sharing your own story. . As you say, I tend to focus on the genetic influences because the scientific evidence for their effects is stronger (e.g., from twin studies, especially for autism). That is a general statement however, about sources of variation in the population - it does not equate to or even really apply to individual cases, where genetic predispositions will interact with experience in shaping the way people are. Also, no one is "blaming" the genes and certainly not blaming the individuals for carrying some particular genetic variants - I am not saying that "an autistic simply brings out the autism in themselves by reinforcing their own behaviors in the school yard". That makes it sound like they are choosing to be autistic, which is absurd and not the point I am trying to make at all. The point is to recognise the effects that genetic variants can have on risk for disorders like autism or dyslexia (or ADHD, schizophrenia, etc.) or on general personality traits and also recognise the effects that a person's innate tendencies can have on their experience. This will hopefully allow intervention to short-circuit this vicious cycle.