Okay, welcome back. This is the final module, the final regular module, there'll be a supplemental module as well, the final regular module in Unit 6, and in this, module, I'm going to talk about a very important application of genetic research on general cognibility, and that is the Genetics of Intellectual Disability. So, I'm going to touch on three things. First of all, I'm just, I'm going to spend a few minutes talking about just what is exactly meant by intellectual disability. I assumed some of us taking the course, some of you taking the course, don't have a background in psychology, so, I'd like to characterize before we get into the genetic research, the phenotype we're talking about. And then secondly, I'm going to talk about two features about, the epidemiology of intellectual disability for which, intel, genetic research has had very important implications. The first in, and these aren't going to necessarily mean a lot at this point, the first is that actually, IQ or general cognibility is not normally distributed, it actually has significant implications for thinking about intellectual disability, and secondly, that males are at higher risk than females for having an intellectual disability. But let's begin with what is meant by intellectual disability? For those of you who maybe took a psychology course, the last time you took a psychology course is ten or 15 years ago, you maybe learned about mental retardation. And in fact, what intellectual dis, disability is today is what mental retardation, the term mental retardation was ten, 15 years ago. But as I'm sure you, you appreciate the term mental retardation has become a pejorative term, a disparaging term, and so, because of that, the field has adopted a new term, a term intellectual disability. But if again, if you've taken a psychology course a long time ago, it's not really unlike what psychologists used to call mental retardation, but no longer use that term. So, what is it? Intellectual disability has three requirements. The first is low cognitive functioning. And in fact, the criterion used is usually having an IQ less than 70. Now, that's a bit arbitrary to just pick 70 as, at as a compo, cut point, because IQ is continuously distributed. But the reason 70 was picked is, if you recall, IQ has a mean of 100 and a standard deviation of 15. So, an IQ of 70 is two standard deviations below the mean. So, that was the arbitrary standard that's adopted. Low cognitive function is not, it's a necessary condition for having an intellectual disability. It's not sufficient. It has to, that low cognitive functioning actually has to impair the individual's ability to live independently. It has to impair their adaptive functioning. And finally, intellectual disability has an onset in childhood, which is really distinguishes it from things like dementia or traumatic brain injuries, are, which are things that have onset in adulthood. Let's look at that necessary intellectual criterion used in defining intellectual disability, which is a low IQ score. Now, I've given you this before which is kind of an isle, idealized distribution of IQ. The distribution of IQ, if you looked at it kind of looks like a normal distribution. In fact, it's not quite a normal distribution. If it were a normal distribution, it would be perfectly symmetric. Intellectual disability is associated with IQs less than 70. It turns out that in the actual IQ distribution, 2.6% of the population falls with an IQ less than, than 70. If the IQ distribution was perfectly symmetric, then people with IQs above 130, above 130 would be considered gifted. People with IQs above 130 would have the same percentage, or actually 2.3% of the population is above an IQ of 130. So, the, the, the departure from normality in the IQ distribution is that there's more individuals in the lower tail of the distribution. There are more individuals in the tail of the distribution associated with having intell, intellectual disability than we would expect, if the distribution were normal. Along with IQ is a grading of intellectual disability which is illustrated on this slide. Individuals that have a mild la, form of intellectual disability, IQs in the 50 to 70 IQ range, can acquire intellectual skills typical of, of somebody graduating from elementary school. They can in, live independently. They can hold jobs. But they usually require some assistance, even though they might live independently. As the IQs decrease, you get labels that indicate a greater severity of the intellectual disability and a great need for supervision for help. People with IQs in this range really can't live independently, they need quite a bit of assistance. What are the implications of that non-normality of the IQ distribution, that there are more individuals in the lower tail of the IQ distribution than we would expect if IQ were actually normally distributed. This is, the, the, the grading of the severity of intellectual disability and what we would expect, how many, what percentage of the population would fall in these var, various classes if IQ were normally distributed. This is actually, what we would observe if we did a large scale population study of IQ. Overall, as I gave in the previous slide, about 2.6% of people in the population have IQs less than 70. If IQ were normally distributed, it would be 2.3%. So, there's an excess. That excess might not seem that big to you, but it does have important implications that I'll get to here in a second. There's two additional points I want to emphasize here in this slide. First of all, most people, the vast majority of people that have an intellectual disability have a mild form of intellectual disability. They have the types of intellectual and academic skills that allow them to have a job, to live independently. But they just require some assistance in doing that. The second thing I want to illustrate is where this excess in the lower tail of the IQ distribution is arising. It's actually arising the further out we get in the distribution. In this part of the distribution, there's just, what I've done here is just divided this, this number by, I'm sorry, this number by that number, the observed by the expected. So, there's just a very slight excess here. If we go to the moderate, to severe forms of intellectual disability, there's a six fold increase risk in observed versus what we'd expect. And there's a 6000 fold increase in the most profound or severe forms of intellectual disability. So, IQ is not normally distributed. And an implication of that is that there are more people with very severe forms of intellectual disability than we would expect to have existed if IQ were normally distributed. The individuals, even though they're the minority of people with intellectual disability. They are, those individuals with intellectual disability that are most likely going to require the most assistance by their families and by society. This excess of cases in the lower tail of, of the IQ distribution has actually led to a conceptual model that most people working in the field of intellectual disability, not only clinically, but actually, in terms of research have adopted, and that model is what's called the Two-Group model of intellectual disability. And the notion is that there's two large classes of groups of individuals at that lower tail of the IQ distribution. The first group, I'll call Group 1, and this comprises maybe 5-10%, so, it's the minority of individuals in the lower tail, of, of the IQ distribution. But these are the individuals that are there because they're not just the, the lower tail of the normal distribution, this is the excessive cases. These are individuals that have the more severe form of intellectual disability. This first group is characterized by individuals who for some reason suffered a major trauma to their developing brain. The source of that major trauma could be genetic, it could be things like aneuploidy Down syndrome, or it could be copy number variance like we talked about Williams' syndrome, or it could be a Mendelian characteristic, like we talked about phenylketonuria if it were untreated, or it could be environmentally, induced. Prenatal alcohol exposure or some perinatal trauma like, anoxia at, at birth. It turns out that them, the vast majority of individuals with this form of intellectual disability have it for genetic reasons. The estimate is 60, 70, 75% have some sort of genetic mutation that underlies the, the intellectual disability and because of that, there's actually quite a lot of genetic research now trying to understand these more severe forms of intellectual disability. What about the genetics causes the intellectual disability and can we intervene? So, about, let's say, 70% have a known genetic etiology, maybe 10 to 50 per, 15% have a known environmental etiology, and whatever the balance is, maybe 10%, we don't know what the actual trauma was. Wa, it could be genetic, it could be environmental. At this point, we don't know. That's the first group. The second group is the vast majority of individuals with an intellectual dis, disability, 90, 95%. These are actually individuals who are at the lower end of the IQ distribution because of the cumulative impact of genetic and environmental factors that affect individual differences in IQ throughout the whole range of IQ. By luck, they've just hit on multiple ones that are associated with low cognitive performance. So, in this case, being at the lower tail of the IQ distribution isn't due to a major trauma. It's due to the impact of many, many factors. Many genetic factors. The polygenic factors. Many environmental factors. The sociocultural disadvantages that we've talked about. This form of intellectual disability is, is typically associated with the more mild forms of intellectual disability. [SOUND] The last thing I want to talk about with intellectual disability is the male excess. Males are at a higher risk for suffering intellectual disability than females. This has been known for a long time. I'll give you one epidemial large scale epidemiological study. This is a large population study from, Western Australia, where they've, assessed a, a large number of children here, for intellectual disability, the number, the rate per thousand in girls versus boys, you can see overall, there's maybe a 50%excess, 40 to 50% excess of boys, and in fact, there's an excess, most of the excess is in the mild to moderate range. But there's an excess of boys at every level. So there's, boys are 40 to 50% more likely to suffer an intellectual disability than a girl. Why is that? Can genetics help us understand why that's the case? Well, yes, in part we know that genetics can help us understand. There's a term called X-linked intellectual disability. And we know that that is a major factor. It might not entirely, and it probably doesn't entirely explain the excess male risk, but it's certainly a major factor in why males are more likely to suffer from intellectual disability than females. Why was that? Well, recall males have one X chromosome and females have two. So, if you have a rare deleterious recessive condition that maps to the X chromosome, what's going to happen, if it's rare and recessive is males were going to be much more likely to have that condition than females. Why is that? Well, again, males have one X chromosome, so, in order to develop that rare, recessive condition, they require one mutation, one hit. Females have two X chromosomes, so, two things have to happen, two rare things have to happen before they get that rare condition. There are rare, lots of rare medical disorders that map to the X chromosome. There's certain forms of hemophilia, the most common form of muscular dystrophy, Duchenne muscular dystrophy are mapped to the X chromosome and they're recessive. Males are much more likely to have Duchenne muscular dystrophy than females. In fact, it's extraordinarily rare to find a female with either X-linked hemophilia or X-linked Duchenne muscular dystrophy, it's almost only affects males, because it only requires one rare event for a male, but two rare events for a female. Well, those are for medical conditions. Is the same thing going on with intellectual disability? Well, geneticists now know of at least 150 different rare, X-linked, recessive conditions associated with intellectual disability. This next side summarizes their work and I understand, I can, I know that this is an extraordinary busy slide. But I'm, I'm using it to illustrate three points. First of all, each, each line here, which I know you can't read the line, but each line here is a rare X-linked recessive condition associated with intellectual disability that geneticists have identified. And there are about 150 lines on these ideograms for the X-chromosome. Those are all conditions that are going to lead males to more likely have intellectual disability than females. The second thing that I should point out is that geneticists distinguish between what are called Syndromic forms of intellectual disability for which there are a lot more lines here, right, than Non-syndromic forms. S, Syndromic intellectual disability is an intellectual disability where the phenotype, where intellectual disability is one symptom of a larger syndromic phenotype. So, there might be some physical manifestations as well as intellectual disability. Maybe some medical complications as well. So, it's not just intellectual disability. Non-syndromic means that the condition seems to be specific to intellectual disability. So, most of these are Syndromic. And the last thing I want to point out here, it's kind of an interesting speculation that geneticists have engaged in when they've seen data like that that's represented on these ideograms. And that is, why there's a lot of genes being mapped to the X-chromosome associated with intellectual disability. Why is that? In fact, there are more genes on the X-chromosome for intellectual disability than on autosomes. Why? Some have speculated that maybe genes that regulate or influence cognitive ability are preferentially put on the X-chromosome. That's a hypothesis that some geneticists are exploring right now. We don't know the answer. But it's kind of an interesting hypothesis. [SOUND] So, X-linked intellectual disability would lead us to expect that males are more likely to have intellectual disability with, than females. Is that enough to explain the 40 to 50% increased risk of intellectual disabilities that we see in males as compared to females? Probably not. It probably accounts for a lot of it, maybe 50, 60%, but right now it doesn't appear to account for all the increase risk that males have for intellectual disability. What accounts for the remainder? What accounts for the remainder is probably based on the phenomena that males are biologically more vulnerable that females. And there's overwhelming evidence of this from human biology, and I'm just going to give you a couple examples of this. We know that, for example, males have a higher mortality rate than females. That higher mortality rate actually starts from the moment of conception. Spontaneous abortus is, are more likely to be male than female abortuses. Throughout life at every age, males are more likely to die than females. We know that males are more like, are more vulnerable to the physical and the neurocognitive sequelae of birth trauma, low birth weight, perinatal traumas of various types. So there's a lot of evidence that males are biologically more vulnerable. And there's speculation that it may be hor, hormonally based. Maybe it has something to do with androgens. That's a hypothesis. That's also manifested in males being, not only at higher risk for intellectual disability, but males are at higher risk for nearly all neurodevelopmental disorders. They're at higher risk, for example, for autism, for Tourette's Syndrome. We've already talked about intellectual disabilities. They're also at higher risk for learning disabilities. That seems to be not entirely explained by X-linked recessivity. It must be some biological vulnerability that males carry. And the last thing I want to point here, is I think a real fascinating study that was, I'm just going to highlight, and some of you might become interested in it. It's a real fascinating study that was published in 2014 in a very prominent journal, American Journal of Human Genetics. And what these individuals did is they took, these are children, so they took girls and boys with an, with a neurodevelopmental disorder and then they actually carefully genotype them to determine how much genetic loading for that neurodevelopmental disorder they actually carried. And what they found is that the girls with the, the neurodevelopmental disorder had a higher genetic loading than the boys with the, with the neurodevelopmental disorder. And the interpretation of that, the conclusion they drew from that, is that for the girl to get the disorder it required that they carry more of the relevant genetic mutations than a boy. Why? Because a boy is biologically more vulnerable than a girl. Fascinating stuff. So Summary of Unit 6. What were the major topics that we tried to go through? First, just the biometric analysis of general cognitive ability. The twin and adoption studies. It appears to be approximately 50% heritable. Roughly a third of the variants or individual differences in general cognitive ability is associated with the environments we share with our siblings when we grow up in the same home with them. And finally, a small portion of the variance is associated with non-shared environmental factors, but because non-shared environmental factors includes measurement error, there's probably not a lot that's going on there. Measurement error may be 10% of that 15% for non-shared environment. Secondly, adoption studies have shown us that sociocultural advantage is also an influence on general cognitive ability. We've looked at those fascinating, that fascinating French adoption study that showed that children placed in the most advantaged socioeconomic ho, homes, experience the greatest boost in their IQ. Third, we found from twin studies that the extent to which IQ is heritable is moderated by this, the, the socioeconomic status of the home you're reared in. Children reared in disadvantaged homes show very low heritability. It appears to be the case that if you're growing up in a disadvantaged environment, you're not able to fully express your genetic potential for general cognitive ability. And then finally, we talked about the attempts to find genetic variance for general cognitive ability. It's been difficult. The candidate gene approach has not yielded much, find much reliable finding, but I think we're, there's reason to be optimistic with GCA. Thank you for your attention. There will be a supplemental lecture in this unit. But if you don't see that one, I hope to see you back in unit seven. Thank you very much.
