Hello folks its Bill Eaton and this is Major Depression in the Population, the Public Health approach. And we're in lecture 4 entitled The Search for Etiologic Clues. So this is the outline of the presentation today. And it's about risk factors. So, prior lecture we studied about research designs and a little bit on methods and psychiatric epidemiology. But now we're going to use those methods, and try to understand what is it that increases the risk for depressive disorder? And you can see we're going to consider inheritance, and stress, social supports, and work life. And then this funny combination of socioeconomic status and social supports and life stage, I'll tell you about that. And then a recency of birth as risk factors for depressive disorder. So the first section on inheritance. Now you remember in the first lecture, I talked a little bit about Alfred Lord Tennyson, and showed you his family tree which was darkly colored with people with depressive disorder of different types. And so now I'm just going to show you a tiny bit more on depressive disorder. This is a slide on family studies of depressive disorder. And you can see, you know, we have this cases and controls language here. So we have cases of depressive disorder, and controls who are like them except they don't have depressive disorder. And then, we're going to study in their first degree relatives the prevalence of depressive disorder in cases and controls. And this is a selection, there are a couple dozen studies in table 8.3 in Peter Zandi's Chapter in Public Mental Health. This is a selection of four of those that I chose. These are some of the strongest studies. And you can see that this literature is a little bit old. We aren't doing that many family studies on depressive disorder anymore because we, we know the results, to some extent. So we have in Gershon's study we have 133 cases. And in their first degree relatives, first degree relatives are siblings, or parents, or children, right? And these first degree relatives share 50% of their genetic material with the case. So there's 17%, 16.6% in the case, but only 5.8% in the controls. And you get a similar preponderance in Winokur's study. 11.2 of prevalence of depressive disorder in their first degree relative of cases, versus 7.3 in the first degree relatives of controls. So this is a little bit repetitive, 14.9 versus 5.6. So, and 19 versus 7.7 in Heun and Maier study. What this shows us is, that we think that depressive disorder is inherited. Now it could be, that it's inherited through cultural patterns and upbringing. But basically we tend to think that it's actually in the genetic material that is making it be inherited. There's a little more evidence here, on twin studies. We have monozygotic twins, MZ pairs. Those twins are formed from the same egg and sperm, so they share 100% of their genetic material. And dizygotic pairs are twins in the same birth process, but they are like siblings sharing 50% of their genetic material. So we have again, I've selected 4 studies from Peter Zandi's fourth table in Chapter 8 in Public Mental Health. And if you look at the first one by McGuffin, there's 84 monozygotic pairs. Of course, it's hard to find these. These are hard to conduct studies because you have to find those twin pairs, and McGuffin got them from a hospital population. And there are 130 dizygotic pairs. And concordance means if the one twin has the disorder, what percentage of the other twin has it? So you can see the monozygotic pairs, if one twin has it, 53% of the other twin has it. For the dizygotic twin pairs, if one twin has it, 28% of the other twin will have it. So its much stronger for the monozygotic, and that makes us think that its inherited. And we actually can calculate a so called heritability estimate. And this is the estimate of the total variance in the population, what percentage of that is so called genetic variance? And 43% is a sizable chunk of the variance. And I've listed in the column called population, different sources of data. And this turns out to be one of the important things in the, research on depression where the data come from. People with depressive disorder in the hospital are different than people from the general population with depressive disorder as in Kendler's study at the bottom. And likewise, they're different from the Veteran's Twin Registry, and from volunteers. But you can see for example, in Mike Lyon's work on the Veteran's Twin Registry, the monozygotic versus dizygotic is 22 versus 14 with a heritability of 36%. And Laura Bierut's larger population, and she's categorized them as to same sex dizygotic pairs, or opposite sex dizygotic pairs. Monozygotic pairs are always the same sex because they have the 100% of the genetic material shared. But dizygotic pairs can have different sex. And she's also tabulated by sex, and you can see there that the females have higher rate of depressive disorder than the males. For example, in the monozygotic twins it's 38 versus 20. That tends to be the tendency. Females have more depressive disorder than males in general, and she gets a heritability of about 44%. Likewise, Ken Kendler with a general population of twins, is called the Virginia Twin Registry, which he formed and has been working on, 38% heritability. So this makes us think look, depression in inherited. And I think nobody would challenge that. The next step is, let's find a gene that's connected to the depressive disorder. Or maybe two genes or three genes. For example, a study of phenylketonuria, there is a single gene. A single location on the genome which is related to phenylketonuria. But we have been searching for that gene, or those genes for decades. And this is the most recent search that I have. It's called a mega analysis, because they looked at 1.2 million single nucleo type polymorphisms. Those are locations on the chromosome single pieces of chemicals on the chromosome. And he had 18,759 subjects, right? So if anything could find it, you'd think this could find it. But you see the second red underlining there. No SNIPs, that's a single nucleotide polymorphism or like in an allele, no SNIP achieved genome-wide significance. And so where the arrows are, although this is the largest genome-wide analysis of major depressive disorder yet conducted, its high prevalence means that the sample is still under powered. So the geneticists are asking for more than 20,000 people, and more money from the taxpayer to search for these genes. And this is referred to as the missing heritability, this paradox we have. We know it's inherited, but we can't find the genes. This is another just example of what happened to the heritability of depressive disorder. When they do a genome-wide scan, that is, they look at, let's say, a million different positions on the chromosome, the 23 chromosome's there. And you can see chromosome 1, 2, 3, on the x axis there. And they plot of all the locations, the significance of the relationship to the phenotype of interest. In this case its height, that is how tall is somebody? Everybody knows that you have tall parents, you have tall kids, short parents short kids, tall father, short mother, medium height kids. Inheritance is inherited, and when you do a genome wide association study, you get something like this, which is called a Manhattan plot, looks like sky scrapers. And if you pay close attention to the left hand, the ordinate there, you can see that's the negative log ten. That's the significance value. And when the significance value is 20 there, that means basically there are 19 zeros after the decimal point. Stating basically, that the finding would occur by chance if it's at that level, 1 in 10 to the 20th times. It's completely impossible to have occured by chance. The value of 8 I've marked down there, is about one in a hundred million. So you can see in this Manhattan plot on chromosome 1, and chromosome 3, and chromosome 6 and 7 and 8 and 12 and 13 and 20, there are hugely important findings. And so this Manhattan plot as we say, it looks like Manhattan. Now let's make a Manhattan plot for depressive disorder. And there's the value of 8. We have to change the scale, but this Manhattan plot does not look like Manhattan. There's nothing in there. It looks like Ames, Iowa. I hope the people from the Midwest won't think I'm prejudice. I think Ames doesn't have very many tall buildings in it. It's been a long time since I've been there. But this is the other issue. We, we, we're almost certain that depression is inherited, but we can't find exactly how its inherited. It's very complicated. Either its lots of different genes acting together, or the genes act with the environment in very complex ways, or they interact together in very complex ways. Still a puzzle. So that's our issue about inheritance. I, I'm sorry we can't come to better conclusion. Just think back to Alfred Lord Tennyson, and the density of his family tree. And now we'll move on to the second most important aspect of depressive disorder, that we also considered in our first lecture, that is stress.
