Heritability and its uses

Published on April 18, 2016   45 min
0:00
My name is Doug Speed, and I'm a Researcher at University College London Genetics Institute. And today, I will be telling about Heritability and Its Uses. And hopefully, I'll convince you why this is the most exciting area in Quantitative Genetics.
0:14
So there are two parts in this talk. First, I'll tell you about traditional heritability analysis, and then, I'll talk to you a bit about SNP-based heritability analysis, which is a very recent area in the last five years, and hopefully, I will give you an idea of all the uses it has in trying to understand complex trades.
0:30
So first of all, here are few books and papers which I find very useful. The first one is Introduction to Quantitative Genetics, and this has more details on lots of the first part of this talk. I've a second too, Introductory Statistics with R and Elements of Statistical Learning are both available at the author's web pages to view online. And then here I have major papers in the field of SNP-based heritability analysis, and so it'll be useful for later.
0:56
It's a bit hard to tell in that previous slide, so I've just added a bit of noise so you can see the individual SNP genotypes. So here we see that adding in copies of the mutant allele increases phenotype on average. So for example, if an individual has one copy, so it's genotype AG, for example, then their effect is higher than if they have zero copies AA. And then, if they have two copies GG, their effect is the same amount higher still. And what we can observe is a linear trend, so each copy of the mutant allele increases for phenotypic effect by the same quantity.
1:33
So heritability is a fundamental concept in quantitative genetics. Really, if you plan to do a genetic analysis of a phenotype, one of the first things you should think about is, what is the heritability of a trait you wish to study. If the heritability is zero, then there's no point doing a genetic analysis, because there are no genetic factors influencing the trait. Whereas, if the heritability is very high, then this suggests that your analysis is likely to be fruitful. We're often interested in very broad comparisons, so for example, the heritability tells us how well we might predict a particular trait. So this could be in plants, and animal genetics, or it could be in human diseases. So for example, if there's two diseases, and one has heritability of 20 percent, and one has heritability 80 percent, then in theory, we could predict the second disease better than the first. So there's probably a good reason to try and study about the second trait.
2:26
There are two main types of phenotypes, and one of the main is quantitative phenotype. So for example, human height, this is a continuous valued trait which takes measurements between say one and a half meters and two meters. Another major type of trait is the case control for binary outcome. So here values only take two possible values, one, if the individual is affected, and zero, if he's unaffected. I'm going to focus mainly on quantitative trait, but towards the end, I'll explain how most of these ideas can be applied to binary traits as well. As well as quantitative and binary traits, there's also count data and survival data, but methods for analyzing these are more complicated.
3:07
So we start with the definition of heritability. So we have our phenotype, which I will represent with the vector Y, and we can think of why it's been made up of a contribution of genetic effects vector G, and environmental noise vector E. And therefore, we can consider a variation in the phenotype Y as to some of the genetic variation and the environmental noise variation. So this model assumes there's no interactions between genetics and environments. So the environmental effects are independent of the genetic effects. With this model, we then get the broad sense heritability is the genetic variance divided by the total phenotypic variance. And so H square tells us what proportion of the total phenotypic variation is attributable to genetics. However, we often consider inside the narrow sense heritability, and this is a slightly different model. Now we assume the phenotype has contributions from A, which is the additive genetic effects, as well as E which is still the environmental noise. And therefore, the narrow sense heritability, which is h squared is the total additive genetic effects divided by the total phenotypic variation.
4:18
So to give an example, for human height, variation is about 20 centimeters. So the average height is maybe 173 centimeters, variation is about 20 centimeters, so most people fall within 10 centimeters above or 10 centimeters below the mean. And we can break down this total variation of 20 centimeters into two components, the genetic component explains about 16 centimeters of this variation and other factors explain about 4 centimeters. And therefore, the heritability of height is 16 divided by 20, so about 80 percent.
4:53
So I mentioned, we often focus on the narrow sense, the additive heritability, so to explain what that means, first of all, we'll be looking a lot at SNP genotypes. So a SNP genotype is typically coded as zero, one, or two, and this number represents the count of the mutant allele. So for example, suppose a SNP has two alleles A and G, if its genotype is zero, then this means it has two copies of A, the homozygous wildtype allele. If the genotype is one, then it means that it is heterozygous, it has an A and a G, and if the genotype is two, it means it has two copies of G, a homozygous mutant. This table below shows how we can think of its effect of particular SNP on the phenotype. So here we have three parameters, µ, the overall mean, A, the additive effect, and D, the dominant effect. And this shows what the effect is for each of the three genotypes. So this might be a bit confusing, but hopefully on the next slide it will make sense.
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Heritability and its uses

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