Penetrance, pleiotropy, and psychiatry 1

Published on August 29, 2021   25 min

A selection of talks on Neuroscience

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Hello, my name is Jacob Vorstman. I'm a child psychiatrist and a researcher in genetics at the Hospital for Sick Children in Toronto, Canada. Today, I'll be giving you a lecture about the intersection between the field of psychiatry and genetics. I will focus on penetrance and pleiotropy, two phenomena that are relevant to this field.
The question that's driving my research is always: what can we learn from genetic factors that influence susceptibility or resilience for neurodevelopmental and psychiatric disorders? I will start today with a bird's-eye view on genetic findings, focusing on autism and schizophrenia. Along the way, I will explain a few key concepts, and then I will illustrate this with some research observations, including my own research on the 22q11.2 deletion syndrome. Finally, I'll explore to what extent these research findings may be relevant for our clinical practice.
Let's start with the introduction.
One distinction we can make is that between common and rare variants. You can take one genetic variant, and count the number of people in a population with that specific variant. If a variant is common, it means that you'll find anywhere between (let's say) 1 per cent and up to 50 per cent of the population, that carries that specific variant. You can intuitively understand that each such common variant can only have a very small effect on disease risk, but then you can look at another variant, and find that a certain proportion of the population carries that variant. You can do that for a number of variants. This is all to show that there will be individuals in the population who, by chance, happen to have many of these risk variants. Even though each of these variants only carries a very small effect, the idea is that cumulatively, thousands of risk variants can amount to a risk effect that has some relevance. Rare variants, in contrast, can potentially have individually large effect sizes, but then again, they are very rare. I will discuss some of these more recently-discovered rare variants that are indeed highly pathogenic. It's important to realize that these two models, the common variant and rare variant model, are not mutually exclusive, and also that the dichotomy is somewhat artificial. In reality, there is a spectrum from very rare to common. By and large, it is fair to say that for schizophrenia, most findings are made in the domain of common genetic variants; whereas for autism or autism spectrum disorder (I will call it ASD in my talk), most of the progress is made in the discovery of rare, often high-impact, genetic variants. But the findings for both disorders are starting to approach each other more recently, and I'll give you a very brief overview.