Approved Research

Untangling the interplay of genetics, environment and intermediate phenotypes in shaping complex traits.

Lay summary

Large datasets combining genome and trait annotations for thousands of people such as the UKBB helped researchers to discover novel relationships between genes and their manifestations. This knowledge allows the development of methods to evaluate disease risk, develop prevention and healthcare strategies, and understand how genetics shapes our organisms. Geneticists often define these relationships as simple associations between differences in the genetic sequence and traits, without describing the underlying mechanisms. Nevertheless, the path from genetics to traits is convoluted. A trait like Body Mass Index, for example, is the result of a complex system including metabolic, developmental and behavioural processes .

We aim to improve our understanding of the biological mechanisms between variants in the genetic sequence and high-level traits, for example by relying on other simpler traits as possible mediators. We will focus on gene expression (a quantification of how much a gene is active) because it is among the first steps through which a genetic variant can produce a biological effect. Another class of biological mediators that we will analyse are functional and morphological measurements extracted from Magnetic Resonance Imaging (MRI). We will start from available brain MRI measurements but also provide others, and investigate whether they can be seen as mediators for complex behavioural and neuropsychiatric traits. Another way to know more about the genetic basis of complex traits is to couple statistical association analyses with evolutionary-derived measurements. For example we will investigate which genes carry signs of natural selection, fast evolution in modern humans or a Neanderthal origin: these elements will be brought to the table in evaluating these genes importance in defining a trait.

In parallel, we will explore how the population and environment of UKBB donors impacts these delicate analyses. Indeed the interaction of genetics and environment, but also demographic aspects, for example how much partners tend to be genetically similar between each other, can confound our statistical estimates. All together we will add many elements to represent the convoluted path from genetics to complex traits and its interaction with the environment. We expect this research to impact public health in the long term. We will elucidate the basis of traits of enormous social importance that are poorly understood in their biological mechanism, including behavioural and neuropsychiatric ones. Additionally, we will develop statistical models to predict these traits that are more complex, biologically-grounded, and better at accounting for confounding variables.