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Exploring the genetic basis of rare diseases using association tests at the gene and pathway level.

par Boutry, Simon
Président du jury Coulie, Pierre G
Promoteur Lenaerts, Tom ;Vikkula, Miikka
Co-Promoteur Helaers, Raphaël
Publication Non publié, 2024-12-17

Thèse de doctorat

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Résumé :

This thesis addresses a critical need in understanding genetic diseases influenced by complex combinations of rare variants, dispersed across multiple genes. Traditional genetic studies often focus on single-gene mutations, which leaves much of the genetic landscape unexplored, particularly for diseases where multiple genetic or environmental factors play a role. This research focuses on aggregation tests, a powerful approach to detecting associations between groups of variants and traits by combining multiple genetic signals into a single, interpretable score. After extensive benchmarking of 59 existing methods, this work introduces Excalibur, a novel aggregation test that demonstrates robust performance across a variety of genetic models. Additionally, this thesis presents DoAggregate, a pipeline designed to facilitate rare-variant analysis across cohorts at the level of genes and pathways. The application of DoAggregate to a dataset of primary lymphedema cases offers new insights into oligogenic inheritance and genetic modifiers, marking a step forward in our understanding of complex genetic conditions.