Thesis defense Raphaël Blanchet

Equipe

Team I - Human Genetics

Directeur de thèse

Romain Bourcier

Co-directeur de thèse

Richard Redon

Co-encadrant

Christian Dina

Rapporteurs

Ynte Ruigrok - Full Professeur, UMC Utrecht - Pays Bas
Gaël Nicolas - PU-PH, Cancer and Brain Genomics Inserm 1245 - Rouen

Examinateurs

Stéphanie Debette - PU-PH - Institut du Cerveau,Hôpital Pitié-Salpêtrière - Paris
Sophie Limou - PU - CR2TI Inserm UMR1064 - Nantes

Abstract

Intracranial aneurysms (IA) are localized deformations of the cerebral artery walls affecting 3.2% of the population and may lead to subarachnoidal hemorrhage, a severe type of stroke. This pathology shows a strong inheritance pattern but remains poorly characterized to this day with 50% of its heritability explained. We here used different approaches to elucidate the underlying genetic architecture of extreme forms of the disease.
In this work we focused on the specific forms of IA, more likely to present genetic causes. Through the analysis of a large family with 6 IA carriers, we identified a rare coding variant in the CTSO gene. We replicated this result with a second variant found in the same gene in a second large pedigree. CTSO was found through functional analysis to impact the composition of the extracellular matrix of cerebral arteries.
From a population of 731 carriers of extreme forms of IA and 1020 controls we extracted rare coding variations using an extensive set of quality and functional filters. We then performed rare variant association testing across the whole transcriptome. We associated transcripts of the SYNE2 gene with the presence of 3 IA or more in cases and with familial forms of the pathology. C6orf136, SLC22A25 and ENTREP2 were associated with multiple IA.
Finally, we implemented tools to process low coverage sequencing data fro common variants association studies and IA rupture risk prediction.
In addition to developed methods, this work shed some light on the genetics of extreme forms of IA, paving the way to the analysis of underlying physiopathologic mechanisms.