The role of evolution in the genetic susceptibility of intracranial aneurysm

Nunavik Inuit is a group of Arctic indigenous people, who have historically presented as a small and isolated population across the Nunavik region of northern Quebec (Canada). The unique genetic profile of Nunavik Inuit is the result of years of adaptation to their living condition, and it is likely responsible for their increased susceptibility to certain pathological conditions. Prior studies have shown that as a consequence of neutral evolution or past adaptive events, today’s Inuit are predisposed to cardio-cerebrovascular disorders, e.g. hypertension and intracranial aneurysm (IA).  IA is defined as localized cerebrovascular weakness which leads to vascular dilation or ballooning, and such distortions are susceptible to disrupt the affected vessels and lead to subarachnoid hemorrhage. It is a complex disorder with a high prevalence (4-8%) and certain populations have been observed to present an increased risk of developing IA. Both environmental and genetic factors are deemed to contribute to the development of IA and in regards to the latter, independent genome-wide association studies (GWAS) have identified multiple loci associated with IA. Nonetheless, there is still a large portion of the genetic heritability of IA, especially in different populations other than Finnish and Japanese that remains unexplained. However, fewer IA genetic studies have taken in consideration the contribution of population specific genetic variants. To address some of the IA missing heritability that is deemed to be accountable to its genetic heterogeneity and low penetrance, we have combined high throughput sequencing (HTS) with SNP-chip genotyping to examine the genetic signatures of two founder populations from Quebec that are predisposed to IA, including Nunavik Inuit and French-Canadians (FC). Because these populations have distinct genetic characteristics, we used different approaches for the identification of genetic risk factors. Nunavik Inuit is an indigenous population and many aspects of its genetic signatures differ from those of separate world-wide major populations; therefore we chose to conduct extensive population genetic studies in regards to their genetic history and genomic profile before we undertook to test if any association could be established between genomic loci and disease susceptibility. We observed many genetic components that are specific to the Nunavik Inuit population, including its homogeneous Inuit ancestry, increased linkage disequilibrium (LD) and genetic signatures which reflect the population had a long history of adaptations to their environment. Previously unidentified signals of natural selection, which focused on coding regions of the genome revealed an accumulation of genetic variants in genes involved in the processes of cell adhesion and immune responses (e.g. CPNE7 and ICAM5). Further analyses revealed a variant in CCM2 to be under positive selection and significantly associated with IA in Nunavik Inuit. In regard to the genetic etiology of IA in the French-Canadian population, we took a different approach and used French-Canadian specific variants that were identified by whole exome sequencing to generate a list of potential risk genes; which were further prioritized using a gene based burden association test. RNF213 emerged as a prime candidate gene that had undergone possible genetic drift and the follow-up genetic and functional examinations further supported its potential contribution to the development of IA among French-Canadians. The results presented in this thesis highlighted the importance of taking into consideration the specific genetic background brought by natural selection or genetic drift, both are driving forces of evolution, when a complex disease is being studied. It also further confirmed that variants in a specific gene (e.g. RNF213 or CCM2) may contribute to the development of different pathogenesis when examined in distinct populations. Overall as our genetic findings identified new genetic “pieces” that further completed the missing heritability “puzzle” of IA genetics; evidence for these “pieces” were interestingly highlighted through population genetics.

Keyphrases: Nunavik Inuit, French-Canadians, intracranial aneurysm, whole exome sequencing, adaptation, cerebrovascular disease, population genetics