Background: The Saguenay-Lac-Saint-Jean (SLSJ) region is located in northeastern Quebec and is known for its unique demographic history and founder effect, characterized by several population bottlenecks followed by rapid expansion. Since founder populations are enriched in unique variants, we aim to show the advantages of using the SLSJ population in the study of rare coding and noncoding regulatory variants in complex traits.

Objectives: Our goals are to first assess differences in variant distribution and characteristics between the SLSJ founder population and four other European populations from Sweden, United Kingdom, France and Finland – with the latter also being a founder population. We will then assess the impact of rare and low frequency variants in asthma-related traits using the SLSJ asthma familial collection.

Research design and Methods: Targeted sequencing of coding and non-coding regulatory regions of immune cells were undertaken in 149 trios (447 individuals) from the SLSJ asthma familial collection as well as on samples from the four European populations. To address our first goal, we paired samples from the five different populations by mean coverage to avoid any bias based on both coverage and number of samples utilized. A total of 76 samples per population were included and the mean coverage for each population was 28.8X. For the second objective, the sequenced trios from SLSJ are part of larger families; genotype was inferred in 95 siblings. Imputation was done on the whole collection (1214 samples) using SHAPEIT and IMPUTE2. Single variant association test and collapsing tests (combined multivariate and collapsing test (CMC), variable-threshold approach (VT) and SNP-set (sequence) kernel association test (SKAT)) were performed for asthma related traits. Kinship coefficient, age and sex were used as covariates.

Results: Even though the founder populations do not appear to have more rare or deleterious variants, we observed that a larger proportion of private variants reached higher frequencies. Thus, a substantial amount of variants unique to these populations can be tested in the context of complex traits. We then focused on these private variants, identifying a low frequency and missense variant located in the third exon of the TTC14 gene that is significantly associated to lung function (Forced vital capacity (FVC) p=2.2e-6, forced expiratory volume in 1 second (FEV₁) p=0.002 and Tiffeneau-Pinelli index (FEV₁/FVC) p=0.02). According to the ExAC database, the frequency variant is 2e-5. We were also able to identify genes associated to cell counts using the collapsing tests.

Conclusion: Using a founder population like the SLSJ to study complex trait, we were able to identify new genes associated to asthma-related traits. This could help better understand genes and pathways implicated in the development of the pathophysiology. Finally, the identification of a private variant associated to lung function may also provide an opportunity for precision medicine in the SLSJ population.