Frequency enrichment of coding variants in a French-Canadian founder population and its implication for inflammatory bowel diseases

Abstract

The genetic features of founder populations with recent bottlenecks, causing some deleterious variants to rise to higher frequencies, can enhance the power of rare variant association studies. French Canadians from Quebec represent a recent founder population with a particular disease heritage comprising more than 30 prevalent Mendelian conditions. Here, we characterize coding variation in this founder population using exome sequencing data from 2,820 French-Canadian participants - patients with inflammatory bowel diseases (IBD), parents and controls from the Quebec IBD cohort. We find that 18% of rare coding variants are 10-100 times more frequent than in non-Finnish Europeans (NFE). A total of 4,133 missense and loss-of-function variants were significantly enriched with a median 28-fold enrichment, revealing the potential for genotype-phenotype associations in this population. We describe significantly enriched pathogenic variants, including those known to account for the increased prevalence of rare diseases in FC compared to other European descent populations, such as Agenesis of corpus callosum and peripheral neuropathy (SLC12A6) and Leigh Syndrome French Canadian type (LRPPRC). Finally, we investigate whether rare protein-coding variants, enriched in French Canadians by the founder effect, contribute to the risk of IBD using trio and case/control cohorts. In addition to replicating associations in NOD2 and IL23R, we identified new candidate association signals, including enriched variants in SLC35E3, and ARSA. Our findings show that, even in well-characterized founder populations like the French Canadians, there remains untapped potential for genetic discovery, revealing both rare and complex disease risk factors through enriched coding variation.

Keywords: French Canadian; Mendelian diseases; exomes; founder effect; genetic association; inflammatory bowel diseases.

Figure 1.. Fine-scale structure of participants in the FC subset of the Quebec IBD cohort

(A) Geographical location of the 11 regional or ethno-cultural groups sampled in the ERRQ Reference Panel in the Province of Quebec (Canada). (B) PCA of the ERRQ Reference Panel. PC1 (1.97% of total variance explained) is shown against PC2 (1.45% of total variance explained) (C) PCA Projection of the FC subset. Abbreviations: ABI: Abitibi-Témiscamingue; OUT: Outaouais; MON: Montreal; BEA: Beauce; QUE: Quebec City; SAG: Saguenay-Lac-Saint-Jean; NS: North-Shore; LOY: Gaspesia Loyalist; GCI: Gaspesia Channel Islanders; GFC: Gaspesia French Canadians; ACA: Gaspesia Acadians.

Figure 2.. Frequency enrichment of protein-coding variants in French-Canadian exomes.

Histograms show the distribution of variants as a function of their MAF ratio in the UNRFC sample relative to gnomAD NFE exomes. Variants with MAF ratio equal or above 10 in the UNRFC are highlighted in blue. Frequency enrichment histograms are shown for (A) all protein-coding variants, (B) synonymous variants, (C) missense variants, (D) high-confidence (HC) pLoF variants.

Figure 3.. Enrichment of pathogenic variants in French-Canadian exomes.

(A) Scatterplot of MAF of ClinVar PLP variants (gray) and previously described French-Canadian founder variants (PLP) in the UNRFC subset relative to gnomAD NFE (B) PCA projection of the UNRFC subset in the ERRQ PCA space, highlighting in red the carriers of SLC12A6 c.2436+1delG pathogenic variant implicated in ACCPN.