Bhérer Claude, Grenier Jean-Christophe, Pelletier Justin, Boucher Gabrielle, Gagnon Genevieve, Goyette Philippe, Ashton-Beaucage Dariel, Stevens Christine, Battat Robert, Bitton Alain, Campeau Philippe M, Laprise Catherine, Huang Hailiang, Daly Mark, Taliun Daniel, Hussin Julie G, Mooser Vincent, Rioux John D
Department of Human Genetics, Faculty of Medicine and Health Sciences, McGill University, Montréal, Québec, Canada.
Canada Excellence Research Chair Program in Genomic Medicine and Victor Philip Dahdaleh Institute of Genomic Medicine, McGill University, Montréal, Québec, Canada.
medRxiv. 2025 Jul 14:2025.07.11.25331388. doi: 10.1101/2025.07.11.25331388.
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 () and Leigh Syndrome French Canadian type (). 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 and , we identified new candidate association signals, including enriched variants in , and . 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.
近期经历瓶颈的奠基者群体的遗传特征，使得一些有害变异的频率升高，这能够增强罕见变异关联研究的效力。来自魁北克的法裔加拿大人代表了一个近期的奠基者群体，具有特定的疾病遗传特征，包含30多种常见的孟德尔疾病。在此，我们利用来自2820名法裔加拿大参与者（炎症性肠病（IBD）患者、魁北克IBD队列中的父母及对照）的外显子组测序数据，对这个奠基者群体中的编码变异进行了特征描述。我们发现，18%的罕见编码变异比非芬兰欧洲人（NFE）中的频率高10至100倍。总共4133个错义变异和功能丧失变异显著富集，中位富集倍数为28倍，揭示了该群体中基因型与表型关联的潜力。我们描述了显著富集的致病变异，包括那些已知导致法裔加拿大人中罕见疾病患病率高于其他欧洲血统人群的变异，如胼胝体发育不全和周围神经病（）以及法裔加拿大型Leigh综合征（）。最后，我们利用三联体和病例/对照队列，研究因奠基者效应在法裔加拿大人中富集的罕见蛋白质编码变异是否会导致IBD风险。除了在和中重复关联外，我们还识别出了新的候选关联信号，包括在、和中富集的变异。我们的研究结果表明，即使在像法裔加拿大人这样特征明确的奠基者群体中，仍存在未被挖掘的遗传发现潜力，通过富集的编码变异揭示罕见和复杂疾病的风险因素。
