@article{pmid41100445,

title = {Rare diseases load through the study of a regional population},

author = {Élisa Michel and Claudia Moreau and Laurence Gagnon and Mylène Gagnon and Josianne Leblanc and Jessica Tardif and Lysanne Girard and Jean Mathieu and Cynthia Gagnon and Mathieu Desmeules and Jean-Denis Brisson and Luigi Bouchard and Simon L Girard},

doi = {10.1371/journal.pgen.1011876},

issn = {1553-7404},

year  = {2025},

date = {2025-10-01},

journal = {PLoS Genet},

volume = {21},

number = {10},

pages = {e1011876},

abstract = {Rare genetic diseases impact many people worldwide and are challenging to diagnose. In this study, we introduce a novel regional population cohort approach to identify pathogenic variants causing Mendelian diseases that occur more frequently within specific populations and are of clinical interest for carrier testing. We utilized a cohort from Quebec, including the Saguenay-Lac-Saint-Jean region, which is known for its founder effect followed by a rapid expansion and higher frequency of certain pathogenic variants. By analyzing both their frequency and origin through shared identical-by-descent segments, we identified founder variants. We calculated and compared their frequency in individuals originating from the Saguenay-Lac-Saint-Jean and from other urban Quebec regions. We validated 38 previously reported variants as being more common due to the founder effect and population expansion. Additionally, we identified 42 unreported founder variants in Quebec or Saguenay-Lac-Saint-Jean, some with carrier rates estimates as high as 1/22. We also observed a greater deleterious mutational load for the studied variants in individuals from the Saguenay-Lac-Saint-Jean compared to other urban Quebec regions. These findings were brought to the clinic, where 12 pathogenic variants were detected in diagnosed patients. Five variants found in this study are responsible for very severe diseases and could be considered for inclusion in a carrier test for the Saguenay-Lac-Saint-Jean population. This study highlights the potential underestimation of rare disease prevalence and presents a population-based approach that could aid clinicians in their diagnostic efforts and patients' management.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40781540,

title = {Rare variants and founder effect in the Beauce region of Quebec},

author = {Mylène Gagnon and Claudia Moreau and Jasmin Ricard and Marie-Claude Boisvert and Alexandre Bureau and Michel Maziade and Simon L Girard},

doi = {10.1038/s42003-025-08630-7},

issn = {2399-3642},

year  = {2025},

date = {2025-08-01},

journal = {Commun Biol},

volume = {8},

number = {1},

pages = {1184},

abstract = {Founder events influenced the genetic diversity within the province of Quebec, increasing the frequency of certain rare pathogenic variants in regional populations. Some regions, such as Beauce, remain understudied despite evidence of a regional founder effect. Leveraging extensive genealogical data, we observe a specific regional structure emerging in Beauce following the initial settlement. It is characterised by a gradual increase in inbreeding and kinship coefficients and a low diversity of ancestors. Taking advantage of the region's genetic distinctiveness, we describe 36 rare pathogenic variants with higher carrier rates in Beauce than in urban regions, likely due to the regional founder effect. This provides the first in-depth study of Beauce's genetic and genealogical landscape, revealing a distinct structure and suggesting that other overlooked regions, in Quebec and elsewhere, could benefit from fine-scale population structure studies to improve the understanding and management of rare diseases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40463523,

title = {A multi-ancestry genetic reference for the Quebec population},

author = {Peyton McClelland and Georgette Femerling and Rose Laflamme and Alejandro Mejia-Garcia and Mohadese Sayahian Dehkordi and Hongyu Xiao and Alex Diaz-Papkovich and Justin Pelletier and Jean-Christophe Grenier and Ken Sin Lo and Luke Anderson-Trocmé and Justin Bellavance and Vincent Chapdelaine and Geneviève Gagnon and Annelie De Mori and Gerardo Martinez and Kristen Mohler and Thibault de Malliard and Catherine Labbé and Marjorie Labrecque and Alexandre Montpetit and Dan Spiegelman and Guy A Rouleau and Jean-François Théroux and Hufeng Zhou and Simon L Girard and Julie G Hussin and Anne-Marie Laberge and Claude Bhérer and Martine Tetreault and Sarah A Gagliano Taliun and Daniel Taliun and Simon Gravel and Guillaume Lettre},

doi = {10.1101/2025.05.14.25327536},

year  = {2025},

date = {2025-05-01},

journal = {medRxiv},

abstract = {While international efforts have characterized genetic variation in millions of individuals, the interplay of environmental, social, cultural, and genetic factors is poorly understood for most worldwide populations. The province of Quebec in Canada has been the site of numerous genetic studies, often focusing on individual Mendelian diseases in founder sub-populations. Here, we profiled and analyzed genome-wide genotyped variation in 29,337 Quebec residents from the large population-based cohort CARTaGENE (CaG), including rich phenotype and environmental data. We also sequenced the whole-genome of 2,173 CaG participants, including 163 and 132 individuals with grandparents born in Haiti and Morocco, respectively. We use this genetic information to gain insight into Quebec's demography and to help interpret the potential significance of variants identified in clinically important genes. We built an imputation panel by phasing the CaG whole-genome sequence data and showed, using genome-wide association studies (GWAS), how it improves the discovery of phenotype-genotype associations in this population. We provide allele frequency information and GWAS results through dedicated and publicly available websites. The genetic data, paired with phenotypic and environmental information, is also available for research use upon scientific and ethical review.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38477791,

title = {Genetic susceptibility and late bone outcomes in childhood acute lymphoblastic leukemia survivors},

author = {Nadeau Geneviève and Yazdanpanah Mojgan and Yazdanpanah Nahid and Forgetta Vincenzo and Girard Simon and Sinnett Daniel and Krajinovic Maja and Alos Nathalie and Manousaki Despoina},

doi = {10.1093/jbmr/zjad013},

issn = {1523-4681},

year  = {2024},

date = {2024-03-01},

journal = {J Bone Miner Res},

volume = {39},

number = {2},

pages = {130--138},

abstract = {Childhood acute lymphoblastic leukemia (cALL) survivors are at increased risk for bone comorbidities, but accurate screening tools for such comorbidities are limited. Polygenic scores (PGS) could stratify cALL survivors for risk of long-term adverse bone outcomes. We evaluated 214 (51% female) cALL survivors from the Prévenir les Effets TArdifs de la LEucémie study (median age 21 yr). Bone mineral density (BMD) measurements were obtained using dual X-ray absorptiometry at the lumbar spine (LS-BMD), femoral neck (FN-BMD), and total body (TB-BMD), and vertebral fractures (VF) were documented using the vertebral deformity criterion. We computed a PGS for adult heel quantitative ultrasound speed of sound (gSOS), known to be associated with the risk of osteoporotic fracture, using imputed genotype data of the participants, and tested it for association with BMD Z-scores and VF risk, adjusting for clinical risk factors, and in sex and prognostic risk-stratified analyses. We found that a gSOS below the mean was associated with lower BMD in all three sites in univariate and multivariate models. In univariate analyses, 1 SD increase in gSOS conferred a 0.16 SD increase in LS-BMD (95% CI 0.005-0.31), whereas a gSOS above the mean was associated with a 0.31 SD higher LS-BMD (95% CI 0.008-0.61), a 0.36 SD higher TB-BMD (95% CI 0.06-0.67), and a 0.43 SD higher FN-BMD (95% CI 0.13-0.72). Models combining gSOS with clinical risk factors explained up to 16% of the variance of BMD phenotypes and obtained an area under the receiver operating characteristic curve for VF of 0.77 in subgroup analyses. Cranial radiation, high cumulative glucocorticoid doses, high risk group, and male sex were significant risk factors for lower BMD Z-scores. In conclusion, a PGS, in combination with clinical risk factors, could be used as a tool to risk stratify cALL survivors for treatment-related bone morbidity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37016017,

title = {Deciphering the genetic structure of the Quebec founder population using genealogies},

author = {Laurence Gagnon and Claudia Moreau and Catherine Laprise and Hélène Vézina and Simon L Girard},

doi = {10.1038/s41431-023-01356-2},

issn = {1476-5438},

year  = {2024},

date = {2024-01-01},

journal = {Eur J Hum Genet},

volume = {32},

number = {1},

pages = {91--97},

abstract = {Using genealogy to study the demographic history of a population makes it possible to overcome the models and assumptions often used in population genetics. The Quebec founder population is one of the few populations in the world having access to the complete genealogy of the last 400 years. The goal of this study is to follow the evolution of the Quebec population structure over time from the beginning of European colonization until the present day. To do so, we calculated the kinship coefficients of all ancestors' pairs in the ascending genealogy of 665 subjects from eight regional and ethnocultural groups per 25-year period. We show that the Quebec population structure appeared progressively in the St. Lawrence valley as early as 1750 with the distinction of the Saguenay and Gaspesian groups. At that time, the ancestors of two groups, the Sagueneans and the Acadians from the Gaspé Peninsula, experienced a marked increase in kinship and inbreeding levels which have shaped the structure and led to the contemporary population structure. Interestingly, this structure arose before the colonization of the Saguenay region and at the very beginning of the Gaspé Peninsula settlement. The resulting regional founder effects in these groups led to differences in the present-day identity-by-descent sharing, the Gaspé and North Shore groups sharing more large segments and the Sagueneans more short segments. This is also reflected by the distribution of the number of most recent common ancestors at different generations and their genetic contribution to the studied subjects.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39499706,

title = {Fine-scale genetic structure and rare variant frequencies},

author = {Laurence Gagnon and Claudia Moreau and Catherine Laprise and Simon L Girard},

doi = {10.1371/journal.pone.0313133},

issn = {1932-6203},

year  = {2024},

date = {2024-01-01},

journal = {PLoS One},

volume = {19},

number = {11},

pages = {e0313133},

abstract = {In response to the current challenge in genetic studies to make new associations, we advocate for a shift toward leveraging population fine-scale structure. Our exploration brings to light distinct fine-structure within populations having undergone a founder effect such as the Ashkenazi Jews and the population of the Quebec' province. We leverage the fine-scale population structure to explore its impact on the frequency of rare variants. Notably, we observed an 8-fold increase in frequency for a variant associated with the Usher syndrome in one Quebec subpopulation. Our study underscores that smaller cohorts with greater genetic similarity demonstrate an important increase in rare variant frequencies, offering a promising avenue for new genetic variants' discovery.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37333772,

title = {Multivariate extension of penalized regression on summary statistics to construct polygenic risk scores for correlated traits},

author = {Meriem Bahda and Jasmin Ricard and Simon L Girard and Michel Maziade and Maripier Isabelle and Alexandre Bureau},

doi = {10.1016/j.xhgg.2023.100209},

issn = {2666-2477},

year  = {2023},

date = {2023-07-01},

journal = {HGG Adv},

volume = {4},

number = {3},

pages = {100209},

abstract = {Genetic correlations between human traits and disorders such as schizophrenia (SZ) and bipolar disorder (BD) diagnoses are well established. Improved prediction of individual traits has been obtained by combining predictors of multiple genetically correlated traits derived from summary statistics produced by genome-wide association studies, compared with single trait predictors. We extend this idea to penalized regression on summary statistics in Multivariate Lassosum, expressing regression coefficients for the multiple traits on single nucleotide polymorphisms (SNPs) as correlated random effects, similarly to multi-trait summary statistic best linear unbiased predictors (MT-SBLUPs). We also allow the SNP contributions to genetic covariance and heritability to depend on genomic annotations. We conducted simulations with two dichotomous traits having polygenic architecture similar to SZ and BD, using genotypes from 29,330 subjects from the CARTaGENE cohort. Multivariate Lassosum produced polygenic risk scores (PRSs) more strongly correlated with the true genetic risk predictor and had better discrimination power between affected and non-affected subjects than previously published sparse multi-trait (PANPRS) and univariate (Lassosum, sparse LDpred2, and the standard clumping and thresholding) methods in most simulation settings. Application of Multivariate Lassosum to predict SZ, BD, and related psychiatric traits in the Eastern Quebec SZ and BD kindred study revealed associations with every trait stronger than those obtained with univariate sparse PRSs, particularly when heritability and genetic covariance depended on genomic annotations. Multivariate Lassosum thus appears promising to improve prediction of genetically correlated traits with summary statistics for a selected subset of SNPs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37756314,

title = {Unraveling the role of non-coding rare variants in epilepsy},

author = {Alexandre Girard and Claudia Moreau and Jacques L Michaud and Berge Minassian and Patrick Cossette and Simon L Girard},

doi = {10.1371/journal.pone.0291935},

issn = {1932-6203},

year  = {2023},

date = {2023-01-01},

journal = {PLoS One},

volume = {18},

number = {9},

pages = {e0291935},

abstract = {The discovery of new variants has leveled off in recent years in epilepsy studies, despite the use of very large cohorts. Consequently, most of the heritability is still unexplained. Rare non-coding variants have been largely ignored in studies on epilepsy, although non-coding single nucleotide variants can have a significant impact on gene expression. We had access to whole genome sequencing (WGS) from 247 epilepsy patients and 377 controls. To assess the functional impact of non-coding variants, ExPecto, a deep learning algorithm was used to predict expression change in brain tissues. We compared the burden of rare non-coding deleterious variants between cases and controls. Rare non-coding highly deleterious variants were significantly enriched in Genetic Generalized Epilepsy (GGE), but not in Non-Acquired Focal Epilepsy (NAFE) or all epilepsy cases when compared with controls. In this study we showed that rare non-coding deleterious variants are associated with epilepsy, specifically with GGE. Larger WGS epilepsy cohort will be needed to investigate those effects at a greater resolution. Nevertheless, we demonstrated the importance of studying non-coding regions in epilepsy, a disease where new discoveries are scarce.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35678011,

title = {Assessment of burden and segregation profiles of CNVs in patients with epilepsy},

author = {Claudia Moreau and Frédérique Tremblay and Stefan Wolking and Alexandre Girard and Catherine Laprise and Fadi F Hamdan and Jacques L Michaud and Berge A Minassian and Patrick Cossette and Simon L Girard},

doi = {10.1002/acn3.51598},

issn = {2328-9503},

year  = {2022},

date = {2022-07-01},

journal = {Ann Clin Transl Neurol},

volume = {9},

number = {7},

pages = {1050--1058},

abstract = {OBJECTIVE: Microdeletions are associated with different forms of epilepsy but show incomplete penetrance, which is not well understood. We aimed to assess whether unmasked variants or double CNVs could explain incomplete penetrance.nnMETHODS: We analyzed copy number variants (CNVs) in 603 patients with four different subgroups of epilepsy and 945 controls. CNVs were called from genotypes and validated on whole-genome (WGS) or whole-exome sequences (WES). CNV burden difference between patients and controls was obtained by fitting a logistic regression. CNV burden was assessed for small and large (>1 Mb) deletions and duplications and for deletions overlapping different gene sets.nnRESULTS: Large deletions were enriched in genetic generalized epilepsies (GGE) compared to controls. We also found enrichment of deletions in epilepsy genes and hotspots for GGE. We did not find truncating or functional variants that could have been unmasked by the deletions. We observed a double CNV hit in two patients. One patient also carried a de novo deletion in the 22q11.2 hotspot.nnINTERPRETATION: We could corroborate previous findings of an enrichment of large microdeletions and deletions in epilepsy genes in GGE. We could also replicate that microdeletions show incomplete penetrance. However, we could not validate the hypothesis of unmasked variants nor the hypothesis of double CNVs to explain the incomplete penetrance. We found a de novo CNV on 22q11.2 that could be of interest. We also observed GGE families carrying a deletion on 15q13.3 hotspot that could be investigated in the Quebec founder population.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34982113,

title = {Association of Essential Tremor With Novel Risk Loci: A Genome-Wide Association Study and Meta-analysis},

author = {Calwing Liao and Charles-Etienne Castonguay and Karl Heilbron and Veikko Vuokila and Miranda Medeiros and Gabrielle Houle and Fulya Akçimen and Jay P Ross and Helene Catoire and Monica Diez-Fairen and Jooeun Kang and Stefanie H Mueller and Simon L Girard and Franziska Hopfner and Delia Lorenz and Lorraine N Clark and Alexandra I Soto-Beasley and Stephan Klebe and Mark Hallett and Zbigniew K Wszolek and Manuela Pendziwiat and Oswaldo Lorenzo-Betancor and Klaus Seppi and Daniela Berg and Carles Vilariño-Güell and Ronald B Postuma and Geneviève Bernard and Nicolas Dupré and Joseph Jankovic and Claudia M Testa and Owen A Ross and Thomas Arzberger and Sylvain Chouinard and Elan D Louis and Paola Mandich and Carmine Vitale and Paolo Barone and Elena García-Martín and Hortensia Alonso-Navarro and José A G Agúndez and Félix Javier Jiménez-Jiménez and Pau Pastor and Alex Rajput and Günther Deuschl and Gregor Kuhlenbaümer and Inge A Meijer and Patrick A Dion and Guy A Rouleau and },

doi = {10.1001/jamaneurol.2021.4781},

issn = {2168-6157},

year  = {2022},

date = {2022-02-01},

journal = {JAMA Neurol},

volume = {79},

number = {2},

pages = {185--193},

abstract = {IMPORTANCE: Essential tremor (ET) is one of the most common movement disorders, affecting 5% of the general population older than 65 years. Common variants are thought to contribute toward susceptibility to ET, but no variants have been robustly identified.nnOBJECTIVE: To identify common genetic factors associated with risk of ET.nnDESIGN, SETTING, AND PARTICIPANTS: Case-control genome-wide association study. Inverse-variance meta-analysis was used to combine cohorts. Multicenter samples collected from European populations were collected from January 2010 to September 2019 as part of an ongoing study. Included patients were clinically diagnosed with or reported having ET. Control individuals were not diagnosed with or reported to have ET. Of 485 250 individuals, data for 483 054 passed data quality control and were used.nnMAIN OUTCOMES AND MEASURES: Genotypes of common variants associated with risk of ET.nnRESULTS: Of the 483 054 individuals included, there were 7177 with ET (3693 [51.46%] female; mean [SD] age, 62.66 [15.12] years), and 475 877 control individuals (253 785 [53.33%] female; mean [SD] age, 56.40 [17.6] years). Five independent genome-wide significant loci and were identified and were associated with approximately 18% of ET heritability. Functional analyses found significant enrichment in the cerebellar hemisphere, cerebellum, and axonogenesis pathways. Genetic correlation (r), which measures the degree of genetic overlap, revealed significant common variant overlap with Parkinson disease (r, 0.28; P = 2.38 × 10-8) and depression (r, 0.12; P = 9.78 × 10-4). A separate fine-mapping of transcriptome-wide association hits identified genes such as BACE2, LRRN2, DHRS13, and LINC00323 in disease-relevant brain regions, such as the cerebellum.nnCONCLUSIONS AND RELEVANCE: The results of this genome-wide association study suggest that a portion of ET heritability can be explained by common genetic variation and can help identify new common genetic risk factors for ET.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}