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Bibliographie

Genome-wide patterns of identity-by-descent sharing in the French Canadian founder population

In genetics the ability to accurately describe the familial relationships among a group of individuals can be very useful. Recent statistical tools succeeded in assessing the degree of relatedness up to 6–7 generations with good power using dense genome-wide single-nucleotide polymorphism data to estimate the extent of identity-by-descent (IBD) sharing. It is therefore important to describe genome-wide patterns of IBD sharing for more remote and complex relatedness between individuals, such as that observed in a founder population like Quebec, Canada. Taking advantage of the extended genealogical records of the French Canadian founder population, we first compared different tools to identify regions of IBD in order to best describe genome-wide IBD sharing and its correlation with genealogical characteristics. Results showed that the extent of IBD sharing identified with FastIBD correlates best with relatedness measured using genealogical data. Total length of IBD sharing explained 85% of the genealogical kinship’s variance. In addition, we observed significantly higher sharing in pairs of individuals with at least one inbred ancestor compared with those without any. Furthermore, patterns of IBD sharing and average sharing were different across regional populations, consistent with the settlement history of Quebec. Our results suggest that, as expected, the complex relatedness present in founder populations is reflected in patterns of IBD sharing. Using these patterns, it is thus possible to gain insight on the types of distant relationships in a sample from a founder population like Quebec

Correspondence between genomic- and genealogical/coalescent-based inference of homozygosity by descent in large French-Canadian genealogies

Research on the genetics of complex traits overwhelmingly focuses on the additive effects of genes. Yet, animal studies have shown that non-additive effects, in particular homozygosity effects, can shape complex traits. Recent investigations in human studies found some significant homozygosity effects. However, most human populations display restricted ranges of homozygosity by descent (HBD), making the identification of homozygosity effects challenging. Founder populations give rise to higher HBD levels. When deep genealogical data are available in a founder population, it is possible to gain information on the time to the most recent common ancestor (MRCA) from whom a chromosomal segment has been transmitted to both parents of an individual and in turn to that individual. This information on the time to MRCA can be combined with the time to MRCA inferred from coalescent models of gene genealogies. HBD can also be estimated from genomic data. The extent to which the genomic HBD measures correspond to the genealogical/coalescent measures has not been documented in founder populations with extensive genealogical data. In this study, we used simulations to relate genomic and genealogical/coalescent HBD measures. We based our simulations on genealogical data from two ongoing studies from the French-Canadian founder population displaying different levels of inbreeding. We simulated single-nucleotide polymorphisms (SNPs) in a 1-Mb genomic segment from a coalescent model in conjunction with the observed genealogical data. We compared genealogical/coalescent HBD to two genomic methods of HBD estimation based on hidden Markov models (HMMs). We found that genomic estimates of HBD correlated well with genealogical/coalescent HBD measures in both study genealogies. We described generation time to coalescence in terms of genomic HBD estimates and found a large variability in generation time captured by genomic HBD when considering each SNP. However, SNPs in longer segments were more likely to capture recent time to coalescence, as expected. Our study suggests that estimating the coalescent gene genealogy from the genomic data to use in conjunction with observed genealogical data could provide valuable information on HBD

Genomic and genealogical investigation of the French Canadian founder population structure

Characterizing the genetic structure of worldwide populations is important for understanding human history and is essential to the design and analysis of genetic epidemiological studies. In this study, we examined genetic structure and distant relatedness and their effect on the extent of linkage disequilibrium (LD) and homozygosity in the founder population of Quebec (Canada). In the French Canadian founder population, such analysis can be performed using both genomic and genealogical data. We investigated genetic differences, extent of LD, and homozygosity in 140 individuals from seven sub-populations of Quebec characterized by different demographic histories reflecting complex founder events. Genetic findings from genome-wide single nucleotide polymorphism data were correlated with genealogical information on each of these sub-populations. Our genomic data showed significant population structure and relatedness present in the contemporary Quebec population, also reflected in LD and homozygosity levels. Our extended genealogical data corroborated these findings and indicated that this structure is consistent with the settlement patterns involving several founder events. This provides an independent and complementary validation of genomic-based studies of population structure. Combined genomic and genealogical data in the Quebec founder population provide insights into the effects of the interplay of two important sources of bias in genetic epidemiological studies, unrecognized genetic structure and cryptic relatedness

Identification of OCA2 as a novel locus for the co-morbidity of asthma-plus-eczema

Background: Numerous genes have been associated with the three most common allergic diseases (asthma, allergic rhinitis or eczema) but these genes explain only a part of the heritability. In the vast majority of genetic studies, complex phenotypes such as co- morbidity of two of these diseases, have not been considered. This may partly explain missing heritability. Objective: To identify genetic variants specifically associated with the co-morbidity of asthma-plus-eczema. Methods: We first conducted a meta-analysis of four GWAS (Genome-Wide Association Study) of the combined asthma-plus-eczema phenotype (total of 8807 European-ancestry subjects of whom 1208 subjects had both asthma and eczema). To assess whether the association with SNP(s) was specific to the co- morbidity, we also conducted a meta-analysis of homogeneity test of association according to disease status (“asthma-plus-eczema” vs. the presence of only one disease “asthma only or eczema only”). We then used a joint test by combining the two test statistics from the co-morbidity-SNP association and the phenotypic heterogeneity of SNP effect meta-analyses. Results: Seven SNPs were detected for specific association to the asthma-plus-eczema co-morbidity, two with significant and five with suggestive evidence using the joint test after correction for multiple testing. The two significant SNPs are located in the OCA2 gene (Oculocutaneous Albinism II), a new locus never detected for significant evidence of association with any allergic disease. This gene is a promising candidate gene, because of its link to skin and lung diseases, and to epithelial barrier and immune mechanisms. Conclusion: Our study underlines the importance of studying sub-phenotypes as co-morbidities to detect new susceptibility genes

Mucolipidosis II : a single causal mutation in the N-acetylglucosamine-1-phosphotransferase gene (GNPTAB) in a French Canadian founder population

Mucolipidosis (ML) II (I-cell disease) is a lysosomal storage disorder caused by a deficiency of UDP-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase. MLII is an autosomal recessive disease with a carrier rate estimated at 1/39 in Saguenay-Lac-Saint-Jean (SLSJ) (Quebec, Canada), which is the highest frequency documented worldwide. To identify the causing mutation, we sequenced GNPTAB exons in 27 parents of 16 MLII-deceased children from the SLSJ region as obligatory and potential carriers. We also performed a genealogical reconstruction for each parent to evaluate consanguinity levels and genetic contribution of ancestors. Our goal was to identify which parameters could explain the high MLII frequency observed in the SLSJ population. A single mutation (c.3503_3504delTC) was found in all obligatory carriers. In addition, 11 apparent polymorphisms were identified. The mutation was not detected in genomic DNA of 50 unrelated controls. Genealogical data show six founders (three couples) with a higher probability of having introduced the mutation in the population. The frequency of the mutation was increased as a consequence of this founder effect and of the resulting population structure. We suggest that c.3503_3504delTC is the allele causing MLII in the SLSJ population, and its high carrier rate is most likely explained by a founder effect

Genetic burden linked to founder effects in Saguenay–Lac-Saint-Jean illustrates the importance of genetic screening test availability

The Saguenay–Lac-Saint-Jean (SLSJ) region located in the province of Quebec was settled in the 19th century by pioneers issued from successive migration waves starting in France in the 17th century and continuing within Quebec until the beginning of the 20th century. The genetic structure of the SLSJ population is considered to be the product of a triple founder effect and is characterised by a higher prevalence of some rare genetic diseases. Several studies were performed to elucidate the historical, demographic and genetic background of current SLSJ inhabitants to assess the origins of these rare disorders and their distribution in the population. Thanks to the development of new sequencing technologies, the genes and the variants responsible for the most prevalent conditions were identified. Combined with other resources such as the BALSAC population database, identifying the causal genes and the pathogenic variants allowed to assess the impacts of some of these founder mutations on the population health and to design precision medicine public health strategies based on carrier testing. Furthermore, it stimulated the establishment of many public programmes. We report here a review and an update of a subset of inherited disorders and founder mutations in the SLSJ region. Data were collected from published scientific sources. This work expands the knowledge about the current frequencies of these rare disorders, the frequencies of other rare genetic diseases in this population, the relevance of the carrier tests offered to the population, as well as the current available treatments and research about future therapeutic avenues for these inherited disorders

Écosystème numérique DESIIR : Données Environnementales et de Santé Intégrées pour une Infrastructure de Recherche

La pandémie de COVID-19 a souligné l’interdépendance des espèces vivantes et de leur environnement, menant au concept de « One Health ». Celui-ci implique une démarche intersectorielle afin de répondre aux enjeux complexes de santé incluant l’impact des changements climatiques sur la santé respiratoire et allergique. Ainsi, ce projet vise à regrouper les données de recherche générées au Saguenay–Lac-Saint-Jean (SLSJ) depuis les années 1970 en environnement, en santé physique et psychosociale et sur la structure populationnelle au sein d’un écosystème numérique nommé DESIIR (Données Environnementales et de Santé Intégrées pour une Infrastructure de Recherche). Le premier volet de ce projet vise à regrouper ces données dans un environnement sécurisé répondant aux principes FAIR et respectant les lois québécoises sur la protection des données. Le deuxième volet utilisera l’asthme comme modèle afin de démontrer l’ampleur des possibilités qu’offrira DESIIR. Le troisième volet aura comme objectif d’évaluer la complétude des différents ensembles de données, de planifier des programmes de recherche pour combler les lacunes identifiées et de développer un plan de valorisation de DESIIR pour maximiser sa visibilité et son utilisation. DESIIR est un vaste projet d’infrastructure qui implique une équipe de 30 chercheuses et chercheurs provenant de 9 établissements universitaires qui sera réalisé en partenariat avec le Centre intégré de santé et de service sociaux du SLSJ, le Cégep de Jonquière, ville Saguenay ainsi que « Secure Data 4 Health » pour la construction de l’infrastructure. Ces chercheurs, chercheuses et partenaires assurent actuellement la gestion des données qui seront regroupées dans DESIIR et la gouvernance du projet. À terme, DESIIR fournira des données conformes aux principes FAIR, de multiples opportunités pour le développement de nouveaux projets de recherche novateurs, des modèles d’analyse qui pourront être élargis à d'autres traits complexes ainsi qu’une preuve de concept de la valeur ajoutée d'un tel écosystème. Il favorisera le développement d’une approche holistique de la recherche en santé durable conduisant au développement et à l’application de nouveaux modèles de prévention et de gestion de la santé. DESIIR contribuera à bâtir un modèle socioéconomique innovant en santé durable pour la population du SLSJ

Genome-wide interaction study of early-life smoking exposure on time-to-asthma onset in childhood

Background: Asthma, a heterogeneous disease with variable age of onset, results from the interplay between genetic and environmental factors. Early-life tobacco smoke (ELTS) exposure is a major asthma risk factor. Only a few genetic loci have been reported to interact with ELTS exposure in asthma. Objective: Our aim was to identify new loci interacting with ELTS exposure on time-to-asthma onset (TAO) in childhood.Methods: We conducted genome-wide interaction analyses of ELTS exposure on time-to-asthma onset in childhood in five European-ancestry studies (totaling 8,273 subjects) using Cox proportional-hazard model. The results of all five genome-wide analyses were meta-analyzed.Results: The 13q21 locus showed genome-wide significant interaction with ELTS exposure (P=4.3x10-8 for rs7334050 within KLHL1 with consistent results across the five studies). Suggestive interactions (P<5x10-6) were found at three other loci: 20p12 (rs13037508 within MACROD2; P=4.9x10-7), 14q22 (rs7493885 near NIN; P=2.9x10-6) and 2p22 (rs232542 near CYP1B1; P=4.1x10-6). Functional annotations and the literature showed that the lead SNPs at these four loci influence DNA methylation in the blood and are located nearby CpG sites reported to be associated with exposure to tobacco smoke components, which strongly support our findings.Conclusion and Clinical Relevance: We identified novel candidate genes interacting with ELTS exposure on time-to-asthma onset in childhood. These genes have plausible biological relevance related to tobacco smoke exposure. Further epigenetic and functional studies are needed to confirm these findings and to shed light on the underlying mechanisms