Cette invention concerne la selection d'un ensemble de marqueurs de polymorphisme utilisables... more Cette invention concerne la selection d'un ensemble de marqueurs de polymorphisme utilisables dans les etudes d'association sur le genome entier reposant sur la cartographie des desequilibres de liaison. En particulier, l'invention concerne les domaines de la pharmacogenomique, du diagnostic, du traitement therapeutique, et l'utilisation des donnees concernant les haplotypes genetiques pour predire la sensibilite d'un sujet a la schizophrenie et/ou sa reponse a un/des medicament(s) donne(s).
La presente invention concerne le gene ATG1611 et les variants genetiques associes a la maladie d... more La presente invention concerne le gene ATG1611 et les variants genetiques associes a la maladie de Crohn. En particulier, l'invention concerne les domaines de pharmacogenomique, de diagnostic, de therapie de patients et l'utilisation d'information d'haplotype genetique pour predire la susceptibilite d'un sujet a la maladie de Crohn et/ou sa reaction a un medicament ou des medicaments particulier(s).
Journal of the American Society of Nephrology, 2022
BackgroundUromodulin, the most abundant protein excreted in normal urine, plays major roles in ki... more BackgroundUromodulin, the most abundant protein excreted in normal urine, plays major roles in kidney physiology and disease. The mechanisms regulating the urinary excretion of uromodulin remain essentially unknown.MethodsWe conducted a meta-analysis of genome-wide association studies for raw (uUMOD) and indexed to creatinine (uUCR) urinary levels of uromodulin in 29,315 individuals of European ancestry from 13 cohorts. We tested the distribution of candidate genes in kidney segments and investigated the effects of keratin-40 (KRT40) on uromodulin processing.ResultsTwo genome-wide significant signals were identified for uUMOD: a novel locus (P 1.24E–08) over the KRT40 gene coding for KRT40, a type 1 keratin expressed in the kidney, and the UMOD-PDILT locus (P 2.17E–88), with two independent sets of single nucleotide polymorphisms spread over UMOD and PDILT. Two genome-wide significant signals for uUCR were identified at the UMOD-PDILT locus and at the novel WDR72 locus previously as...
Uncovering the interaction between genomes and the environment is a principal challenge of modern... more Uncovering the interaction between genomes and the environment is a principal challenge of modern genomics and preventive medicine. While theoretical models are well defined, little is known of the G × E interactions in humans. We used an integrative approach to comprehensively assess the interactions between 1.6 million data points, encompassing a range of environmental exposures, health, and gene expression levels, coupled with whole-genome genetic variation. From ∼1000 individuals of a founder population in Quebec, we reveal a substantial impact of the environment on the transcriptome and clinical endophenotypes, overpowering that of genetic ancestry. Air pollution impacts gene expression and pathways affecting cardio-metabolic and respiratory traits, when controlling for genetic ancestry. Finally, we capture four expression quantitative trait loci that interact with the environment (air pollution). Our findings demonstrate how the local environment directly affects disease risk ...
One of the most rapidly evolving genes in humans, PRDM9, is a key determinant of the distribution... more One of the most rapidly evolving genes in humans, PRDM9, is a key determinant of the distribution of meiotic recombination events. Mutations in this meiotic-specific gene have previously been associated with male infertility in humans and recent studies suggest that PRDM9 may be involved in pathological genomic rearrangements. In studying genomes from families with children affected by B-cell precursor acute lymphoblastic leukemia (B-ALL), we characterized meiotic recombination patterns within a family with two siblings having hyperdiploid childhood B-ALL and observed unusual localization of maternal recombination events. The mother of the family carries a rare PRDM9 allele, potentially explaining the unusual patterns found. From exomes sequenced in 44 additional parents of children affected with B-ALL, we discovered a substantial and significant excess of rare allelic forms of PRDM9. The rare PRDM9 alleles are transmitted to the affected children in half the cases; nonetheless ther...
Sickle cell disease (SCD) is a congenital blood disease, affecting predominantly children from su... more Sickle cell disease (SCD) is a congenital blood disease, affecting predominantly children from sub-Saharan Africa, but also populations world-wide. Although the causal mutation of SCD is known, the sources of clinical variability of SCD remain poorly understood, with only a few highly heritable traits associated with SCD having been identified. Phenotypic heterogeneity in the clinical expression of SCD is problematic for follow-up (FU), management, and treatment of patients. Here we used the joint analysis of gene expression and whole genome genotyping data to identify the genetic regulatory effects contributing to gene expression variation among groups of patients exhibiting clinical variability, as well as unaffected siblings, in Benin, West Africa. We characterized and replicated patterns of whole blood gene expression variation within and between SCD patients at entry to clinic, as well as in follow-up programs. We present a global map of genes involved in the disease through an...
Mutations in the mitochondrial genome are associated with multiple diseases and biological proces... more Mutations in the mitochondrial genome are associated with multiple diseases and biological processes; however, little is known about the extent of sequence variation in the mitochondrial transcriptome. By ultra-deeply sequencing mitochondrial RNA (>6000×) from the whole blood of ~1000 individuals from the CARTaGENE project, we identified remarkable levels of sequence variation within and across individuals, as well as sites that show consistent patterns of posttranscriptional modification. Using a genome-wide association study, we find that posttranscriptional modification of functionally important sites in mitochondrial transfer RNAs (tRNAs) is under strong genetic control, largely driven by a missense mutation in MRPP3 that explains ~22% of the variance. These results reveal a major nuclear genetic determinant of posttranscriptional modification in mitochondria and suggest that tRNA posttranscriptional modification may affect cellular energy production.
Cette invention concerne la selection d'un ensemble de marqueurs de polymorphisme utilisables... more Cette invention concerne la selection d'un ensemble de marqueurs de polymorphisme utilisables dans les etudes d'association sur le genome entier reposant sur la cartographie des desequilibres de liaison. En particulier, l'invention concerne les domaines de la pharmacogenomique, du diagnostic, du traitement therapeutique, et l'utilisation des donnees concernant les haplotypes genetiques pour predire la sensibilite d'un sujet a la schizophrenie et/ou sa reponse a un/des medicament(s) donne(s).
La presente invention concerne le gene ATG1611 et les variants genetiques associes a la maladie d... more La presente invention concerne le gene ATG1611 et les variants genetiques associes a la maladie de Crohn. En particulier, l'invention concerne les domaines de pharmacogenomique, de diagnostic, de therapie de patients et l'utilisation d'information d'haplotype genetique pour predire la susceptibilite d'un sujet a la maladie de Crohn et/ou sa reaction a un medicament ou des medicaments particulier(s).
Journal of the American Society of Nephrology, 2022
BackgroundUromodulin, the most abundant protein excreted in normal urine, plays major roles in ki... more BackgroundUromodulin, the most abundant protein excreted in normal urine, plays major roles in kidney physiology and disease. The mechanisms regulating the urinary excretion of uromodulin remain essentially unknown.MethodsWe conducted a meta-analysis of genome-wide association studies for raw (uUMOD) and indexed to creatinine (uUCR) urinary levels of uromodulin in 29,315 individuals of European ancestry from 13 cohorts. We tested the distribution of candidate genes in kidney segments and investigated the effects of keratin-40 (KRT40) on uromodulin processing.ResultsTwo genome-wide significant signals were identified for uUMOD: a novel locus (P 1.24E–08) over the KRT40 gene coding for KRT40, a type 1 keratin expressed in the kidney, and the UMOD-PDILT locus (P 2.17E–88), with two independent sets of single nucleotide polymorphisms spread over UMOD and PDILT. Two genome-wide significant signals for uUCR were identified at the UMOD-PDILT locus and at the novel WDR72 locus previously as...
Uncovering the interaction between genomes and the environment is a principal challenge of modern... more Uncovering the interaction between genomes and the environment is a principal challenge of modern genomics and preventive medicine. While theoretical models are well defined, little is known of the G × E interactions in humans. We used an integrative approach to comprehensively assess the interactions between 1.6 million data points, encompassing a range of environmental exposures, health, and gene expression levels, coupled with whole-genome genetic variation. From ∼1000 individuals of a founder population in Quebec, we reveal a substantial impact of the environment on the transcriptome and clinical endophenotypes, overpowering that of genetic ancestry. Air pollution impacts gene expression and pathways affecting cardio-metabolic and respiratory traits, when controlling for genetic ancestry. Finally, we capture four expression quantitative trait loci that interact with the environment (air pollution). Our findings demonstrate how the local environment directly affects disease risk ...
One of the most rapidly evolving genes in humans, PRDM9, is a key determinant of the distribution... more One of the most rapidly evolving genes in humans, PRDM9, is a key determinant of the distribution of meiotic recombination events. Mutations in this meiotic-specific gene have previously been associated with male infertility in humans and recent studies suggest that PRDM9 may be involved in pathological genomic rearrangements. In studying genomes from families with children affected by B-cell precursor acute lymphoblastic leukemia (B-ALL), we characterized meiotic recombination patterns within a family with two siblings having hyperdiploid childhood B-ALL and observed unusual localization of maternal recombination events. The mother of the family carries a rare PRDM9 allele, potentially explaining the unusual patterns found. From exomes sequenced in 44 additional parents of children affected with B-ALL, we discovered a substantial and significant excess of rare allelic forms of PRDM9. The rare PRDM9 alleles are transmitted to the affected children in half the cases; nonetheless ther...
Sickle cell disease (SCD) is a congenital blood disease, affecting predominantly children from su... more Sickle cell disease (SCD) is a congenital blood disease, affecting predominantly children from sub-Saharan Africa, but also populations world-wide. Although the causal mutation of SCD is known, the sources of clinical variability of SCD remain poorly understood, with only a few highly heritable traits associated with SCD having been identified. Phenotypic heterogeneity in the clinical expression of SCD is problematic for follow-up (FU), management, and treatment of patients. Here we used the joint analysis of gene expression and whole genome genotyping data to identify the genetic regulatory effects contributing to gene expression variation among groups of patients exhibiting clinical variability, as well as unaffected siblings, in Benin, West Africa. We characterized and replicated patterns of whole blood gene expression variation within and between SCD patients at entry to clinic, as well as in follow-up programs. We present a global map of genes involved in the disease through an...
Mutations in the mitochondrial genome are associated with multiple diseases and biological proces... more Mutations in the mitochondrial genome are associated with multiple diseases and biological processes; however, little is known about the extent of sequence variation in the mitochondrial transcriptome. By ultra-deeply sequencing mitochondrial RNA (>6000×) from the whole blood of ~1000 individuals from the CARTaGENE project, we identified remarkable levels of sequence variation within and across individuals, as well as sites that show consistent patterns of posttranscriptional modification. Using a genome-wide association study, we find that posttranscriptional modification of functionally important sites in mitochondrial transfer RNAs (tRNAs) is under strong genetic control, largely driven by a missense mutation in MRPP3 that explains ~22% of the variance. These results reveal a major nuclear genetic determinant of posttranscriptional modification in mitochondria and suggest that tRNA posttranscriptional modification may affect cellular energy production.
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Papers by Vanessa Bruat