Variabilité Génétique et Maladies Humaines
Présentation
Les objectifs généraux du programme de recherche de l’UMR-946 sont :
- d'identifier les facteurs génétiques impliqués dans les maladies humaines
- de comprendre les mécanismes d'action de ces gènes
- de caractériser les autres facteurs (environnementaux, mode de vie...) qui peuvent moduler l’effet des gènes sur la maladie.
Ce programme s'articule autour de 2 thématiques principales et complémentaires :
- Méthodologie Statistique en Génétique Epidémiologique
- Etudes de Génétique Epidémiologique de Maladies Multifactorielles
Au total, le programme de recherche de l' UMR-946 est conçu pour répondre aux nouveaux défis posés par les avancées sans cesse croissantes dans les technologies de génotypage et de séquençage et de la biologie à grande échelle afin de progresser vers une approche de biologie des systèmes des maladies.
Thèmes de recherche
1. Méthodologie Statistique en Génétique Epidémiologique
Les objectifs de nos développements méthodologiques sont :
- de prendre en compte les mécanismes complexes impliqués dans les maladies multifactorielles :
interactions GènexGène, GènexEnvironnement, pléiotropie, hétérogénéité génétique…
- d’étendre les méthodes basées sur la consanguinité pour faciliter l’identification des gènes
- de permettre l’étude d'un large spectre de variabilité génétique
- d’intégrer les données de la biologie à grande échelle (génomique, transcriptomique, épigenomique,…)
2. Etudes de Génétique Epidémiologique de Maladies Multifactorielles
Nos études de génétique épidémiologique sont principalement ciblées sur l'asthme, les maladies allergiques et les cancers. Ces études reposent sur de grandes collections de données que nous avons recueillies pour divers cancers (mélanome, cancer du poumon, cancer des voies aérodigestives supérieures, cancer de la vessie) ou auxquelles notre unité est étroitement associée (comme l’Etude épidémiologique des facteurs Génétiques et Environnementaux de l’asthme (EGEA). Ces études intègrent des études d'association pangénomique et des approches de biologie à grande échelle appliquées à de nombreux phénotypes associés aux maladies. Ces études sont menées dans un cadre pluridisciplinaire et dans un contexte de nombreuses collaborations nationales, européennes et internationales.
Les principaux objectifs de ces études sont :
- d’identifier de nouveaux gènes et des interactions gène-environnement impliqués dans ces maladies
- de mieux comprendre les mécanismes moléculaires qui sous-tendent le processus pathologique
- de traduire les résultats de la recherche en applications médicales
[hal-04304740] Functional variation in allelic methylomes underscores a strong genetic contribution and reveals novel epigenetic alterations in the human epigenome
Date: 24 nov 2023 - 12:08
Desc: Following publication of the original article [1], the authors reported an error in Additional file 1. The updated Additional file 1 is given below.
[hal-04305779] Functional variation in allelic methylomes underscores a strong genetic contribution and reveals novel epigenetic alterations in the human epigenome
Date: 24 nov 2023 - 16:27
Desc: Background: The functional impact of genetic variation has been extensively surveyed, revealing that genetic changes correlated to phenotypes lie mostly in non-coding genomic regions. Studies have linked allele-specific genetic changes to gene expression, DNA methylation, and histone marks but these investigations have only been carried out in a limited set of samples. Results: We describe a large-scale coordinated study of allelic and non-allelic effects on DNA methylation, histone mark deposition, and gene expression, detecting the interrelations between epigenetic and functional features at unprecedented resolution. We use information from whole genome and targeted bisulfite sequencing from 910 samples to perform genotype-dependent analyses of allele-specific methylation (ASM) and non-allelic methylation (mQTL). In addition, we introduce a novel genotype-independent test to detect methylation imbalance between chromosomes. Of the ~2.2 million CpGs tested for ASM, mQTL, and genotype-independent effects, we identify ~32% as being genetically regulated (ASM or mQTL) and ~14% as being putatively epigenetically regulated. We also show that epigenetically driven effects are strongly enriched in repressed regions and near transcription start sites, whereas the genetically regulated CpGs are enriched in enhancers. Known imprinted regions are enriched among epigenetically regulated loci, but we also observe several novel genomic regions (e.g., HOX genes) as being epigenetically regulated. Finally, we use our ASM datasets for functional interpretation of disease-associated loci and show the advantage of utilizing naïve T cells for understanding autoimmune diseases. Conclusions: Our rich catalogue of haploid methylomes across multiple tissues will allow validation of epigenome association studies and exploration of new biological models for allelic exclusion in the human genome.
[hal-04321205] Genome‐wide association study of body mass index in 23 000 individuals with and without asthma
Date: 4 déc 2023 - 14:37
Desc: Background-Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co-morbidity between these conditions. Objective-To identify genetic variants that are associated with body mass index (BMI) in asthmatic children and adults, and to evaluate if there are differences between the genetics of BMI in asthmatics and healthy individuals. Methods-In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23,000 individuals with predominantly European descent, of whom 8,165 are asthmatics. Results-We report associations between several DENND1B variants (p=2.2×10 −7 for rs4915551) on chromosome 1q31 and BMI from a meta-analysis of GWAS data using 2,691 asthmatic children (screening data). The top DENND1B SNPs were next evaluated in seven independent replication data sets comprising 2,014 asthmatics, and rs4915551 was nominally replicated (p<0.05) in two of the seven studies and of borderline significance in one (p=0.059). However, strong evidence of effect heterogeneity was observed and overall, the association between rs4915551 and BMI was not significant in the total replication data set, p=0.71. Using a random effects model, BMI was overall estimated to increase by 0.30 kg/m 2 (p=0.01 for combined screening and replication data sets, N=4,705) per additional G allele of this DENND1B SNP. FTO was confirmed as an important gene for adult and childhood BMI regardless of asthma status. Conclusions and Clinical Relevance-DENND1B was recently identified as an asthma susceptibility gene in a GWAS on children, and here we find evidence that DENND1B variants may also be associated with BMI in asthmatic children. However, the association was overall not replicated in the independent data sets and the heterogeneous effect of DENND1B points to complex associations with the studied diseases that deserve further study.
[inserm-00624798] Genome-wide association study of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Europe.
Date: 19 sep 2011 - 18:40
Desc: UNLABELLED: ABSTRACT: BACKGROUND: Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are rare but extremely severe cutaneous adverse drug reactions in which drug-specific associations with HLA-B alleles were described. OBJECTIVES: To investigate genetic association at a genome-wide level on a large sample of SJS/TEN patients. METHODS: We performed a genome wide association study on a sample of 424 European cases and 1,881 controls selected from a Reference Control Panel. RESULTS: Six SNPs located in the HLA region showed significant evidence for association (OR range: 1.53-1.74). The haplotype formed by their risk allele was more associated with the disease than any of the single SNPs and was even much stronger in patients exposed to allopurinol (ORallopurinol = 7.77, 95%CI = [4.66; 12.98]). The associated haplotype is in linkage disequilibrium with the HLA-B*5801 allele known to be associated with allopurinol induced SJS/TEN in Asian populations. CONCLUSION: The involvement of genetic variants located in the HLA region in SJS/TEN is confirmed in European samples, but no other locus reaches genome-wide statistical significance in this sample that is also the largest one collected so far. If some loci outside HLA play a role in SJS/TEN, their effect is thus likely to be very small.
[inserm-04274192] Genetic heterogeneity according to age at onset in bipolar disorder: a combined positional cloning and candidate gene approach
Date: 7 nov 2023 - 17:39
Desc: This study is the first that formally tests for genetic heterogeneity of bipolar disorder (BD) according to age at onset (AAO) sub-groups by combining positional cloning and candidate gene approaches. Our previous genome-wide linkage-scan identified five genomic regions linked to early-onset form of BD. The present study uses association analysis to test genetic heterogeneity of candidate genes located in these five regions in a sample of 443 unrelated bipolar patients and 1,731 controls. The study involved the following steps: (1) test of heterogeneity by comparing early-onset BD patients versus later-onset BD patients; and (2) for significant results in step 1, comparison of early-onset BD patients and later-onset BD patients separately to controls. Two types of analyses were used: the single SNP test and the gene-based association test. We provide evidence for genetic heterogeneity within the ADRB2 (beta-2adrenoreceptor) gene region that is specifically associated with the early onset form of BD with an OR of 1.8. Unfortunately, the genotyping coverage of ADRB2 in the Wellcome Trust Case Control Consortium sample meant undermined our efforts to undertake a replication. However, as the ADRB2 gene product directly interacts with the CACNA1C gene product, and is known to be implicated in BD susceptibility, we conclude that further exploration of the relationships between ADRB2 and BD needs to be undertaken.
Autres contacts
Hôpital St Louis - Centre Hayem
1, avenue Claude Vellefaux
75475 PARIS CEDEX 10