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Variabilité Génétique et Maladies Humaines

Tutelles >

Université Paris Diderot

UFR de rattachement >

Institut Universitaire Hématologie (IUH)

Label unité >

UMRS

Partenaires >

INSERM

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-02196327] Integration of the human exposome with the human genome to advance medicine

Date: 27 juil 2019 - 22:43

Desc: Identifying precise and predictive biomarkers of health and disease is a critical objective of clinical biochemistry and biomedical research. New concepts and technologies have emerged recently that could support such an objective. The exposome corresponds to the totality of exposure over the lifetime. Research in this field allowed the development of sensors and biological biomarkers using omics technologies that are relevant for predicting the effect of those exposure on human health. Precision medicine has primarily focused on adapting treatments to the genetic profiles of tumors, when in fact, it had originally a wider scope including the use of robust biomarkers for disease prevention. Large-scale genetic studies have also contributed to highlight gene environment interactions, and were extended more recently to epigenetics. In line with the systems medicine approach, we propose to integrate the genome and exposome data in what we present as the exposome-genome paradigm. Such an integrated view will help strengthen approaches to identify relevant predictive markers that can support precise prevention actions both at the population and at the individual levels.

[inserm-01616494] A novel role for cilia function in atopy: ADGRV1 and DNAH5 interactions

Date: 13 oct 2017 - 17:57

Desc: BACKGROUND: Atopy, an endotype underlying allergic diseases, has a substantial genetic component. OBJECTIVE: Our goal was to identify novel genes associated with atopy in asthma-ascertained families. METHODS: We implemented a three-step analysis strategy in three datasets: The Epidemiological study on the Genetics and Environment of Asthma (EGEA) dataset: 1,660 subjects; The Saguenay-Lac-Saint-Jean (SLSJ) dataset: 1,138 subjects; and The Medical Research Council (MRC) dataset: 446 subjects). This strategy included a single-SNP genome-wide association study (GWAS), the selection of related gene pairs based on statistical filtering of GWAS results and text-mining filtering using GRAIL and SNP-SNP interaction analysis of selected gene pairs. RESULTS: We identified the 5q14 locus, harboring the adhesion G protein-coupled receptor V1 (ADGRV1) gene, that showed genome-wide significant association with atopy (rs4916831; Pmeta=6.8x10-9). Statistical filtering of GWAS results followed by text-mining filtering revealed relationships between ADGRV1 and three genes showing suggestive association with atopy (P≤10-4). SNP-SNP interaction analysis between ADGRV1 and these three genes showed significant interaction between ADGRV1 rs17554723 and two correlated SNPs (rs2134256 and rs1354187) within dynein axonemal heavy chain 5 (DNAH5) gene (Pmeta-int=3.6x10-5 and 6.1x10-5, that met the multiple-testing corrected threshold of 7.3x10-5). Further conditional analysis indicated that rs2134256 alone accounted for the interaction signal with rs17554723. CONCLUSION: As both DNAH5 and ADGRV1 contribute to function of cilia, this study suggests that cilia dysfunction may represent a novel mechanism underlying atopy. Combining GWAS and epistasis analysis driven by statistical and knowledge-based evidence represents a promising approach for identifying new genes involved in complex traits.

[hal-02151167] Detecting the dominance component of heritability in isolated and outbred human populations

Date: 7 juin 2019 - 18:29

Desc: [...]

[inserm-01645064] Strategies for Phasing and Imputation in a Population Isolate

Date: 22 nov 2017 - 18:44

Desc: In the search for genetic associations with complex traits, population isolates offer the advantage of reduced genetic and environmental heterogeneity. In addition, cost-efficient next-generation association approaches have been proposed in these populations where only a sub-sample of representative individuals is sequenced and then genotypes are imputed into the rest of the population. Gene mapping in such populations thus requires high quality genetic imputation and preliminary phasing. To identify an effective study-design, we compare by simulation a range of phasing and imputation software and strategies. We simulated 1,115,604 variants on chromosome 10 for 477 members of the large complex pedigree of Campora, a village within the established isolate of Cilento in southern Italy. We assessed the phasing performance of IBD-based software ALPHAPHASE and SLRP, LD-based software SHAPEIT2, SHAPEIT3, and BEAGLE, and new software EAGLE which combines both methodologies. For imputation we compared IMPUTE2, IMPUTE4, MINIMAC3, BEAGLE, and new software PBWT. Genotyping errors and missing genotypes were simulated to observe their effects on the performance of each software. Highly accurate phased data were achieved by all software with SHAPEIT2, SHAPEIT3, and EAGLE2 providing the most accurate results. MINIMAC3, IMPUTE4, and IMPUTE2 all performed strongly as imputation software and our study highlights the considerable gain in imputation accuracy provided by a genome sequenced reference panel specific to the population isolate.