Integrative Biology & Data Science

"All my life I have been incapable of resigning myself to fragmented knowledge, I have never been able to separate a subject under study from its context, its history or its future.” Edgar Morin, Introduction à la pensée complexe.

Analysis of multi-omic data layers associated with genetics variants, to identify molQTLs (molecular Quantitative Trait Loci) that ultimately will help pinpoint the regulatory variants implicated in diabetes susceptibility and its complications (graphical abstract from Vandiedonck C. Clinical Genetics 2018).

Diabetes and its complications result from a cascade of complex cellular events, themselves caused by multiple and potentially interacting molecular events. High-throughput biology, notably with the Next-Generation-Sequencing (NGS), now provides a unique opportunity to characterize these events, thus generating large datasets. These data include multi-omic, in particular genetic, epigenetic, transcriptomic and metabolomic, as well as cellular phenotypes (single-cell omics and immunophenotypes). Metadata including clinical features and environmental records (e.g. nutrition) must also be accounted for.

The purpose of the Integrative Biology group is to analyze the multiple datasets jointly to better understand the pathogenesis of diabetes and the different genetic and genomic factors at play in its etiology and complications.

To achieve this goal, the group actions are:

  • To follow the lab’s cohort overtime to identify the most relevant clinical features
  • To help set up the experimental design of the lab omics projects
  • To analyze the data with both computational and biostatistical approaches

Specific objectives:

  • Genetic and genomic factors implicated in the etiology of diabetes and their complications
  • Biomarkers for the diagnosis and care of diabetic patients
  • Ultimately precision medicine

Keywords: epidemiological genetics, systems genetics, omics, functional genomics, NGS, biomarkers, nutrigenomics, eQTL, molecular QTLs, networks

 

The group members remotely meeting during SARS-COV2 lockdown.
The group members remotely meeting during SARS-COV2 lockdown.

Key facts

Current studies

  • Multi-omics data integration of type 2 diabetes patients with high cardiovascular risk
  • Epidemiological studies of type 2 diabetes
  • Genetical genomics of type 1 diabetes

Human resources: (team composition):

Technical / Biological Resources: (main techniques)

  • Computational biology
  • Biostatistics
  • Analysis of genetics data: GWAS, Mendelian randomization,…
  • Analysis of OMICS data: bulk RNASeq, single-cell RNA-seq, ATAC-seq, ChIP-seq, RBBS, metabolomic…
  • Patients cohorts
  • Access to the IFB core cluster
  • github repositories: https://github.com/immediab

Collaborations/Industry/international links

  • iPOP-UP Idex
  • Labex Inflammex with Henri-Jean Garchon in IRIS lab (UVSQ): MOGIS (Multi-Omic and Genetics data analysis to identify specific and shared Inflammatory Signatures)
  • comité scientifique de la cohorte D.E.S.I.R. (Données épidémiologiques sur le syndrome d’insulino-resistance)
  • CEA (Commissariat à l’énergie atomique et aux énergies alternatives)
  • Université de Paris, CNRS UMR 8251-BFA – Unité de Biologie Fonctionnelle et Adaptative – Équipe 2 : Régulation de la glycémie par le système nerveux central (REGLYS) Direction Christophe Magnan

Financial support

  • Université de Paris
  • Labex Inflamex
  • Inserm
  • ERC
  • AP-HP

Knowledge dissemination

– Teaching at the DU Bioinformatique Intégrative by Université de Paris et Institut Français de Bioinformatique: https://du-bii.github.io/accueil/

– Project PLASMA (Plateforme d’e-Learning pour l’Analyse de données Scientifiques MAssives), https://doi.org/10.5281/zenodo.3630819, compte twitter @plasmabio

– Public engagement: Institut Pasteur-Colloque Chercheurs et participants aux recherches, 2016, https://www.youtube.com/watch?v=sinJgj4kpUU&feature=youtu.be

A screenshot composition of an Rstudio session, code in bash, an .Rmd notebook published in html, graphs and statistics.
A screenshot composition of an Rstudio session, code in bash, an .Rmd notebook published in html, graphs and statistics.

Major publications by team members

Sanchez M, Hoang S, Kannengiesser C, Potier, L, Hadjadj S, Marre M, Roussel R, Velho G, Mohammedi K. Leukocyte Telomere Length, DNA Oxidation, and Risk of Lower-Extremity Amputation in Patients With Long-standing Type 1 Diabetes. Diabetes Care 2020 Apr;43:828-834. DOI: 10.2337/dc19-0973

Castan-Laurell I, El Boustany R, Pereira O, Potier L, Marre M, Fumeron F, Valet P, Gourdy P, Velho G, Roussel R. Plasma Apelin and Risk of Type 2 Diabetes in a Cohort From the Community. Diabetes Care 2020 Feb;43:e15-e16. DOI: 10.2337/dc19-1865

Neou M, Villa C, Armignacco R, Jouinot A, Raffin-Sanson M-L, Septier A, Letourneur F, Diry S, Diedisheim M, Izac B, Gaspar C, Perlemoine K, Verjus V, Bernier M, Boulin A, Emile J-F, Bertagna X, Jaffrezic F, Laloe D, Baussart B, Bertherat J, Gaillard S, Assie G. Pangenomic classification of pituitary neuroendocrine tumors. Cancer Cell 2020 Jan. DOI:10.1016/j.ccell.2019.11.002

Potier L, Roussel R, Marre M, Bjornstad P, Cherney DZ, El Boustany R, Fumeron F, Venteclef N, Gautier JF, Hadjadj S, Mohammedi K, Velho G. Plasma Copeptin and Risk of Lower-Extremity Amputation in Type 1 and Type 2 Diabetes. Diabetes Care 2019 Dec ;42:2290-2297. DOI: 10.2337/dc19-1062

Mortreux M, Foppen E, Denis RG, Montaner M, Kassis N, Denom J, Vincent M, Fumeron F, Kujawski-Lafourcade M, Andréelli F, Balkau B, Marre M, Roussel R, Magnan C, Gurden H, Migrenne-Li S. New roles for prokineticin 2 in feeding behavior, insulin resistance and type 2 diabetes: Studies in mice and humans. Mol Metab. 2019 Nov; 29:182–196. DOI: 10.1016/j.molmet.2019.08.016

Gonzalez-Duque S, Azoury ME, Colli ML, Afonso G, Turatsinze J-V, Nigi L, Lalanne AI, Sebastiani G, Carré A, Pinto S, Culina S, Corcos N, Bugliani M, Marchetti P, Armanet M, Diedisheim M, Kyewski B, Steinmetz LM, Buss S, You S, Dubois-Laforgue D, Larger E, Beressi J-P, Bruno G, Dotta F, Scharfmann R, Eizirik D, Verdier Y, Vinh J, Mallone R. Conventional and Neo-Antigenic Peptides Presented by ǃ Cells Are Targeted by Circulating Naïve CD8+ T Cells in Type 1 Diabetic and Healthy Donors. Cell Metab. 2018 Dec 28(6). DOI: 10.1016/j.cmet.2018.07.007

Velho G, Ragot S, El Boustany R, Saulnier PJ, Fraty M, Mohammedi K, Fumeron F, Potier L, Marre M, Hadjadj S, Roussel R. Plasma copeptin, kidney disease, and risk for cardiovascular morbidity and mortality in two cohorts of type 2 diabetes. Cardiovasc Diabetol 17(1), 2018 Aug:110. DOI: 10.1186/s12933-018-0753-5

El Boustany R, Tasevska I, Meijer E, Kieneker LM, Enhörning S, Lefèvre G, Mohammedi K, Marre M, Fumeron F, Balkau B, Bouby N, Bankir L, Bakker SJL, Roussel R, Melander O, Gansevoort RT, Velho G. Plasma copeptin and chronic kidney disease risk in 3 European cohorts from the general population. JCI Insight. 2018 Jul; 3(13):e121479. https://doi.org/10.1172/jci.insight.121479

Diedisheim M, Oshima M, Albagli O, Huldt  CW, Ahlstedt I, Clausen M, Menon S, Aivazidis A, Andreasson A-C, Haynes WG, Marchetti P, Marselli L, Armanet M, Chimienti F, Scharfmann R. Modeling human pancreatic beta cell dedifferentiation. Mol Metab. 2018 Apr;10:74-86. DOI: 10.1016/j.molmet.2018.02.002

Vandiedonck C (2018). Genetic association of molecular traits: a help to identify causative variants in complex diseases. Clinical Genetics, 2018 Mar, 93(3) :520-532. DOI: 10.1111/cge.13187

Oshima M, Knoch KP, Diedisheim M, Petzold A, Cattan P, Bugliani M, Marchetti P, Choudhary P, Huang G-C, Bornstein SR, Solimena M, Albagli-Curiel O, Scharfmann R. Virus-like infection induces human β cell dedifferentiation. JCI Insight. 2018 Feb 8;3(3). DOI: 10.1172/jci.insight.97732

Bonnet-Serrano F, Diedisheim M, Mallone R, Larger E. Decreased β-cell mass and early structural alterations of the exocrine pancreas in patients with type 1 diabetes: An analysis based on the nPOD repository. PLoS One. 2018 Jan 19;13(1). DOI: 10.1371/journal.pone.0191528

Lenfant C, Baz P, Degavre A, Philippi A, Senée V, Vandiedonck C, Derbois C, Nicolino M, Zalloua P, Julier C. (2017) Juveline-onset diabetes and congenital cataract: « double-gene » mutations mimicking a syndromic diabetes presentation. Genes, 2017 Nov, 8(11). doi: 10.3390/genes8110309

Sudres M, Maurer M, Robinet M, Bismuth J, Truffault F, Girard D, Dragin N, Attia M, Fadel E, Santelmo N, Sicsic C, Brenner T, Berrih-Aknin S (2017) Preconditioned mesenchymal stem cells treat myasthenia gravis in a humanized preclinical model. JCI Insight 2017 Apr 6;2(7):e89665. DOI: 10.1172/jci.insight.89665

Gwinner F, Boulday G, Vandiedonck C, Arnould M, Cardoso C, Nikolayeva I, Guitart-Pla O, Denis CV, Christophe OD, Beghain J, Tournier-Lasserve E, Schwikowski B. (2017) Network-based analysis of omics data: The LEAN method. Bioinformatics, 2017 Mar 1;33(5):701-709. DOI: 10.1093/bioinformatics/btw676

Nicolas A, Mohammedi K, Bastard J-P, Fellahi S, Bellili-Muñoz N, Roussel R, Hadjadj S, Marre M, Velho G, Fumeron F. T-cadherin gene variants are associated with nephropathy in subjects with type 1 diabetes. Nephrol Dial Transplant 2017 Dec: 32; 1987–1993. DOI: 10.1093/ndt/gfx290

Nicolas A, Aubert R, Bellili-Muñoz N, Balkau B, Bonnet F, Tichet J, Velho G, Marre M, Roussel R, Fumeron F. T-cadherin gene variants are associated with type 2 diabetes and the Fatty Liver Index in the French population. Diabetes Metab 2017 Feb; 43: 33–39. DOI: 10.1016/j.diabet.2016.05.005

Roussel R, El Boustany R, Bouby N, Potier L, Fumeron F, Mohammedi K, Balkau B, Tichet J, Bankir L, Marre M, Velho G. Plasma Copeptin, AVP Gene Variants, and Incidence of Type 2 Diabetes in a Cohort From the Community. J Clin Endocrinol Metab 2016 Jan; 101: 2432-2439. DOI: 10.1210/jc.2016-1113

Diedisheim M, Mallone R, Boitard C, Larger E. Beta-cell Mass in Nondiabetic Autoantibody-Positive Subjects: An Analysis Based on the Network for Pancreatic Organ Donors Database. J Clin Endocrinol Metab. 2016 Apr;101(4):1390-7. DOI: 10.1210/jc.2015-3756

Lamri A, Bonnefond A, Meyre D, Balkau B, Roussel R, Marre M, Froguel P, Fumeron F and the D.E.S.I.R. study Group. Interaction between GPR120 p.R270H loss-of-function variant and dietary fat intake on incident type 2 diabetes risk in the D.E.S.I.R. study. Nutr Metab Cardiovasc Dis 2016 Oct;26,931-936. DOI: 10.1016/j.numecd.2016.04.010

Mohammedi K, Potier L, Belhatem N, Matallah N, Hadjadj S, Roussel R, Marre M, Velho G. Lower-extremity amputation as a marker for renal and cardiovascular events and mortality in patients with long standing type 1 diabetes. Cardiovasc Diabetol 2016 Oct;15:5. DOI:10.1186/s12933-015-0322-0

Velho G, El Boustany R, Lefevre G, Mohammedi K, Fumeron F, Potier L, Bankir L, Bouby N, Hadjadj S, Marre M, Roussel R. Plasma Copeptin, Kidney Outcomes, Ischemic Heart Disease, and All-Cause Mortality in People With Long-standing Type 1 Diabetes. Diabetes Care 2016 Dec; 39:2288-2295. DOI: 10.2337/dc16-1003

Onengut-Gumuscu S, Chen WM, Burren O, Cooper NJ, Quinlan AR, Mychaleckyj JC, Farber E, Bonnie JK, Szpak M, Schofield E, Achuthan P, Guo H, Fortune MD, Stevens H, Walker NM, Ward LD, Kundaje A, Kellis M, Daly MJ, Barrett JC, Cooper JD, Deloukas P; Type 1 Diabetes Genetics Consortium*, Todd JA, Wallace C, Concannon P, Rich SS. (2015) Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers. Nature Genetics, 2015 April; 47 (4):381-386 *Vandiedonck C among the 426 collaborators. DOI: 10.1038/ng.3245

Patente TA, Mohammedi K, Bellili-Munoz N, Driss F, Sanchez M, Fumeron F, Roussel R, Hadjadj S, Correa-Giannella ML, Marre M, Velho G. Allelic variations in the CYBA gene of NADPH oxidase and risk of kidney complications in patients with type 1 diabetes. Free Radic Biol Med 86:16-24, 2015. DOI: 10.1016/j.freeradbiomed.2015.04.002

Velho G, Ragot S, Mohammedi K, Gand E, Fraty M, Fumeron F, Saulnier PJ, Bellili-Munoz N, Bouby N, Potier L, Alhenc-Gelas F, Marre M, Hadjadj S, Roussel R. Plasma adrenomedullin, allelic variation in the ADM gene and kidney disease in people with type 2 diabetes. Diabetes 2015 Sep;64:3262-3272. DOI: 10.2337/db14-1852

Lamri A, Abi Khalil C, Jaziri R, Velho G, Lantieri O, Vol S, Froguel P, Balkau B, Marre M, Fumeron F and the D.E.S.I.R. Study Group. Dietary fat intake and polymorphisms at the PPARG locus modulate BMI and type 2 diabetes risk in the D.E.S.I.R. prospective study. Int J Obes 2015 Sept;36:218–224. DOI: 10.1016/j.freeradbiomed.2015.04.002

Vandiedonck C, Taylor MS, Lockstone HE, Plant K, Taylor JM, Durrant C, Broxholme J, Fairfax BP and Knight JC (2011) Pervasive haplotypic variation in the spliceo-transcriptome of the human MHC. Genome Research, 2011 Jul ; 21(7) :1042-54. DOI: 10.1101/gr.116681.110

Jaziri R, Aubert R, Roussel R, Emery N, Maimaitiming S, Bellili N, Miot A, Saulnier PJ, Travert F, Hadjadj S, Marre M, Fumeron F, for the DIABHYCAR and SURDIAGENE Study Groups. Association of ADIPOQ genetic variants and plasma adiponectin isoforms with the risk of incident renal events in Type 2 Diabetes. Nephrol Dial Transplant 2010 Jul;25:2231-2237. DOI: 10.1093/ndt/gfp771

Giraud M, Taubert R, Vandiedonck C, Ke X, Levi-Strauss M, Pagani F, Baralle FE, Eymard B, Tranchant C, Gajdos P, Vincent A, Willcox N, Beeson D, Kyewski B, Garchon HJ. An IRF8-binding promoter variant and AIRE control CHRNA1 promiscuous expression in thymus. Nature, 2007 Aug; 448:934-937. DOI: 10.1038/nature06066

Porchay-Baldérelli I, Péan F, Bellili N, Jaziri R, Marre M, Fumeron F. The CETP TaqIB polymorphism is associated with the risk of sudden death in type 2 diabetic patients. Diabetes Care 2007 Nov;30:2863-2867. DOI: 10.2337/dc07-0869

Vandiedonck C, Capdevielle C, Giraud M, Krumeich S, Jais JP, Eymard B, Tranchant C, Gajdos P, Garchon HJ. Association of the PTPN22*R620W Polymorphism with Autoimmune Myasthenia Gravis. Annals of Neurology, 2006 Feb;59:404-407. DOI: 10.1002/ana.20751

Vandiedonck C, Beaurain G, Giraud M, Hue-Beauvais C, Eymard B, Tranchant C, Gajdos P, Dausset J, Garchon HJ. Pleiotropic effects of the 8.1 HLA haplotype in patients with autoimmune myasthenia gravis and thymus hyperplasia. Proc Natl Acad Sci U S A, 2004 Oct;101:15464-15469. DOI: 10.1073/pnas.0406756101

Fumeron F, Aubert R, Siddiq A, Betoulle D, Péan F, Hadjadj S, Balkau B, Tichet J, Wilpart E, Chesnier MC, Froguel P, Marre M for the D.E.S.I.R. study group. Adiponectin gene polymorphisms and adiponectin levels are independently associated with the development of hyperglycemia during a 3-year period: The Epidemiologic Data on the Insulin Resistance Syndrome Prospective Study. Diabetes 2004 Apr; 53: 1150-1157. DOI: 10.2337/diabetes.53.4.1150

Mammès O, Betoulle D, Aubert R, Giraud V, Tuzet S, Petiet A, Colas-Linhart N, Fumeron F. Novel polymorphisms in the 5’ region of the LEP gene: Association with leptin levels and response to low calorie diet in human obesity. Diabetes 1998 Mar; 47: 487-489. DOI: 10.2337/diabetes.47.3.487

Fumeron F, Betoulle D, Luc G, Behague I, Ricard S, Poirier O, Jemaa R, Evans A, Arveiler D, Marques-Vidal P, Bard JM, Fruchard JC, Ducimetiere P, Apfelbaum M, Cambien F. Alcohol intake modulates the effect of a polymorphism of the cholesteryl ester transfer protein gene on plasma high density lipoprotein and the risk of myocardial infarction. J Clin Invest 1995 Sep;96:1664-1671. DOI: 10.1172/JCI118207

Mandenoff A, Fumeron F, Apfelbaum M, Margules DL. Endogenous opiates and energy balance. Science 1982 Mar;215:1536-1538. DOI: 10.1126/science.7063865