1 / 13

Network of Networks, Cambridge UK 6 Octobre 2005

Network of Networks, Cambridge UK 6 Octobre 2005. GENOMOS “Genetic Markers for Osteoporosis” RSC: Ioannidis, Ralston, Uitterlinden EU FP5 sponsored 3 mio euro QLK6-CT-2002-02629 Jan 2003 - Jan 2007. Osteoporosis is a genetic disease. Classical genetic studies :

sherryw
Download Presentation

Network of Networks, Cambridge UK 6 Octobre 2005

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Network of Networks, Cambridge UK 6 Octobre 2005 GENOMOS “Genetic Markers for Osteoporosis” RSC: Ioannidis, Ralston, Uitterlinden EU FP5 sponsored 3 mio euro QLK6-CT-2002-02629 Jan 2003 - Jan 2007

  2. Osteoporosis is a genetic disease • Classical genetic studies: • - FAMILIAL CLUSTERING: no Mendelian segregation patterns • - TWIN STUDIES: DNA similarity ~ bone similarity • Human Genome Project: 15-20 million DNA polymorphisms • -DNA = Blue-print of life • - There is no “wild-type”: Each human has a unique genome • >> Genome variation causes bone variation

  3. Dissection of a Complex Disease/Trait : identify “risk” alleles of susceptibility genes Resolution Effectiveness Type of approach “Top-down”/hypothesis free * Whole-Genome-Linkage analysis - Pedigrees - Sib-pairs - Human, mouse * Whole-Genome-Association analysis - 100K – 1000K SNP analysis in cases/controls “Bottom-up”/up-front hypothesis * Association analyses of candidate gene polymorphisms (based on biology) - 5-20 million bp +/? 5-50 thousand bp +/- 1 bp >>All approaches converge to testing (candidate) gene polymorphisms !

  4. Molecular Genetic Epidemiology

  5. IGFI, IGFBP3 GR, 11B-HSD Cortisol IGF/GH TSHR, DIO1, DIO2, DIO3, MCT8 Thyroid Hormone ERα, ERβ, Aromatase, LH, LHR, GnRH VDR,DBP Vitamin D Estrogen Genetic determinants of osteoporosis ? TGFb/BMP/Wnt-signalling homocysteine Matrix molecules MTHFR, MS, MTRR, CBS, THYMS TGFb, LRP5/6, BMP2, FRZB, SOST Collagen Ia1, osteocalcin, AHSG, LOX

  6. Candidate gene association analysis “in practice”: Many controversial & ir-reproducible results because of: • Small sample size • Ill-defined choice of polymorphisms • Lack of standardized genotyping • Lack of standardized phenotype data • Publication bias • >> How to improve? • Combine study populations across Europe: meta-analysis • Rationalise choice of polymorphisms (functionality, haplotypes) • Standardize genotyping methods: e.g., reference plate • Standardize phenotypes across populations: meta-analysis • Run prospective meta-analyses

  7. GENOMOS (per january 2003) a large-scale multicentre study for prospective meta-analyses of osteoporosis candidate gene variants “Genetic Markers for Osteoporosis” EU FP5 sponsored 3 mio euro Jan 2003 – Jan 2007 “Maiden” publication: ESR1, JAMA Nov 3, 2004: Ioannidis et al. Aberdeen 2 Aarhus Total number of subjects: 18.917 14.622 women 4.295 men 4.952 fractures 1.072 vertebral fx 3 Cambridge 5 6 Rotterdam 1 Oxford 7 Antwerp 4 Firenze 9 Barcelona 8 Ioannina = Participant + Epidemiological Cohort 9 = Participant 7

  8. STRUCTURE OF “GENOMOS” WORKPLAN WP 1 GENOTYPING WP 2 FAMILY DATA WP 3 HAPLOTYPING WP 4 MONOGENIC GENES WP 5 DNA POOLING DATA GENERATION GENOTYPE DATA OF POPULATIONS META-ANALYSES DATA ANALYSIS WP 7: GENE ENVIRONMENT INTERACTIONS: Gene-nutrient interaction WP6: ASSOCIATION WITH FRACTURE, BMD, BONE LOSS WP 8: GENE ENVIRONMENT INTERACTIONS: Response-to-Treatment DELIVERABLES OSTEOPOROSIS SUSCEPTIBILITY- ALLELES DIETARY MODIFICATION TREATMENT MODIFICATION DISSEMINATION, COMMERCIALISATION

  9. STRUCTURE OF “GENOMOS” MANAGEMENT European Commission Scientific Officer: Dr Christian Wimmer COORDINATOR participant 1 (Uitterlinden) ADVISORY BOARD Briggs (ESDN) Kaufman (NEMO) Levi (GENOSPORA) Ralston (ANABONOS) RESEARCH STEERING COMMITTEE participant 1 (Uitterlinden) participant 2 (Ralston) participant 8 (Ioannidis) WP 1 GENOTYPING POPULATIONS coordinator participant 1 (Uitterlinden) WP 8 RESPONSE TO HRT-TREATMENT INTERACTION coordinator participant 3 (Langdahl) WP 7 GENE-NUTRIENT INTERACTION (Ca++) coordinator participant 5 (Reeve) WP 2 GENOTYPING FAMILIES coordinator participant 6 (Carey) WP 3 HAPLOTYPING coordinator participant 1 (Uitterlinden) WP 5 DNA POOLING coordinator participant 2 (Ralston) WP 6 META-ANALYSES coordinator participant 8 (Ioannidis) WP 4 MONOGENIC GENES coordinator participant 7 (van Hul)

  10. Candidate gene association analyses in GENOMOS • Genotype polymorphisms with prior evidence: • “fixed” polymorphisms • Then genotype other polymorphisms with some evidence: • “free” polymorphisms

  11. SIZE MATTERS !!

  12. “GENOMOS” (per may 2005) a large-scale, multi-centre study for prospective meta-analyses of osteoporosis candidate gene variants “Genetic Markers for Osteoporosis” EU FP5 sponsored: 3 mio euro Jan 2003 – Jan 2007 Total number of subjects: 26,264 18,405 women 7,859 men 6,498 fractures 2,380 vertebral fx Genes analysed: - ESR1 (JAMA Nov 3, 2004: Ioannidis et al.) - COLIA1 (manuscript subm) - VDR (manuscript subm) - TGFb (ongoing) - LRP5&6 (ongoing) Aberdeen 16 2 14 Aarhus 13 15 3 Cambridge 5 Amsterdam 12 Warsaw 1 Rotterdam* 10 7 Antwerp Graz 11 4 Firenze 9 Barcelona 8 = Participant + Epidemiological Cohort Ioannina 9 = Participant 7 *coordinating centre

More Related