So, just exactly when will genetics revolutionise medicine? - Part 1

Transcription

1 So, just exactly when will genetics revolutionise medicine? - Part 1 PRO F. M A RT IN K E N N E DY D EPA RT M ENT O F PAT H O LO GY & C A R N E Y C E N T R E FO R PH A R M ACO GEN O M IC S U N IVERSIT Y O F OTAGO, C H R ISTCHURC H

2 Roadmap Genome variation Genetic architecture and GWAS Exome/genome sequencing Pharmacogenetics and genomics Personal genomics Waiting for the revolution 8/20/2013

3 EM DNA

4 SNPs (Single nucleotide polymorphisms) Common in the genome (about 10 million) Convenient markers for genetic studies Standard nomenclature e.g. rs Automated high throughput analysis (DNA chips)

5 Many other types of DNA variants Frazer (2009) Nature Reviews Genetics

6 Copy number variants CNVs

7 Roadmap Genome variation Genetic architecture and GWAS Exome/genome sequencing Pharmacogenetics and genomics Personal genomics Waiting for the revolution 8/20/2013

8 Two main categories of traits 1. Mendelian one causative gene weak environmental influences 2. Complex many risk genes (small effects) strong environmental influences

9 G x E contributions antenatal smoking nutrition GENETIC EFFECTS depression autism IBD cystic fibrosis cognition BMI cardiomyopathy infection asthma handedness DMD height ENVIRONMENTAL EFFECTS

10 8/20/2013

11 Why search for genes underlying complex traits? Window on aetiology, pathology & biology Development of new therapies Diagnostic/prognostic information

12 GWAS: Genome wide association studies Evolved from the convergence of: Identification of millions of SNPs Chip genotyping technologies Large case-control cohorts Sophisticated informatics Statistical theory 8/20/2013

13 Genome Wide Association Studies - GWAS Slide courtesy of Nick Martin (QIMR)

14 GWAS: finding genes for complex traits Need many patients and unaffected controls Compare distribution of SNPs Manhattan plot points to underlying genes:

15 Published Genome-Wide Associations through 07/2012 NHGRI GWA Catalog

16 Complex traits - key messages Many genes involved in most complex traits Each variant has tiny effect Poor predictive power at individual level Cannot account for most heritability Remains to be seen whether more complex multigene predictive approaches useful

17 IBD pathogenesis (as illuminated by GWAS)

18 Roadmap Genome variation Genetic architecture and GWAS Exome/genome sequencing Pharmacogenetics and genomics Personal genomics Waiting for the revolution 8/20/2013

19 DNA sequencing technology 8/20/ bases, 2 weeks 600 gigabases, 2 days (600,000,000,000 bases)

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21 Personal genomes A single DNA sequencer can now generate in a day what it took 10 years to collect for the human genome project

22 The human exome 20,000 genes 180,000 exons 1% of the human genome Contains ~85% of mutations Costs less than $1000

23 We are all mutants! Each genome has damaged genes of these implicated in inherited disorders Millions of polymorphism (variants)

24 Exome sequencing and Mendelian traits 8/20/2013

25 Roadmap Genome variation Genetic architecture and GWAS Exome/genome sequencing Pharmacogenetics and genomics Personal genomics Waiting for the revolution 8/20/2013

26 Pharmacogenetics/omics

27 CYP2D6 polymorphism Drug:metabolite ratio

28 CYP2D6 examples codeine tamoxifen (Prodrug) CYP2D6 CYP2D6 morphine endoxifen (Drug)

29 Pharmacogenetics tests in clinical use TPMT and thiopurine drugs CYP2D6 and tamoxifen VKORC1, CYP2C9 and warfarin dose Drug hypersensitivity and HLA-B*5701 CYP2C19 and clopidogrel Cetuximab and K-RAS mutations Herceptin and HER2

30 Translational issues? Evidence base for clinical utility of tests Frequency of the gene variant/phenotype Accessibility of tests Clinical guidelines for test results Reimbursement and payment for tests Complex vs. Mendelian phenotypes

31 GWAS and pharmacogenetics

32 Small steps: UDRUGS Study Understanding Drug Reactions and Unusual responses by Genomic Sequencing Identify and recruit patients with severe ADR Analysis of entire genes (e.g. CYP2D6, CYP2C19) Analysis of whole exomes Biobank samples International GWAS consortia Contact

33 Roadmap Genome variation Genetic architecture and GWAS Exome/genome sequencing Pharmacogenetics and genomics Personal genomics Waiting for the revolution 8/20/2013

34 The era of personal genomes

35 Clinical drivers for personal genomes Pgx Complex disease Mendelian disease

36 How to improve pharmacogenetic testing? Test results available prior to prescribing Comprehensive information on all pharmacogenes All gene variants, not just common ones Clear guidance on meaning of results Relatively inexpensive Single test

37 The human exome 20,000 genes 180,000 exons 1% of the human genome Contains ~85% of mutations Costs less than $1000

38 The new Guthrie card? Will personal genomes eventually supersede birth blood spot tests? More costly, but Comprehensive pharmacogenetics Mendelian disease screening Continual updating of interpretome as evidence grows Complex disease Pharmacogenomics Mendelian disease

39 Avoiding GATTACA Genome sequence data: Need secure information management Age-appropriate data release Multidisciplinary approach Potential to overwhelm existing clinical genetics capacity

40 Roadmap Genome variation Genetic architecture and GWAS Exome/genome sequencing Pharmacogenetics and genomics Personal genomics Waiting for the revolution 8/20/2013

41 The road to 2020 GWAS will continue to identify many complex trait genes New understanding of pathophysiology Drug repurposing New drug development Exome/genome analysis will identify genes for many Mendelian traits Cancer genomics Personal genomes in pharmacogenetics? Prospective trial of exomes in practice?

42 Personal genomes in routine use by 2020? 20 years ago the notion of sequencing the human genome was viewed as utterly implausible science fiction 8/20/2013

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