1. Cardiovascular Continuum Sampling from Extremes Padmanabhan S et al. PLoS Genet 2011

2. Cardiovascular Continuum Sampling from Extremes Padmanabhan S et al. PLoS Genet 2011

3. Cardiovascular Continuum UMOD Gene Padmanabhan S et al. PLoS Genet 2011

4. Cardiovascular Continuum UMOD: a Novel Hypertension Candidate Gene Padmanabhan S et al. PLoS Genet 2011

5. Monogenic TraitsUMOD Gene Köttgen A et al. Nat Genet 2009

6. Monogenic Traits Padmanabhan S et al. Hypertension 2014 Uromodulin and Blood Pressure

7. Monogenic TraitsBlood Pressure in Umod +/+ (WT) and Umod −/− (KO) Graham LA et al. Hypertension 2014

8. Monogenic Traits Graham LA et al. Hypertension 2014 Umod +/+ Umod -/- Salt Sensitivity in Umod +/+ (WT) and Umod −/− (KO)

9. Monogenic Traits Graham LA et al. Hypertension 2014 Pressure Natriuresis Curves

10. Monogenic Traits What have we learned from GWAS?

11. Monogenic Traits New Targets? What Have we Learned from GWAS?

12. NHGRI GWA Catalog www.genome.gov/GWAStudies www.ebi.ac.uk/fgpt/gwas/ Published Genome-Wide Associations through 12/2012 Published GWA at p≤5X10 -8 for 17 trait categories

13. Monogenic TraitsUromodulin? Padmanabhan S et al. Hypertension 2014

14. Monogenic Traits Risk Prediction/Stratification? What Have we Learned from GWAS?

15. Monogenic TraitsRisk Prediction? Padmanabhan S et al. Trends Genet 2012

16. Monogenic Traits No direct genetic links between CKD and Hypertension (Exception: UMOD) What Have we Learned from GWAS?

17. Monogenic Traits Current and future strategies

18. Thomas SR 2009 Monogenic Forms of Hypertension

19. Cardiovascular Continuum Detection of Rare/Private Mutations Lifton RP et al. Nat Genet 2008

20. Cardiovascular Continuum Detection of rare/private mutations Lifton RP et al. Nat Genet 2008

21. Rare (private) mutations could explain the "missing heritability", i.e. heritability that is not explained by common genetic variants. "Missing Heritability"

22. Systems Biology and "Omics" DNA mRNA Protein Metabolites small molecules Proteomics Metabolomics Genomics Transcriptomics miRNAs

23. Monogenic Traits DNA MethylationHistone Modification Non-coding RNAs, microRNAs Epigenetics Friso S et al. Translat Res 2014

24. Cardiovascular Continuum Dzau V et al. Circulation 2006 Risk factors Oxidative and mechanical stress Inflammation Early tissue dysfunction Atherothrombosis and progressive CV disease Tissue injury (MI, stroke, renal insufficiency, peripheral arterial insufficiency) Pathological remodeling Target organ damage End-organ failure (CHF, ESRD) Death Altered gene expression Altered protein expression Genome

27. BHF Glasgow Cardiovascular Research Centre

28. Log Rank (Mantel-Cox) P=0.021 CAD Score: Survival Analysis in ASCOT < Mean > Mean Brown C et al. SCF 2013

29. Collagen alpha-1(II) chain

30. Collagen alpha-1(III) chain

31. Roscioni SS et al. Diabetologia 2013 Normo  MicroMicro  Macro Prediction of Diabetic Nephropathy

32. Roscioni SS et al. Diabetologia 2013 Normo  NormoNormo  MicroMicro  MicroMicro  Macro Prediction of Diabetic Nephropathy

33. WTCCC Why did WTCCC find "hits" for many diseases, but not for hypertension?

34. WTCCC. Nature 2007 Cases and Controls in WTCCC

35. If 5% of controls would meet the definition of cases, then loss of power of the GWAS is approximately the same as that due to the reduction of sample size by 10%. "Caseness" of Controls WTCCC. Nature 2007

36. Challenges Possible caseness of controls Accurate definition of the phenotype Precise assessment of the phenotype Multiple pathways, multiple genes What can be done?

37. Cardiovascular Continuum Increasing the Sample Size OR=1.5

38. CHARGE Consortium Levy D et al. Nat Genet 2009

39. CHARGE Consortium: 29,136 Subjects Levy D et al. Nat Genet 2009