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

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

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

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

Monogenic TraitsUMOD Gene Köttgen A et al. Nat Genet 2009

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

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

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

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

Monogenic Traits What have we learned from GWAS?

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

NHGRI GWA Catalog Published Genome-Wide Associations through 12/2012 Published GWA at p≤5X10 -8 for 17 trait categories

Monogenic TraitsUromodulin? Padmanabhan S et al. Hypertension 2014

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

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

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

Monogenic Traits Current and future strategies

Thomas SR 2009 Monogenic Forms of Hypertension

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

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

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

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

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

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

BHF Glasgow Cardiovascular Research Centre

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

Collagen alpha-1(II) chain

Collagen alpha-1(III) chain

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

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

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

WTCCC. Nature 2007 Cases and Controls in WTCCC

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

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

Cardiovascular Continuum Increasing the Sample Size OR=1.5

CHARGE Consortium Levy D et al. Nat Genet 2009

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