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Sampling from Continuum
Extremes
Cardiovascular
Padmanabhan S et al. PLoS Genet 2011
Sampling from Continuum
Extremes
Cardiovascular
Padmanabhan S et al. PLoS Genet 2011
UMOD Gene
Cardiovascular
Continuum
Padmanabhan S et al. PLoS Genet 2011
UMOD: a Novel
Hypertension
Candidate Gene
Cardiovascular
Continuum
Padmanabhan S et al. PLoS Genet 2011
Monogenic
UMOD Gene
Traits
Köttgen A et al. Nat Genet 2009
Uromodulin
Monogenic
and Blood
Traits
Pressure
Padmanabhan S et al. Hypertension 2014
Blood Pressure inMonogenic
Umod+/+ (WT)
Traits
and Umod−/− (KO)
Graham LA et al. Hypertension 2014
Salt Sensitivity inMonogenic
Umod+/+ (WT)
Traits
and Umod−/− (KO)
Umod+/+
Umod-/-
Graham LA et al. Hypertension 2014
Pressure
Monogenic
Natriuresis
Traits
Curves
Graham LA et al. Hypertension 2014
Monogenic Traits
What have we learned from GWAS?
What HaveMonogenic
we LearnedTraits
from GWAS?
New Targets?
Published Genome-Wide Associations through 12/2012
Published GWA at p≤5X10-8 for 17 trait categories
NHGRI GWA Catalog
www.genome.gov/GWAStudies
www.ebi.ac.uk/fgpt/gwas/
Monogenic
Uromodulin?
Traits
Padmanabhan S et al. Hypertension 2014
What HaveMonogenic
we LearnedTraits
from GWAS?
Risk Prediction/Stratification?
Risk
Monogenic
Prediction?
Traits
Padmanabhan S et al. Trends Genet 2012
What HaveMonogenic
we LearnedTraits
from GWAS?
No direct genetic links
between CKD and Hypertension
(Exception: UMOD)
Monogenic Traits
Current and future strategies
Monogenic Forms of Hypertension
Thomas SR 2009
Detection
of Rare/Private
Mutations
Cardiovascular
Continuum
Lifton RP et al. Nat Genet 2008
Detection
of rare/private
mutations
Cardiovascular
Continuum
Lifton RP et al. Nat Genet 2008
"Missing Heritability"
Rare (private) mutations could
explain the "missing heritability",
i.e. heritability that is not explained
by common genetic variants.
Systems Biology and "Omics"
DNA
Genomics
mRNA
miRNAs
Transcriptomics
Protein
Proteomics
Metabolites
small molecules
Metabolomics
Monogenic
Traits
Epigenetics
DNA Methylation
Histone Modification
Non-coding RNAs, microRNAs
Friso S et al. Translat Res 2014
Cardiovascular
Cardiovascular Continuum
Continuum
Tissue injury
(MI, stroke, renal
insufficiency,
peripheral arterial
insufficiency)
Atherothrombosis and
progressive CV disease
Pathological
remodeling
Altered gene expression
Early tissue dysfunction
Altered protein expression
Target organ damage
End-organ failure
(CHF, ESRD)
Oxidative and
mechanical stress
Inflammation
Genome
Risk factors
Death
Dzau V et al. Circulation 2006
BHF Glasgow Cardiovascular Research Centre
CAD Score: Survival Analysis in ASCOT
< Mean
> Mean
Log Rank (Mantel-Cox)
P=0.021
Brown C et al. SCF 2013
Collagen alpha-1(II) chain
250
200
150
100
50
0
10
100
1000
ID:35339
10000
100000
Collagen alpha-1(III) chain
180
160
140
120
100
80
60
40
20
0
1
10
100
1000
ID:156878
10000
100000
1000000
Prediction of Diabetic Nephropathy
Normo  Micro
Micro  Macro
Roscioni SS et al. Diabetologia 2013
Prediction of Diabetic Nephropathy
Normo  Normo
Normo  Micro
Micro  Micro
Micro  Macro
Roscioni SS et al. Diabetologia 2013
WTCCC
Why did WTCCC find "hits" for many
diseases, but not for hypertension?
Cases and Controls in WTCCC
Collection
No Samples
% Male /
%Female
Eastern
E&WRidings
London
Midlands
Northern
North
Midlands
Northwestern
Southeastern
Southern
Southwestern
Scotland
Wales
58C
1480
50/50
UKBS
1458
48/52
BD
1868
37/63
CAD
1926
79/21
CD
1748
39/61
HT
1952
40/60
RA
1860
25/75
T1D
1963
51/49
T2D
1924
58/42
11
9
8
9
8
7
12
6
5
12
10
3
3
1
7
24
9
6
10
26
2
6
10
15
25
0
22
1
20
1
16
1
18
4
3
13
20
10
2
16
3
8
17
10
4
6
8
7
26
0
10
1
15
5
11
7
8
8
10
5
11
11
8
9
9
5
3
5
6
6
10
21
8
4
4
6
5
5
1
1
14
1
14
0
3
8
5
3
24
1
19
2
12
1
3
1
11
3
8
9
10
7
3
2
18
19
0
1
WTCCC. Nature 2007
"Caseness" of Controls
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%.
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?
Increasing
the Sample
Size
Cardiovascular
Continuum
OR=1.5
CHARGE Consortium
Levy D et al. Nat Genet 2009
CHARGE Consortium: 29,136 Subjects
Levy D et al. Nat Genet 2009