GWS:is hypertension a special case

Genome Scans in complex traits: is hypertension a

special case?

Anna F Dominiczak

Guilt by association- WTCCC

In a tour-de-force demonstration of feasibility, a

consortium of 50 research teams used 500,000 genetic markers from each of 17,000

individuals to identify 24 genetic risk factors for 7 common human diseases

Nature, 7 June 2007

• 2,000 individuals for each of the 7 major diseases

• 3000 shared controls

• 24 independent association signals identified at p<5x10-7

• Across all diseases-58 loci

• (6 for HT) with p values between 10-5 and 5 x10-7

Genome-wide association scan

Genome-wide scan for seven diseases

WTCCC, Nature 7 June 2007

P<1x10-5

Green

The WTCCC & Risk

• The overall increase in risk (1.2-1.5 times) conferred by the genetic risk factors identified is in agreement with those reported by others

• However, these factors are unlikely to explain completely the clustering of any of the 7 diseases in families, and there are other genes (either many of small effect or rarer variants of genes) still to be identified

GWA- WTCCC : Control groups

• there were 2000 cases for each disease and 3000 common controls

• there is a potential for misclassification bias as phenotyping is not available for the shared control group

• it was estimated that if 5% of controls would meet the definition of cases, that loss of power is approx. the same as that due to reduction of sample size by 10%

• however, hypertension might have had 30% not 5% misclassification bias.....

• thus “hypercontrols” would have been more suitable than common controls.

GWS & Hypertension• failure to detect a prominent association

signal in the WTCCC cannot provide conclusive exclusion of any given gene

Due to:Due to:

1.1. less than complete coverage of common variation less than complete coverage of common variation genome-wide on the Affymetrix chip;genome-wide on the Affymetrix chip;

2.2. poor coverage (by design) of rare variants;poor coverage (by design) of rare variants;

3.3. despite the sample size, relatively low power to despite the sample size, relatively low power to detect variants with modest effects = OR < 1.2detect variants with modest effects = OR < 1.2

4.4. and specifically for hypertension – common controls and specifically for hypertension – common controls without phenotypeswithout phenotypes

WTCCC- Replication

• WTCCC report is based on initial studies but “independent” groups have confirmed the involvement of all but one of these most significant regions

• Some of the other identified regions with less statistically significant disease association are also likely to be true indicators of genetic risk further evaluation needed

• The WTCCC data are publicly available = resource to other groups /networks.

WTCCC genome-wide association scan: What next?

• The next step will be to study the exact nature of the disease-causing variants

• Variations leading to common diseases are diverse, including coding and regulatory regions of genes

• Thus the understanding of biological function of disease-risk-associated genomic regions will be challenging

BRIGHT and drug response

2010 Sib Pairs2010 Sib Pairs

Unresponsive to anti-HTN drug combinationsUnresponsive to anti-HTN drug combinations

ABCDABCD

ABAB CDCD

288 families288 families

89 families89 families 76 families76 families

A – ACEI/ARBA – ACEI/ARBB – Beta blockersB – Beta blockersC – CCBC – CCBD - DiureticsD - Diuretics

11

22

33

44

55

5050 100100 150150 200200 250250 300300cMcM

LO

DLO

DD

2S33

7

D2S28

6

D2S233

3

D2S221

6D2S39

1 D2S236

8

PRKCE

PRKCE

EPAS1

EPAS1

ATP

6V1E

2

ATP

6V1E

2RHOQ

RHOQ

CALM

2

CALM

2KCNK12

KCNK12

GPR75

GPR75

PSM

E4

PSM

E4

RPS27

A

RPS27

A

FANCL

FANCL

USP34

USP34

CALC

INEU

RIN

B

CALC

INEU

RIN

B

PLE

KPLE

KARHGAP25

ARHGAP25

ANXA4

ANXA4

ADD2

ADD2

ATP

6V1B

1

ATP

6V1B

1NAT8

NAT8

MTH

FD2

MTH

FD2

SLC

4A5

SLC

4A5

PRSS25

PRSS25

DOK1

DOK1

FABP1

FABP1

RAB1A

RAB1A

USP39

USP39

Padmanabhan et al, Hypertension 2006;47:603

AB non-responders =AB non-responders =ACEI & beta blockersACEI & beta blockers

ADD2 = ADD2 = ß subunit of adducin SLC4A5 =SLC4A5 =sodium bicarbonate transporter

Genome wide screen identifies new loci linked to response to antihypertensive treatment

Modified from Barkley et al. Hypertension 2004;43:477Modified from Barkley et al. Hypertension 2004;43:477

0

1

2

3

4

5

6

0 50 100 150 200 250 300

BRIGHT AB only

4.84

2.7

1

Salt Sensitive LocusSalt Sensitive Locus

LO

D

Ingenious strategyIngenious strategy

Hypercontrols

Increase odds ratio

Increase power

Better LD coverage using HapMap2

550K Illumina BeadChip

Cases – HypertensiveAge <60 yearsBP>160/100

Controls – Age >50 yearsBP <120/80

Not on antiHTNNo prevalent CVD (MI,CVA)

No incident CVD on follow-up until 2001

Malmo – All Swedish subjects

InGenious HyperCare Investigators

BHF Glasgow Cardiovascular Research Centre

Human & Experimental Genomics

Oxidative stress & Gene Transfer

Dr Christian Dr Christian DellesDellesDr S Dr S PadmanabhanPadmanabhan Dr Lukas Dr Lukas ZimmerliZimmerliDr Wai Kwong Dr Wai Kwong LeeLeeDr Martin Dr Martin McBrideMcBrideDr Delyth Dr Delyth Graham Graham Dr Maria MorenoDr Maria MorenoDr John McClureDr John McClureDr M Dr M GaasenbeekGaasenbeekElisabeth Elisabeth BeattieBeattieKirsten GildayKirsten GildayJames PolkeJames PolkeCaline Koh-TanCaline Koh-TanCarol JenkinsCarol JenkinsJames McCullochJames McCullochDeborah ClarkDeborah Clark

Prof Andrew Baker Prof Andrew Baker Dr Carlene HamiltonDr Carlene HamiltonDr Stuart NicklinDr Stuart NicklinDr Lorraine WorkDr Lorraine WorkDr William Miller Dr William Miller Dr Angelika KritzDr Angelika KritzDr Tracey GrahamDr Tracey GrahamDr Laura DenbyDr Laura DenbyDr Alan ParkerDr Alan ParkerKatie WhyteKatie WhyteRachel MassonRachel MassonNicola BrittonNicola BrittonLaura GrahamLaura GrahamRuth MackenzieRuth Mackenzie

CollaboratoCollaboratorsrsMRC BRIGHT InvestigatorsMRC BRIGHT Investigators

WTCCCWTCCCWellcome CVS Functional GenomicsWellcome CVS Functional Genomics

EURATools InvestigatorsEURATools Investigators InGenious HyperCare InvestigatorsInGenious HyperCare Investigators