gws:is hypertension a special case
DESCRIPTION
GWS:is hypertension a special case. Genome Scans in complex traits: is hypertension a special case? Anna F Dominiczak. Guilt by association- WTCCC. - PowerPoint PPT PresentationTRANSCRIPT
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