Download Slides 5 - InGenious HyperCare

Genome
in complex
traits:case
GWS:is Scans
hypertension
a special
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
Genome-wide association scan
• 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 scan for seven diseases
P<1x10-5
Green
WTCCC, Nature 7 June 2007
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:
1. less than complete coverage of common variation genomewide on the Affymetrix chip;
2. poor coverage (by design) of rare variants;
3. despite the sample size, relatively low power to detect
variants with modest effects = OR < 1.2
4. and specifically for hypertension – common controls without
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 Pairs
Unresponsive to anti-HTN drug combinations
ABCD
AB
89 families
288 families
CD
76 families
A
B
C
D
– ACEI/ARB
– Beta blockers
– CCB
- Diuretics
Genome wide screen identifies new loci linked to
response to antihypertensive treatment
LOD
5
4
3
AB non-responders =
ACEI & beta blockers
2
1
50
ADD2 = ß subunit of adducin
SLC4A5 =sodium bicarbonate transporter
100
150
200
250
300cM
Padmanabhan et al, Hypertension 2006;47:603
Salt Sensitive Locus
4.84
BRIGHT AB only
LOD
2.7
1
Modified from Barkley et al. Hypertension 2004;43:477
Ingenious strategy
Malmo – All Swedish subjects
Cases – Hypertensive
Controls – Age >50 years
Age <60 years
BP>160/100
BP <120/80
Not on antiHTN
No prevalent CVD (MI,CVA)
No incident CVD on follow-up until 2001
550K Illumina BeadChip
Hypercontrols
Increase odds ratio
Increase power
Better LD coverage using HapMap2
InGenious HyperCare
Investigators
BHF Glasgow Cardiovascular Research
Centre
Human & Experimental
Genomics
Dr Christian Delles
Dr S Padmanabhan
Dr Lukas Zimmerli
Dr Wai Kwong Lee
Dr Martin McBride
Dr Delyth Graham
Dr Maria Moreno
Dr John McClure
Dr M Gaasenbeek
Elisabeth Beattie
Kirsten Gilday
James Polke
Caline Koh-Tan
Carol Jenkins
James McCulloch
Deborah Clark
Oxidative stress &
Gene Transfer
Collaborators
MRC BRIGHT Investigators
WTCCC
Wellcome CVS Functional Genomics
EURATools Investigators
InGenious HyperCare Investigators
Prof Andrew Baker
Dr Carlene Hamilton
Dr Stuart Nicklin
Dr Lorraine Work
Dr William Miller
Dr Angelika Kritz
Dr Tracey Graham
Dr Laura Denby
Dr Alan Parker
Katie Whyte
Rachel Masson
Nicola Britton
Laura Graham
Ruth Mackenzie