GWS:is hypertension a special case

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GWSis hypertension a special case
Genome Scans in complex traits is hypertension a
special case?Anna F Dominiczak
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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
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Genome-wide association scan

• 2,000 individuals for each of the 7 major
  diseases
• 3000 shared controls
• 24 independent association signals identified at
  plt5x10-7
• Across all diseases-58 loci
• (6 for HT) with p values between 10-5 and 5 x10-7

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Genome-wide scan for seven diseases
Plt1x10-5 Green
WTCCC, Nature 7 June 2007
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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

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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.

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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
   genome-wide 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 lt 1.2
4. and specifically for hypertension common
   controls without phenotypes

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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.

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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

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BRIGHT and drug response
2010 Sib Pairs
Unresponsive to anti-HTN drug combinations
288 families
ABCD
A ACEI/ARB B Beta blockers C CCB D -
Diuretics
AB
CD
89 families
76 families
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Genome wide screen identifies new loci linked to
response to antihypertensive treatment
AB non-responders ACEI beta blockers
Padmanabhan et al, Hypertension 200647603
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Salt Sensitive Locus
4.84
BRIGHT AB only
2.7
LOD
1
Modified from Barkley et al. Hypertension
200443477
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Ingenious strategy
Malmo All Swedish subjects
Controls Age gt50 years BP lt120/80 Not on
antiHTN No prevalent CVD (MI,CVA) No incident CVD
on follow-up until 2001
Cases Hypertensive Age lt60 years BPgt160/100
550K Illumina BeadChip
Hypercontrols Increase odds ratio Increase
power Better LD coverage using HapMap2
InGenious HyperCare Investigators
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• 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
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
Collaborators
MRC BRIGHT Investigators WTCCC Wellcome CVS
Functional Genomics EURATools Investigators
InGenious HyperCare Investigators