Associated signal for CAD on Chr 9 - haploview

red boxes=recomb hotspots

LD coefficient values for SNPs genotyped in case subjects with CAD in the WTCCC

Samani et al, NEJM 2007;357:443

CDKN=Cyclin-dependent kinase inhibitors

Replication,replication,replication…

WTCCC : Control group• 2000 cases for each disease and 3000 common controls

• a potential for misclassification bias as phenotyping not available for controls

• it was estimated that if 5% of controls would meet the definition of cases, the loss of power is approx. the same as 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

GWAS & Hypertension• failure to detect a prominent

association signal in the WTCCC cannot provide conclusive exclusion of any given geneDue 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 and specifically for hypertension – common controls without phenotypescontrols without phenotypes

Rare functional variants under purifying selection protect against hypertension

Gitelman’sSyndr

Bartter’sSyndr

Ji et al, Nat Genet,6 April 2008

““60% reduction in 60% reduction in the risk of the risk of hypertension at age hypertension at age 60…”60…”