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Associated signal for CAD on Chr 9 - haploview

Associated signal for CAD on Chr 9 - haploview. CDKN =Cyclin-dependent kinase inhibitors. 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. Replication,replication,replication…. WTCCC : Control group.

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Associated signal for CAD on Chr 9 - haploview

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  1. Associated signal for CAD on Chr 9 - haploview CDKN=Cyclin-dependent kinase inhibitors 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

  2. Replication,replication,replication…

  3. 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

  4. GWAS & Hypertension • failure to detect a prominent association signal in the WTCCC cannot provide conclusive exclusion of any given gene Due to: • less than complete coverage of common variation genome-wide on the Affymetrix chip; • poor coverage (by design) of rare variants; • despite the sample size, relatively low power to detect variants with modest effects = OR < 1.2 • and specifically for hypertension – common controls without phenotypes

  5. “60% reduction in the risk of hypertension at age 60…” Gitelman’s Syndr Bartter’s Syndr Rare functional variants under purifying selection protect against hypertension Ji et al, Nat Genet,6 April 2008

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