PMC3784826_01
Testing schematic for the GoKinD collection. Subjects with type 1 diabetes with (affected) and without (unaffected) diabetic nephropathy were studied for genetic association. Population- and family-based subsets were either tested in a typical straight-forward single-step strategy or in a two-step combination strategy with conditional screening for power, association testing and subsequent combination of the two. To distinguish between the data subsets used, 1' s indicate unrelateds and 2' s are from the family samples. A denotes affected and U unaffected. The analytic methods used are indicated above the corresponding arrows.
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F1
We then implemented a two-step approach combining statistical tests across unrelated and family-based study designs (Figure 1).
Manhattan plot for population-based study with pooled singletons and trio probands. Summary of genome-wide association scan results in the GoKinD population-based singletons and trios combined. The -log10P-values were calculated for SNP association with diabetic nephropathy among subjects with type 1 diabetes using the Cochran-Armitage test for trend for an additive genetic model adjusted for sex and stratified by center ascertainment using Cochran-Mantel-Haenszel method. The red horizontal line corresponds to genome-wide significance (P-value = 0.05/357,887 = 1.4 x 10-7). The blue horizontal line corresponds to suggestive significance (P-value = 1 x 10-5).
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F2
Principal component analysis (PCA) was applied to both population-based subsets to minimize spurious associations due to population substructure by removing potential ethnic outliers (Price et al.,) (Supplemental Figure 2).