Phenotypic misclassification (between cases) has been shown to reduce the power to detect association in genetic studies. However, it is conceivable that complex traits are heterogeneous with respect to individual genetic susceptibility and disease pathophysiology, and that the effect of heterogeneity has a larger magnitude than the effect of phenotyping errors. Although an intuitively clear concept, the effect of heterogeneity on genetic studies of common diseases has received little attention. Here we investigate the impact of phenotypic and genetic heterogeneity on the statistical power of genome wide association studies (GWAS). We first performed a study of simulated genotypic and phenotypic data. Next, we analyzed the Wellcome Trust Case-Control Consortium (WTCCC) data for diabetes mellitus (DM) type 1 (T1D) and type 2 (T2D), using varying proportions of each type of diabetes in order to examine the impact of heterogeneity on the strength and statistical significance of association previously found in the WTCCC data. In both simulated and real data, heterogeneity (presence of “non-cases”) reduced the statistical power to detect genetic association and greatly decreased the estimates of risk attributed to genetic variation. This finding was also supported by the analysis of loci validated in subsequent large-scale meta-analyses. For example, heterogeneity of 50% increases the required sample size by approximately three times. These results suggest that accurate phenotype delineation may be more important for detecting true genetic associations than increase in sample size.

Background-To translate our knowledge about neuroanatomy of bipolar disorder (BD) into a diagnostic tool, it is necessary to identify the neural signature of predisposition for BD and separate it from effects of long-standing illness and treatment. Thus, we examined the associations among genetic risk, illness burden, lithium treatment, and brain structure in BD.

Whereas patients with limited lifetime Li exposure had significantly lower hippocampal volumes than controls, patients with comparable illness burden, but with over two years of Li treatment, or young Li-naïve BD patients, showed hippocampal volumes comparable to controls. These results provide indirect support for neuroprotective effects of Li and negative effects of illness burden on hippocampal volumes in bipolar disorders.

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