Chunk #87 — 7.0 Recommendations to Advance Endophenotype Genetics — 7.3 Adequate power to detect individual effects is crucial but almost never attained in existing endophenotype genetic association studies — 7.3.1. Power and sampling schemes in GWAS
Take a simple example: a phenotypic sample selection scheme to enroll individuals who have suffered from severe and recurrent depression versus controls who have never been depressed. All individuals are assessed for depression and also a depression-related endophenotype, such as EEG alpha frontal asymmetry. Because the selection scheme will increase the variation of disorder-related genetic variants, this study design is more powerful than an unselected sample for detecting variants associated with depressed mood. Because selected individuals will be at the extreme ends of the distribution of the endophenotype measure, this scheme is also a potentially powerful design for the depression endophenotype. However, any association between variant and endophenotype could easily be spurious, resulting from the correlation and confounding of depression, on which the sample was selected, with endophenotype level. Determining whether an endophenotype-associated variant is independently associated with the endophenotype is difficult, to say the least. Indeed, any other variable, including an endophenotype, that correlates with depression in this sample will be subject to the same difficulty, rendering this depression-based sampling scheme limited for understanding anything other than depression. A
