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Power in GWAS: lifting the curse of the clinical cut-off

Molecular Psychiatry volume 18, pages 2–3 (2013)Cite this article

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Although genome-wide association studies (GWAS), in general, facilitated important discovery of new biological knowledge about diseases,1, 2, 3 identified variants for psychiatric disorders explain little variation, and insight into the role of genes in highly heritable psychiatric traits remains poor.4, 5 Low statistical power is seen as the main reason for the failure to locate more variants, and has resulted in a call for larger samples. Our present study, however, shows that better use of (available) phenotypic information can also increase power considerably.

Many GWAS of psychiatric disorders involve comparisons of allele frequencies between cases and controls. This binary phenotype is usually based on (diagnostic) questionnaire data (e.g., Center for Epidemiologic Studies Depression Scale (CES-D),6 Conners’ Rating Scales7) or the number of endorsed symptoms as listed in the Diagnostic and Statistical Manual of Mental Disorders.8 Such clinical measures are developed to facilitate diagnosis and include items referring to extreme behavior (e.g., ‘I had crying spells’, ‘Temper outbursts and unpredictable behavior’). Although these items distinguish well between cases and controls, they provide little information about phenotypic differences among controls who rarely report such extreme behavior. Indeed, if subjects answer initial screening questions negatively, entire sections of diagnostic questionnaires are regularly skipped under the assumption that none of the items in these sections will be endorsed. Consequently, although controls clearly do show phenotypic variation, they receive very similar test scores (calculated across all items), i.e., the existing phenotypic variation is not well represented in the test scores. Scores on diagnostic instruments are therefore highly skewed in the general population in which controls are in the majority.

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Authors and Affiliations

  1. Department of Functional Genomics and Clinical Genetics, Complex Trait Genetics, Center for Neurogenomics and Cognitive Research (CNCR), FALW-VUA, Neuroscience Campus Amsterdam, VU University Amsterdam and VU University Medical Center, Amsterdam, The Netherlands

    S van der Sluis, D Posthuma & M Verhage

  2. Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands

    M G Nivard & C V Dolan

  3. Department of Psychology, FMG, University of Amsterdam, Amsterdam, The Netherlands

    C V Dolan

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  1. S van der Sluis
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  2. D Posthuma
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  3. M G Nivard
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  4. M Verhage
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  5. C V Dolan
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Correspondence to S van der Sluis.

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van der Sluis, S., Posthuma, D., Nivard, M. et al. Power in GWAS: lifting the curse of the clinical cut-off. Mol Psychiatry 18, 2–3 (2013). https://doi.org/10.1038/mp.2012.65

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