title: Phenotypic complexity, measurement bias, and poor phenotypic resolution contribute to the missing heritability problem in genetic association studies.
abstract: BACKGROUND
  The variance explained by genetic variants as identified in (genome-wide) genetic association studies is typically small compared to family-based heritability estimates. Explanations of this 'missing heritability' have been mainly genetic, such as genetic heterogeneity and complex (epi-)genetic mechanisms.
  
  
  METHODS
  We used comprehensive simulation studies to show that three phenotypic measurement issues also provide viable explanations of the missing heritability: phenotypic complexity, measurement bias, and phenotypic resolution. We identify the circumstances in which the use of phenotypic sum-scores and the presence of measurement bias lower the power to detect genetic variants. In addition, we show how the differential resolution of psychometric instruments (i.e., whether the instrument includes items that resolve individual differences in the normal range or in the clinical range of a phenotype) affects the power to detect genetic variants.
  
  
  CONCLUSIONS
  We conclude that careful phenotypic data modelling can improve the genetic signal, and thus the statistical power to identify genetic variants by 20-99%.
authors.affiliation: Functional Genomics Section, Department of Clinical Genetics, Center for Neurogenomics and Cognitive Research, VU University and VU University Medical Center, Amsterdam, The Netherlands. sophie.van.der.sluis@cncr.vu.nl
authors.forename: Sophie
authors.initials: S
authors.lastname: van der Sluis
authors.forename: Matthijs
authors.initials: M
authors.lastname: Verhage
authors.forename: Danielle
authors.initials: D
authors.lastname: Posthuma
authors.forename: Conor V
authors.initials: CV
authors.lastname: Dolan
mesh_terms: D000818:Animals; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D008297:Male; D008957:Models, Genetic; D010641:Phenotype