title: To stratify or not to stratify: power considerations for population-based genome-wide association studies of quantitative traits.
abstract: Meta-analyses of genome-wide association studies require numerous study partners to conduct pre-defined analyses and thus simple but efficient analyses plans. Potential differences between strata (e.g. men and women) are usually ignored, but often the question arises whether stratified analyses help to unravel the genetics of a phenotype or if they unnecessarily increase the burden of analyses. To decide whether to stratify or not to stratify, we compare general analytical power computations for the overall analysis with those of stratified analyses considering quantitative trait analyses and two strata. We also relate the stratification problem to interaction modeling and exemplify theoretical considerations on obesity and renal function genetics. We demonstrate that the overall analyses have better power compared to stratified analyses as long as the signals are pronounced in both strata with consistent effect direction. Stratified analyses are advantageous in the case of signals with zero (or very small) effect in one stratum and for signals with opposite effect direction in the two strata. Applying the joint test for a main SNP effect and SNP-stratum interaction beats both overall and stratified analyses regarding power, but involves more complex models. In summary, we recommend to employ stratified analyses or the joint test to better understand the potential of strata-specific signals with opposite effect direction. Only after systematic genome-wide searches for opposite effect direction loci have been conducted, we will know if such signals exist and to what extent stratified analyses can depict loci that otherwise are missed.
authors: Department of Epidemiology and Preventive Medicine, Regensburg University Medical Center, Franz-Josef-Strauss-Allee 11, Regensburg, Germany.
authors: Gundula
authors: G
authors: Behrens
authors: Thomas W
authors: TW
authors: Winkler
authors: Mathias
authors: M
authors: Gorski
authors: Michael F
authors: MF
authors: Leitzmann
authors: Iris M
authors: IM
authors: Heid
mesh_terms: D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods* / Q000706:statistics & numerical data*; D006801:Humans; D007668:Kidney / Q000502:physiology; D016014:Linear Models; D008297:Male; D008957:Models, Genetic; D015233:Models, Statistical; D009765:Obesity / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D019655:Quantitative Trait, Heritable; D049629:Waist-Hip Ratio