title: Strategies for genetic model specification in the screening of genome-wide meta-analysis signals for further replication.
abstract: BACKGROUND
  Meta-analysis is increasingly being employed as a screening procedure in large-scale association studies to select promising variants for follow-up studies. However, standard methods for meta-analysis require the assumption of an underlying genetic model, which is typically unknown a priori. This drawback can introduce model misspecifications, causing power to be suboptimal, or the evaluation of multiple genetic models, which augments the number of false-positive associations, ultimately leading to waste of resources with fruitless replication studies. We used simulated meta-analyses of large genetic association studies to investigate naïve strategies of genetic model specification to optimize screenings of genome-wide meta-analysis signals for further replication.
  
  
  METHODS
  Different methods, meta-analytical models and strategies were compared in terms of power and type-I error. Simulations were carried out for a binary trait in a wide range of true genetic models, genome-wide thresholds, minor allele frequencies (MAFs), odds ratios and between-study heterogeneity (τ²).
  
  
  RESULTS
  Among the investigated strategies, a simple Bonferroni-corrected approach that fits both multiplicative and recessive models was found to be optimal in most examined scenarios, reducing the likelihood of false discoveries and enhancing power in scenarios with small MAFs either in the presence or in absence of heterogeneity. Nonetheless, this strategy is sensitive to τ² whenever the susceptibility allele is common (MAF ≥ 30%), resulting in an increased number of false-positive associations compared with an analysis that considers only the multiplicative model.
  
  
  CONCLUSIONS
  Invoking a simple Bonferroni adjustment and testing for both multiplicative and recessive models is fast and an optimal strategy in large meta-analysis-based screenings. However, care must be taken when examined variants are common, where specification of a multiplicative model alone may be preferable.
authors.affiliation: Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), São Paulo University Medical School, University of São Paulo, São Paulo, Brazil.
authors.forename: Tiago V
authors.initials: TV
authors.lastname: Pereira
authors.forename: Nikolaos A
authors.initials: NA
authors.lastname: Patsopoulos
authors.forename: Alexandre C
authors.initials: AC
authors.lastname: Pereira
authors.forename: José E
authors.initials: JE
authors.lastname: Krieger
mesh_terms: D005787:Gene Frequency; D055106:Genome-Wide Association Study; D015201:Meta-Analysis as Topic; D008957:Models, Genetic; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide