title: A unified framework for detecting rare variant quantitative trait associations in pedigree and unrelated individuals via sequence data.
abstract: OBJECTIVE
  There is great interest to sequence unrelated or pedigree samples for detecting rare variant quantitative trait associations. In order to reduce the cost of sequencing and improve power, many studies sequence selected samples with extreme traits. Existing methods for detecting rare variant associations were developed for unrelated samples. Methods are needed to analyze (selected or randomly ascertained) pedigree samples.
  
  
  METHODS
  We propose a unified framework of modeling extreme trait genetic associations (MEGA) with rare variants. Using MEGA and appropriate permutation algorithms, many rare variant tests can be extended to family data. As an application, we compared study designs using both sib-pairs and unrelated individuals. Extensive simulations were carried out using realistic population genetic and complex trait models.
  
  
  RESULTS
  It is demonstrated that when extreme sampling is implemented within equal-sized cohorts of unrelated individuals or sib-pairs, analyzing unrelated individuals is consistently more powerful than studying sib-pairs. A higher portion of rare variants can be identified through sequencing unrelated samples compared to sibs. Alternatively, if samples are ascertained using fixed thresholds from an infinite-sized population, sequencing one sib with the most extreme trait from each extreme concordant sib-pair is consistently the most powerful design.
  
  
  CONCLUSIONS
  MEGA will play an important role in the analysis of sequence-based genetic association studies.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Dajiang J
authors.initials: DJ
authors.lastname: Liu
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Leal
mesh_terms: D014644:Genetic Variation; D006801:Humans; D008957:Models, Genetic; D009765:Obesity / Q000235:genetics*; D010375:Pedigree; D019655:Quantitative Trait, Heritable; D017422:Sequence Analysis, DNA