title: Next-generation gene discovery for variants of large impact on lipid traits.
abstract: OBJECTIVE
  Detection of high-impact variants on lipid traits is complicated by complex genetic architecture. Although genome-wide association studies (GWAS) successfully identified many novel genes associated with lipid traits, it was less successful in identifying variants with a large impact on the phenotype. This is not unexpected, as the more common variants detectable by GWAS typically have small effects. The availability of large familial datasets and sequence data has changed the paradigm for successful genomic discovery of the novel genes and pathogenic variants underlying lipid disorders.
  
  
  RESULTS
  Novel loci with large effects have been successfully mapped in families, and next-generation sequencing allowed for the identification of the underlying lipid-associated variants of large effect size. The success of this strategy relies on the simplification of the underlying genetic variation by focusing on large single families segregating extreme lipid phenotypes.
  
  
  CONCLUSIONS
  Rare, high-impact variants are expected to have large effects and be more relevant for medical and pharmaceutical applications. Family data have many advantages over population-based data because they allow for the efficient detection of high-impact variants with an exponentially smaller sample size and increased power for follow-up studies.
authors: aDepartment of Medicine (Medical Genetics) bDepartment of Genome Sciences, University of Washington, Seattle, Seattle, Washington, USA.
authors: Elisabeth
authors: E
authors: Rosenthal
authors: Elizabeth
authors: E
authors: Blue
authors: Gail P
authors: GP
authors: Jarvik
mesh_terms: D000818:Animals; D050171:Dyslipidemias / Q000235:genetics*; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
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