title: Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels.
abstract: So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels.
  
  
  
  We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ∼60 000 individuals in the discovery stage and ∼90 000 samples in the replication stage.
  
  
  
  Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene.
  
  
  
  This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
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authors.affiliation: Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
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authors.affiliation: Department of Genetics, Washington University School of Medicine, St Louis, USA.
authors.forename: Ingrid B
authors.initials: IB
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authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, USA Human Genetics Center, The University of Texas School of Public Health, Houston, USA.
authors.forename: Eric
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authors.lastname: Boerwinkle
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, USA Division of Genomic Outcomes, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, USA Departments of Pediatrics, Medicine, and Human Genetics, UCLA, Los Angeles, USA.
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.affiliation: The Framingham Heart Study, NHLBI Cardiovascular Epidemiology and Human Genomics Branch, Framingham, USA Department of Genetics, Washington University School of Medicine, St Louis, USA.
authors.forename: L Adrienne
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authors.lastname: Cupples
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
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mesh_terms: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000235:genetics*; D005091:Exons / Q000235:genetics*; D005215:Fasting / Q000502:physiology; D005260:Female; D015894:Genome, Human / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins
keywords: Complex traits; Epidemiology; Genetics; Genome-wide; circulating lipid levels