title: Multiple associated variants increase the heritability explained for plasma lipids and coronary artery disease.
abstract: BACKGROUND
  Plasma lipid levels as well as coronary artery disease (CAD) have been shown to be highly heritable with estimates ranging from 40% to 60%. However, top variants detected by large-scale genome-wide association studies explain only a fraction of the total variance in plasma lipid phenotypes and CAD.
  
  
  RESULTS
  We performed a conditional and joint association analysis using summary-level statistics from 2 large genome-wide association meta-analyses: the Global Lipids Genetics Consortium (GLGC) study, and the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) study. There were 100 184 individuals from 46 GLGC studies for plasma lipids, and 22 233 cases and 64 762 controls from 14 studies for CAD. We detected several loci where multiple independent single-nucleotide polymorphisms were associated with lipid traits within a locus (12 out of 33 loci for high-density lipoprotein cholesterol, 10 of 35 loci for low-density lipoprotein cholesterol, 13 of 44 loci for total cholesterol, and 8 of 28 loci for triglycerides), reaching genome-wide significance (P<5×10(-8)), nearly doubling the heritability explained by genome-wide association studies (from 3.6 to 7.6% for high-density lipoprotein cholesterol, from 5.0 to 8.8% for low-density lipoprotein cholesterol, from 5.5 to 8.8% for total cholesterol, and from 5.7 to 8.5% for triglycerides). Multiple single-nucleotide polymorphisms were also associated with CAD (3 of 15 loci; an increase from 9.6% to 11.4% of heritability explained).
  
  
  CONCLUSIONS
  These results demonstrate that a portion of the missing heritability for lipid traits and CAD can be explained by multiple variants at each locus.
authors.affiliation: From the Center for Human Genetic Research, Massachusetts General Hospital, Boston (H.T., H.-H.W., G.M.P., S.K.); Broad Institute, Program in Medical and Population Genetics, Cambridge, MA (H.T., H.-H.W., G.M.P., S.K.); Department of Clinical Sciences, Lund University, Lund, Sweden (O.M.); Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden (O.M.); and Queensland Institute of Medical Research, Brisbane, Queensland, Australia (J.Y.).
authors.forename: Hayato
authors.initials: H
authors.lastname: Tada
authors.affiliation: From the Center for Human Genetic Research, Massachusetts General Hospital, Boston (H.T., H.-H.W., G.M.P., S.K.); Broad Institute, Program in Medical and Population Genetics, Cambridge, MA (H.T., H.-H.W., G.M.P., S.K.); Department of Clinical Sciences, Lund University, Lund, Sweden (O.M.); Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden (O.M.); and Queensland Institute of Medical Research, Brisbane, Queensland, Australia (J.Y.).
authors.forename: Hong-Hee
authors.initials: HH
authors.lastname: Won
authors.affiliation: From the Center for Human Genetic Research, Massachusetts General Hospital, Boston (H.T., H.-H.W., G.M.P., S.K.); Broad Institute, Program in Medical and Population Genetics, Cambridge, MA (H.T., H.-H.W., G.M.P., S.K.); Department of Clinical Sciences, Lund University, Lund, Sweden (O.M.); Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden (O.M.); and Queensland Institute of Medical Research, Brisbane, Queensland, Australia (J.Y.).
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
authors.affiliation: From the Center for Human Genetic Research, Massachusetts General Hospital, Boston (H.T., H.-H.W., G.M.P., S.K.); Broad Institute, Program in Medical and Population Genetics, Cambridge, MA (H.T., H.-H.W., G.M.P., S.K.); Department of Clinical Sciences, Lund University, Lund, Sweden (O.M.); Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden (O.M.); and Queensland Institute of Medical Research, Brisbane, Queensland, Australia (J.Y.).
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.affiliation: From the Center for Human Genetic Research, Massachusetts General Hospital, Boston (H.T., H.-H.W., G.M.P., S.K.); Broad Institute, Program in Medical and Population Genetics, Cambridge, MA (H.T., H.-H.W., G.M.P., S.K.); Department of Clinical Sciences, Lund University, Lund, Sweden (O.M.); Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden (O.M.); and Queensland Institute of Medical Research, Brisbane, Queensland, Australia (J.Y.).
authors.forename: Gina M
authors.initials: GM
authors.lastname: Peloso
authors.affiliation: From the Center for Human Genetic Research, Massachusetts General Hospital, Boston (H.T., H.-H.W., G.M.P., S.K.); Broad Institute, Program in Medical and Population Genetics, Cambridge, MA (H.T., H.-H.W., G.M.P., S.K.); Department of Clinical Sciences, Lund University, Lund, Sweden (O.M.); Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden (O.M.); and Queensland Institute of Medical Research, Brisbane, Queensland, Australia (J.Y.). sekar@broadinstitute.org.
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
mesh_terms: D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D003324:Coronary Artery Disease / Q000097:blood* / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D008055:Lipids / Q000097:blood*; D008957:Models, Genetic; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012016:Reference Values
chemical_list: D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D008055:Lipids
keywords: coronary artery disease; genetics; genome-wide association study; lipids