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Author (up) Holmen, O.L.; Zhang, H.; Fan, Y.; Hovelson, D.H.; Schmidt, E.M.; Zhou, W.; Guo, Y.; Zhang, J.; Langhammer, A.; Lochen, M.-L.; Ganesh, S.K.; Vatten, L.; Skorpen, F.; Dalen, H.; Zhang, J.; Pennathur, S.; Chen, J.; Platou, C.; Mathiesen, E.B.; Wilsgaard, T.; Njolstad, I.; Boehnke, M.; Chen, Y.E.; Abecasis, G.R.; Hveem, K.; Willer, C.J. url  doi
  Title Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk Type Journal Article
  Year 2014 Publication Nature Genetics Abbreviated Journal Nat Genet  
  Volume 46 Issue 4 Pages 345-351  
  Keywords Animals; Cholesterol, LDL/blood/genetics; Exome/genetics; Gene Knockdown Techniques; *Genetic Variation; Genome-Wide Association Study; Genotype; Humans; Lipids/*blood/genetics; Membrane Proteins/*genetics; Mice; Mice, Inbred C57BL; Mutation, Missense/genetics; Myocardial Infarction/*epidemiology/*genetics; Norway/epidemiology; Risk Factors  
  Abstract Blood lipid levels are heritable, treatable risk factors for cardiovascular disease. We systematically assessed genome-wide coding variation to identify new genes influencing lipid traits, fine map known lipid loci and evaluate whether low-frequency variants with large effects exist for these traits. Using an exome array, we genotyped 80,137 coding variants in 5,643 Norwegians. We followed up 18 variants in 4,666 Norwegians and identified ten loci with coding variants associated with a lipid trait (P < 5 x 10(-8)). One variant in TM6SF2 (encoding p.Glu167Lys), residing in a known genome-wide association study locus for lipid traits, influences total cholesterol levels and is associated with myocardial infarction. Transient TM6SF2 overexpression or knockdown of Tm6sf2 in mice alters serum lipid profiles, consistent with the association observed in humans, identifying TM6SF2 as a functional gene within a locus previously known as NCAN-CILP2-PBX4 or 19p13. This study demonstrates that systematic assessment of coding variation can quickly point to a candidate causal gene.  
  Address 1] Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA. [3] Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1061-4036 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:24633158 Approved no  
  Call Number HUNT @ maria.stuifbergen @ Serial 1597  
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