title: Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk.
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 × 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.
authors.affiliation: 1] HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway. [2] St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway. [3].
authors.forename: Oddgeir L
authors.initials: OL
authors.lastname: Holmen
authors.affiliation: 1] Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA. [2].
authors.forename: He
authors.initials: H
authors.lastname: Zhang
authors.affiliation: 1] Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA. [2].
authors.forename: Yanbo
authors.initials: Y
authors.lastname: Fan
authors.affiliation: 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.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Hovelson
authors.affiliation: 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.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Schmidt
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Ji
authors.initials: J
authors.lastname: Zhang
authors.affiliation: HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway.
authors.forename: Arnulf
authors.initials: A
authors.lastname: Langhammer
authors.affiliation: Epidemiology of Chronic Diseases Research Group, Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway.
authors.forename: Maja-Lisa
authors.initials: ML
authors.lastname: Løchen
authors.affiliation: 1] Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Santhi K
authors.initials: SK
authors.lastname: Ganesh
authors.affiliation: Department of Public Health, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Lars
authors.initials: L
authors.lastname: Vatten
authors.affiliation: Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Frank
authors.initials: F
authors.lastname: Skorpen
authors.affiliation: 1] Department of Medicine, Levanger Hospital, Nord-Trøndelag Health Trust, Levanger, Norway. [2] Medical Imaging Laboratory for Innovative Future Healthcare, Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Håvard
authors.initials: H
authors.lastname: Dalen
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Jifeng
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Pennathur
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Medicine, Levanger Hospital, Nord-Trøndelag Health Trust, Levanger, Norway.
authors.forename: Carl
authors.initials: C
authors.lastname: Platou
authors.affiliation: 1] Brain and Circulation Research Group, Department of Clinical Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway. [2] Brain and Circulation Research Group, University Hospital of North Norway, Tromsø, Norway.
authors.forename: Ellisiv B
authors.initials: EB
authors.lastname: Mathiesen
authors.affiliation: Epidemiology of Chronic Diseases Research Group, Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway.
authors.forename: Tom
authors.initials: T
authors.lastname: Wilsgaard
authors.affiliation: Epidemiology of Chronic Diseases Research Group, Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway.
authors.forename: Inger
authors.initials: I
authors.lastname: Njølstad
authors.affiliation: Department of Biostatistics, Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Boehnke
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Y Eugene
authors.initials: YE
authors.lastname: Chen
authors.affiliation: Department of Biostatistics, Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.
authors.forename: Gonçalo R
authors.initials: GR
authors.lastname: Abecasis
authors.affiliation: 1] HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway. [2] Department of Medicine, Levanger Hospital, Nord-Trøndelag Health Trust, Levanger, Norway.
authors.forename: Kristian
authors.initials: K
authors.lastname: Hveem
authors.affiliation: 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.
authors.forename: Cristen J
authors.initials: CJ
authors.lastname: Willer
mesh_terms: D000818:Animals; D008078:Cholesterol, LDL / Q000097:blood / Q000235:genetics; D059472:Exome / Q000235:genetics; D055785:Gene Knockdown Techniques; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008055:Lipids / Q000097:blood* / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D020125:Mutation, Missense / Q000235:genetics; D009203:Myocardial Infarction / Q000453:epidemiology* / Q000235:genetics*; D009664:Norway / Q000453:epidemiology; D012307:Risk Factors
chemical_list: D008078:Cholesterol, LDL; D008055:Lipids; D008565:Membrane Proteins; C419195:TM6SF2 protein, human