Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk

Oddgeir L Holmen; He Zhang; Yanbo Fan; Daniel H Hovelson; Ellen M Schmidt; Wei Zhou; Yanhong Guo; Ji Zhang; Arnulf Langhammer; Maja-Lisa Løchen; Santhi K Ganesh; Lars Vatten; Frank Skorpen; Håvard Dalen; Jifeng Zhang; Subramaniam Pennathur; Jin Chen; Carl Platou; Ellisiv B Mathiesen; Tom Wilsgaard; Inger Njølstad; Michael Boehnke; Y Eugene Chen; Gonçalo R Abecasis; Kristian Hveem; Cristen J Willer

doi:10.1038/ng.2926

Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk

Nat Genet. 2014 Apr;46(4):345-51. doi: 10.1038/ng.2926. Epub 2014 Mar 16.

Authors

Oddgeir L Holmen¹, He Zhang², Yanbo Fan², Daniel H Hovelson³, Ellen M Schmidt³, Wei Zhou⁴, Yanhong Guo⁴, Ji Zhang⁴, Arnulf Langhammer⁵, Maja-Lisa Løchen⁶, Santhi K Ganesh⁷, Lars Vatten⁸, Frank Skorpen⁹, Håvard Dalen¹⁰, Jifeng Zhang⁴, Subramaniam Pennathur¹¹, Jin Chen⁴, Carl Platou¹², Ellisiv B Mathiesen¹³, Tom Wilsgaard⁶, Inger Njølstad⁶, Michael Boehnke¹⁴, Y Eugene Chen⁴, Gonçalo R Abecasis¹⁴, Kristian Hveem¹⁵, Cristen J Willer¹⁶

Affiliations

¹ 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].
² 1] Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA. [2].
³ 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.
⁴ Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA.
⁵ HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway.
⁶ Epidemiology of Chronic Diseases Research Group, Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway.
⁷ 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.
⁸ Department of Public Health, Norwegian University of Science and Technology, Trondheim, Norway.
⁹ Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway.
¹⁰ 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.
¹¹ Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan, USA.
¹² Department of Medicine, Levanger Hospital, Nord-Trøndelag Health Trust, Levanger, Norway.
¹³ 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.
¹⁴ Department of Biostatistics, Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.
¹⁵ 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.
¹⁶ 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.

PMID: 24633158
PMCID: PMC4169222
DOI: 10.1038/ng.2926

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cholesterol, LDL / blood
Cholesterol, LDL / genetics
Exome / genetics
Gene Knockdown Techniques
Genetic Variation*
Genome-Wide Association Study
Genotype
Humans
Lipids / blood*
Lipids / genetics
Membrane Proteins / genetics*
Mice
Mice, Inbred C57BL
Mutation, Missense / genetics
Myocardial Infarction / epidemiology*
Myocardial Infarction / genetics*
Norway / epidemiology
Risk Factors

Substances

Cholesterol, LDL
Lipids
Membrane Proteins
TM6SF2 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding