Title |
Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk
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Published in |
Nature Genetics, March 2014
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DOI | 10.1038/ng.2926 |
Pubmed ID | |
Authors |
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 |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 3 | 38% |
Norway | 1 | 13% |
Canada | 1 | 13% |
Unknown | 3 | 38% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Scientists | 5 | 63% |
Members of the public | 2 | 25% |
Science communicators (journalists, bloggers, editors) | 1 | 13% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 3 | 2% |
Germany | 1 | <1% |
Canada | 1 | <1% |
Belgium | 1 | <1% |
Mexico | 1 | <1% |
Greece | 1 | <1% |
Spain | 1 | <1% |
Unknown | 169 | 95% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 48 | 27% |
Student > Ph. D. Student | 33 | 19% |
Student > Master | 15 | 8% |
Student > Doctoral Student | 13 | 7% |
Other | 13 | 7% |
Other | 32 | 18% |
Unknown | 24 | 13% |
Readers by discipline | Count | As % |
---|---|---|
Medicine and Dentistry | 52 | 29% |
Agricultural and Biological Sciences | 49 | 28% |
Biochemistry, Genetics and Molecular Biology | 27 | 15% |
Immunology and Microbiology | 3 | 2% |
Nursing and Health Professions | 3 | 2% |
Other | 7 | 4% |
Unknown | 37 | 21% |