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

Journal article


Holmen, Oddgeir L., Zhang, He, Fan, Yanbo, Hovelson, Daniel H., Schmidt, Ellen, Zhou, Wei, Guo, Yanhong, Zhang, Ji, Langhammer, Arnulf, Løchen, Maja-Lisa, Ganesh, Santhi K., Vatten, Lars, Skorpen, Frank, Dalen, Havard, Zhang, Jifeng, Pennathur, Subramaniam, Chen, Jin, Platou, Carl, Mathiesen, Ellisiv B., ... Willer, Cristen J.. (2014) Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk. Nature Genetics. 46(4), pp. 345 - 351. https://doi.org/10.1038/ng.2926
AuthorsHolmen, Oddgeir L., Zhang, He, Fan, Yanbo, Hovelson, Daniel H., Schmidt, Ellen, Zhou, Wei, Guo, Yanhong, Zhang, Ji, Langhammer, Arnulf, Løchen, Maja-Lisa, Ganesh, Santhi K., Vatten, Lars, Skorpen, Frank, Dalen, Havard, Zhang, Jifeng, Pennathur, Subramaniam, Chen, Jin, Platou, Carl, Mathiesen, Ellisiv B., Wilsgaard, Tom, Njølstad, Inger, Boehnke, Michael, Chen, Y. Eugene, Abecasis, Goncalo R., Hveem, Kristian and Willer, Cristen J.
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.

Keywordsgenetics research; genome-wide association studies; myocardial infarction
Year2014
JournalNature Genetics
Journal citation46 (4), pp. 345 - 351
PublisherNature Publishing Group
ISSN1061-4036
Digital Object Identifier (DOI)https://doi.org/10.1038/ng.2926
Scopus EID2-s2.0-84898058547
Page range345 - 351
Research GroupMary MacKillop Institute for Health Research
Place of publicationUnited States of America
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