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

被引：223

作者：

Holmen, Oddgeir L. ^{[1
,2
]}

Zhang, He ^{[3
]}

Fan, Yanbo ^{[3
]}

Hovelson, Daniel H. ^{[3
,4
]}

Schmidt, Ellen M. ^{[3
,4
]}

Zhou, Wei ^{[3
]}

Guo, Yanhong ^{[3
]}

Zhang, Ji ^{[3
]}

Langhammer, Arnulf ^{[1
]}

Lochen, Maja-Lisa ^{[5
]}

Ganesh, Santhi K. ^{[3
,6
]}

Vatten, Lars ^{[7
]}

Skorpen, Frank ^{[8
]}

Dalen, Havard ^{[9
,10
]}

Zhang, Jifeng ^{[3
]}

Pennathur, Subramaniam ^{[11
]}

Chen, Jin ^{[3
]}

Platou, Carl ^{[9
]}

Mathiesen, Ellisiv B. ^{[12
,13
]}

Wilsgaard, Tom ^{[5
]}

Njolstad, Inger ^{[5
]}

Boehnke, Michael ^{[14
]}

Chen, Y. Eugene ^{[3
]}

Abecasis, Goncalo R. ^{[14
]}

Hveem, Kristian ^{[1
,9
]}

Willer, Cristen J. ^{[3
,4
,6
]}

机构：

[1] Norwegian Univ Sci & Technol, HUNT Res Ctr, Dept Publ Hlth & Gen Practice, Levanger, Norway

[2] Univ Trondheim Hosp, St Olavs Hosp, Trondheim, Norway

[3] Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA

[4] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA

[5] UiT Arctic Univ Norway, Fac Hlth Sci, Dept Community Med, Epidemiol Chron Dis Res Grp, Tromso, Norway

[6] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA

[7] Norwegian Univ Sci & Technol, Dept Publ Hlth, N-7034 Trondheim, Norway

[8] Norwegian Univ Sci & Technol, Dept Lab Med Childrens & Womens Hlth, N-7034 Trondheim, Norway

[9] Levanger Hosp, Nord Trondelag Hlth Trust, Dept Med, Levanger, Norway

[10] Norwegian Univ Sci & Technol, Dept Circulat & Med Imaging, Med Imaging Lab Innovat Future Healthcare, N-7034 Trondheim, Norway

[11] Univ Michigan, Dept Internal Med, Div Nephrol, Ann Arbor, MI 48109 USA

[12] UiT Arctic Univ Norway, Fac Hlth Sci, Dept Clin Med, Brain & Circulat Res Grp, Tromso, Norway

[13] Univ Hosp North Norway, Brain & Circulat Res Grp, Tromso, Norway

[14] Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Dept Biostat, Ann Arbor, MI 48109 USA

来源：

NATURE GENETICS | 2014年 / 46卷 / 04期

关键词：

DENSITY-LIPOPROTEIN CHOLESTEROL; RARE VARIANTS; MISSING HERITABILITY; COHORT PROFILE; LOCI; DISEASE; ASSOCIATION;

D O I：

10.1038/ng.2926

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 Chi 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.

引用

页码：345 / +

页数：9

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