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].
1] Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA. [2].
Nat Genet. 2014 Apr;46(4):345-51. doi: 10.1038/ng.2926. Epub 2014 Mar 16.
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.
血脂水平是心血管疾病可遗传、可治疗的危险因素。我们系统地评估了全基因组编码变异，以鉴定影响脂质特征的新基因，精细定位已知的脂质基因座，并评估这些特征是否存在低频、大效应的变异。我们使用外显子组阵列对 5643 名挪威人进行了 80137 个编码变异的基因分型。我们对 4666 名挪威人进行了 18 个变体的随访，并确定了 10 个与脂质特征相关的编码变体的基因座（P<5×10(-8))。TM6SF2 中的一个变体（编码 p.Glu167Lys），位于已知的与脂质特征相关的全基因组关联研究基因座内，影响总胆固醇水平，与心肌梗死相关。瞬时 TM6SF2 过表达或在小鼠中敲低 Tm6sf2 会改变血清脂质谱，与人类观察到的相关性一致，表明 TM6SF2 是先前称为 NCAN-CILP2-PBX4 或 19p13 的基因座内的一个功能基因。本研究表明，对编码变异的系统评估可以快速指向候选因果基因。
