多个相关变体增加了对血浆脂质和冠状动脉疾病的遗传力解释。

Multiple associated variants increase the heritability explained for plasma lipids and coronary artery disease.

作者信息

Tada Hayato, Won Hong-Hee, Melander Olle, Yang Jian, Peloso Gina M, Kathiresan Sekar

机构信息

From the Center for Human Genetic Research, Massachusetts General Hospital, Boston (H.T., H.-H.W., G.M.P., S.K.); Broad Institute, Program in Medical and Population Genetics, Cambridge, MA (H.T., H.-H.W., G.M.P., S.K.); Department of Clinical Sciences, Lund University, Lund, Sweden (O.M.); Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden (O.M.); and Queensland Institute of Medical Research, Brisbane, Queensland, Australia (J.Y.).

出版信息

Circ Cardiovasc Genet. 2014 Oct;7(5):583-7. doi: 10.1161/CIRCGENETICS.113.000420. Epub 2014 Aug 28.

DOI:10.1161/CIRCGENETICS.113.000420

PMID:25170055

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4341828/

Abstract

BACKGROUND

Plasma lipid levels as well as coronary artery disease (CAD) have been shown to be highly heritable with estimates ranging from 40% to 60%. However, top variants detected by large-scale genome-wide association studies explain only a fraction of the total variance in plasma lipid phenotypes and CAD.

METHODS AND RESULTS

We performed a conditional and joint association analysis using summary-level statistics from 2 large genome-wide association meta-analyses: the Global Lipids Genetics Consortium (GLGC) study, and the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) study. There were 100 184 individuals from 46 GLGC studies for plasma lipids, and 22 233 cases and 64 762 controls from 14 studies for CAD. We detected several loci where multiple independent single-nucleotide polymorphisms were associated with lipid traits within a locus (12 out of 33 loci for high-density lipoprotein cholesterol, 10 of 35 loci for low-density lipoprotein cholesterol, 13 of 44 loci for total cholesterol, and 8 of 28 loci for triglycerides), reaching genome-wide significance (P<5×10(-8)), nearly doubling the heritability explained by genome-wide association studies (from 3.6 to 7.6% for high-density lipoprotein cholesterol, from 5.0 to 8.8% for low-density lipoprotein cholesterol, from 5.5 to 8.8% for total cholesterol, and from 5.7 to 8.5% for triglycerides). Multiple single-nucleotide polymorphisms were also associated with CAD (3 of 15 loci; an increase from 9.6% to 11.4% of heritability explained).

CONCLUSIONS

These results demonstrate that a portion of the missing heritability for lipid traits and CAD can be explained by multiple variants at each locus.

摘要

背景

血浆脂质水平以及冠状动脉疾病（CAD）已被证明具有高度遗传性，估计遗传率在40%至60%之间。然而，大规模全基因组关联研究检测到的顶级变异仅解释了血浆脂质表型和CAD总变异的一小部分。

方法与结果

我们使用来自两项大型全基因组关联荟萃分析的汇总统计数据进行了条件和联合关联分析：全球脂质遗传学联盟（GLGC）研究和冠状动脉疾病全基因组复制与荟萃分析（CARDIoGRAM）研究。对于血浆脂质，有来自46项GLGC研究的100184名个体；对于CAD，有来自14项研究的22233例病例和64762名对照。我们检测到几个位点，其中多个独立的单核苷酸多态性与一个位点内的脂质性状相关（高密度脂蛋白胆固醇的33个位点中有12个，低密度脂蛋白胆固醇的35个位点中有10个，总胆固醇的44个位点中有13个，甘油三酯的28个位点中有8个），达到全基因组显著性水平（P<5×10⁻⁸），全基因组关联研究解释的遗传率几乎翻倍（高密度脂蛋白胆固醇从3.6%增至7.6%，低密度脂蛋白胆固醇从5.0%增至8.8%，总胆固醇从5.5%增至8.8%，甘油三酯从5.7%增至8.5%）。多个单核苷酸多态性也与CAD相关（15个位点中有3个；解释的遗传率从9.6%增至11.4%）。