Ottensmann Linda, Tabassum Rubina, Ruotsalainen Sanni E, Gerl Mathias J, Klose Christian, McCartney Daniel L, Widén Elisabeth, Simons Kai, Ripatti Samuli, Vitart Veronique, Hayward Caroline, Pirinen Matti
Institute for Molecular Medicine Finland, HiLIFE, University of Helsinki, Helsinki, Finland; Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
Institute for Molecular Medicine Finland, HiLIFE, University of Helsinki, Helsinki, Finland.
EBioMedicine. 2025 Apr;114:105671. doi: 10.1016/j.ebiom.2025.105671. Epub 2025 Mar 28.
Genome-wide association studies of lipid species have identified several loci shared with various diseases, however, the relationship between lipid species and disease risk remains poorly understood. Here we investigated whether the plasma levels of lipid species are causally linked to disease risk.
We built genetic predictors of 179 lipid species, measured in 7174 Finnish individuals, by utilising either 11 high-impact genomic loci or genome-wide polygenic scores (PGS). We assessed the impact of the lipid species on seven diseases by performing disease association across FinnGen (n = 500,348), UK Biobank (n = 420,531), and Generation Scotland (n = 20,032). We performed univariable Mendelian randomisation (MR) and multivariable MR (MVMR) analyses to examine whether lipid species impact disease risk independently of standard lipids.
PGS explained >4% of the variance for 34 lipid species but variants outside the high-impact loci had only a marginal contribution. Variants within the high-impact loci showed association with all seven diseases. MVMR supported a causal role of ApoB in ischaemic heart disease after accounting for lipid species. Phosphatidylethanolamine-increasing LIPC variants seemed to lower age-related macular degeneration risk independently of HDL-cholesterol. MVMR suggested a protective effect of four lipid species containing arachidonic acid on cholelithiasis risk independently of Total Cholesterol.
Our study demonstrates how genetic predictors of lipid species can be utilised to gain insights into disease risk. We report potential links between lipid species and age-related macular degeneration and cholelithiasis risk, which can be explored for their utility in disease risk prediction and therapy.
The funders had no role in the study design, data analyses, interpretation, or writing of this article.
脂质种类的全基因组关联研究已经确定了几个与多种疾病共有的基因座，然而，脂质种类与疾病风险之间的关系仍知之甚少。在这里，我们研究了血浆中脂质种类的水平是否与疾病风险存在因果关系。
我们通过利用11个高影响力基因组位点或全基因组多基因评分（PGS），构建了在7174名芬兰个体中测量的179种脂质种类的遗传预测因子。我们通过在芬兰基因库（n = 500,348）、英国生物银行（n = 420,531）和苏格兰一代研究（n = 20,032）中进行疾病关联分析，评估了脂质种类对七种疾病的影响。我们进行了单变量孟德尔随机化（MR）和多变量MR（MVMR）分析，以检查脂质种类是否独立于标准脂质影响疾病风险。
PGS解释了34种脂质种类超过4%的方差，但高影响力位点之外的变异只有微不足道的贡献。高影响力位点内的变异与所有七种疾病均有关联。在考虑脂质种类后，MVMR支持载脂蛋白B在缺血性心脏病中的因果作用。增加磷脂酰乙醇胺的LIPC变异似乎独立于高密度脂蛋白胆固醇降低年龄相关性黄斑变性风险。MVMR表明，四种含有花生四烯酸的脂质种类对胆石症风险具有保护作用，独立于总胆固醇。
我们的研究展示了如何利用脂质种类的遗传预测因子来深入了解疾病风险。我们报告了脂质种类与年龄相关性黄斑变性和胆石症风险之间的潜在联系，可探索其在疾病风险预测和治疗中的效用。
资助者在本文的研究设计、数据分析、解读或撰写过程中没有参与。
