Plasma lipids are known heritable risk factors for cardiovascular disease, but increasing evidence also supports shared genetics with diseases of other organ systems. We devised a comprehensive three-phase framework to identify new lipid-associated genes and study the relationships among lipids, genotypes, gene expression and hundreds of complex human diseases from the Electronic Medical Records and Genomics (347 traits) and the UK Biobank (549 traits). Aside from 67 new lipid-associated genes with strong replication, we found evidence for pleiotropic SNPs/genes between lipids and diseases across the phenome. These include discordant pleiotropy in the HLA region between lipids and multiple sclerosis and putative causal paths between triglycerides and gout, among several others. Our findings give insights into the genetic basis of the relationship between plasma lipids and diseases on a phenome-wide scale and can provide context for future prevention and treatment strategies.

血浆脂质是心血管疾病的已知遗传风险因素，但越来越多的证据也支持与其他器官系统疾病的共同遗传学。我们设计了一个全面的三阶段框架来识别新的脂质相关基因，并研究脂质、基因型、基因表达与来自电子病历和基因组学（347 个特征）和英国生物银行（549 个特征）的数百种复杂人类疾病之间的关系). 除了具有强复制性的 67 个新的脂质相关基因外，我们还发现了整个现象中脂质与疾病之间多效性 SNP/基因的证据。这些包括HLA中不一致的多效性脂质和多发性硬化症之间的区域以及甘油三酯和痛风之间的推定因果关系等等。我们的研究结果在现象组范围内提供了血浆脂质与疾病之间关系的遗传基础的见解，并可以为未来的预防和治疗策略提供背景。