A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, and which show convergent evidence across functional datasets supporting their roles in lipid biology.

中文翻译：

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多层功能基因组分析以了解脂质中的非编码遗传变异


全基因组关联研究（GWAS）的一个主要挑战是将表型关联转化为生物学见解。在这里，我们将涉及来自五个血统的 160 万人的血脂大型 GWAS 与广泛的功能基因组数据集相结合，以发现脂质关联的调控机制。我们首先优先考虑具有表达数量性状基因座（eQTL）共定位的脂质相关基因，然后添加染色质相互作用数据以缩小功能基因的搜索范围。对来自大量组织和细胞类型的 697 个注释进行的多基因富集分析证实了肝脏在脂质水平中的核心作用，并强调了高密度脂蛋白胆固醇和甘油三酯中脂肪特异性染色质标记的选择性富集。转录因子 (TF) 结合位点与脂质相关基因座的重叠可识别与脂质生物学相关的 TF。此外，我们提出了一个综合框架来优先考虑 GWAS 位点的因果变异，生成具有多层功能证据的候选因果基因和变异的全面列表。我们重点介绍了两个优先基因，它们显示了跨功能数据集的聚合证据，支持它们在脂质生物学中的作用。