全基因组关联研究（GWAS）与多组学整合分析揭示了循环脂肪酸的新基因座及其分子机制。

GWAS and multi-omics integrative analysis reveal novel loci and their molecular mechanisms for circulating fatty acids.

作者信息

Sun Yitang, Xu Huifang, Ye Kaixiong

机构信息

Department of Genetics, University of Georgia, Athens, GA 30602, USA.

Department of Genetics, University of Georgia, Athens, GA 30602, USA; Institute of Bioinformatics, University of Georgia, Athens, GA 30602, USA.

出版信息

HGG Adv. 2025 Jun 21;6(4):100470. doi: 10.1016/j.xhgg.2025.100470.

DOI:10.1016/j.xhgg.2025.100470

PMID:40545721

Abstract

Previous genome-wide association studies (GWAS) have identified genetic loci associated with the circulating levels of fatty acids (FAs), but the biological mechanisms of these genetic associations remain largely unexplored. Here, we conducted GWAS to identify additional genetic loci for 19 circulating FA traits in UK Biobank participants of European ancestry (n = 239,268) and five other ancestries (n = 508-4,663). We leveraged the GWAS findings to characterize genetic correlations and colocalized regions among FAs, explore sex differences, examine FA loci influenced by lipoprotein metabolism, and apply statistical fine-mapping to pinpoint putative causal variants. We integrated GWAS signals with multi-omics quantitative trait loci (QTL) to reveal intermediate molecular phenotypes mediating the associations between the genetic loci and FA levels. We identified 215 genome-wide significant, independent loci for polyunsaturated fatty acid (PUFA)-related traits in European participants, 163 loci for monounsaturated fatty acid (MUFA)-related traits, and 119 loci for saturated fatty acid (SFA)-related traits, including 70, 61, and 54 novel loci, respectively. A novel locus for total FAs, the percentage of omega-6 PUFAs in total FAs, and total MUFAs (around genes GSTT1/2/2B) colocalized with QTL signals for all six molecular phenotypes examined, including gene expression, protein abundance, DNA methylation, splicing, histone modification, and chromatin accessibility. Across 19 FA traits, 35% of GWAS loci colocalized with QTL signals for at least one molecular phenotype. Our study identifies novel genetic loci for circulating FA levels and systematically uncovers their underlying molecular mechanisms.

摘要

以往的全基因组关联研究（GWAS）已经确定了与循环脂肪酸（FAs）水平相关的基因位点，但这些基因关联的生物学机制在很大程度上仍未得到探索。在此，我们进行了GWAS，以确定欧洲血统（n = 239,268）的英国生物银行参与者以及其他五个血统（n = 508 - 4,663）中19种循环FA性状的其他基因位点。我们利用GWAS的研究结果来表征FAs之间的遗传相关性和共定位区域，探索性别差异，检查受脂蛋白代谢影响的FA位点，并应用统计精细定位来确定推定的因果变异。我们将GWAS信号与多组学定量性状位点（QTL）整合，以揭示介导基因位点与FA水平之间关联的中间分子表型。我们在欧洲参与者中确定了215个全基因组显著的、独立的与多不饱和脂肪酸（PUFA）相关性状的基因位点，163个与单不饱和脂肪酸（MUFA）相关性状的基因位点，以及119个与饱和脂肪酸（SFA）相关性状的基因位点，分别包括7个、61个和54个新位点。一个与总FAs、总FAs中ω-6 PUFAs的百分比以及总MUFAs相关的新位点（位于基因GSTT1/2/2B附近）与所检查的所有六种分子表型的QTL信号共定位，包括基因表达、蛋白质丰度、DNA甲基化、剪接、组蛋白修饰和染色质可及性。在19种FA性状中，35%的GWAS位点与至少一种分子表型的QTL信号共定位。我们的研究确定了循环FA水平的新基因位点，并系统地揭示了其潜在的分子机制。