塔尔图大学Priit Palta小组的一项最新研究揭示了619372人循环代谢性状的遗传分析。该项研究成果发表在2026年5月20日出版的《自然》上。

在这里，课题组研究人员对爱沙尼亚生物银行和英国生物银行中多达619,372人的249个循环代谢特征进行了GWAS荟萃分析。该团队从8,398个基因座中确定了88127个共同和低频的位点-性状关联，这些位点聚合在共享基因和途径上。利用统计精细制图、系统全现象共定位和顺式孟德尔随机化，该研究团队探索了代谢性状与疾病结局之间的假定的因果关系。

研究人员预测，尽管在观察性研究中发现血浆支链氨基酸（BCAAs）与2型糖尿病相关，但通过BCAA分解代谢途径降低BCAA水平不太可能降低2型糖尿病风险。利用他们的大样本量和高质量的基因型插入，该课题组研究人员发现19.4%的自信精细定位变异的等位基因频率在0.1到1%之间，这些变异在预测错义和剪接改变变异方面富集了两倍。他们的研究结果突出了将低频变异整合到遗传关联研究中的价值。

据了解，通过更好地理解这些变异的分子后果，可以更好地解释遗传变异与复杂性状之间的关系。尽管针对复杂疾病的全基因组关联研究（GWAS）通常对超过100万人进行了分析，但对分子特征的研究却落后了。

附：英文原文

Title: Genetic analysis of circulating metabolic traits in 619,372 individuals

Author: Tambets, Ralf, Jesse, Mihkel, Kronberg, Jaanika, van der Graaf, Adriaan, Abner, Erik, Vsa, Urmo, Rahu, Ida, Taba, Nele, Kolde, Anastassia, Yarish, Dzvenymyra, Abdullayeva, Sariyya, Alekseienko, Anastasiia, Veidenberg, Andres, Fischer, Krista, Kutalik, Zoltn, Esko, Tnu, Alasoo, Kaur, Palta, Priit

Issue&Volume: 2026-05-20

Abstract: Interpreting the association of genetic variants with complex traits can be improved by gaining a greater understanding of the molecular consequences of these variants. Although genome-wide association studies (GWAS) for complex diseases routinely profile over one million individuals1,2,3,4,5, studies of molecular traits have lagged behind. Here we performed a GWAS meta-analysis for 249 circulating metabolic traits in the Estonian Biobank and the UK Biobank in up to 619,372 individuals. We identified 88,127 common and low-frequency locus–trait associations from 8,398 loci that converged on shared genes and pathways. Using statistical fine mapping, systematic phenome-wide colocalization and cis-Mendelian randomization, we explored putative causal links between metabolic traits and disease outcomes. We predict that although plasma branched-chain amino acids (BCAAs) have been associated with type 2 diabetes in observational studies6,7, lowering BCAA levels by targeting the BCAA catabolism pathway is unlikely to reduce type 2 diabetes risk. Leveraging our large sample size and high-quality genotype imputation, we found that 19.4% of the confidently fine-mapped variants had minor allele frequencies between 0.1 and 1%, and these variants were twofold enriched for predicted missense and splice-altering variants. Our results highlight the value of integrating low-frequency variants into genetic association studies.

DOI: 10.1038/s41586-026-10532-5

Source: https://www.nature.com/articles/s41586-026-10532-5