Variation in levels of the human metabolome reflect changes in homeostasis, providing a window into health and disease. The genetic impact on circulating metabolites in Hispanics, a population with high cardiometabolic disease burden, is largely unknown. We conducted genome-wide association analyses on 640 circulating metabolites in 3,926 Hispanic Community Health Study/Study of Latinos participants. The estimated heritability for 640 metabolites ranged between 0%–54% with a median at 2.5%. We discovered 46 variant-metabolite pairs (p value < 1.2 × 10⁻¹⁰, minor allele frequency ≥ 1%, proportion of variance explained [PEV] mean = 3.4%, PEV_range = 1%–22%) with generalized effects in two population-based studies and confirmed 301 known locus-metabolite associations. Half of the identified variants with generalized effect were located in genes, including five nonsynonymous variants. We identified co-localization with the expression quantitative trait loci at 105 discovered and 151 known loci-metabolites sets. rs5855544, upstream of SLC51A, was associated with higher levels of three steroid sulfates and co-localized with expression levels of SLC51A in several tissues. Mendelian randomization (MR) analysis identified several metabolites associated with coronary heart disease (CHD) and type 2 diabetes. For example, two variants located in or near CYP4F2 (rs2108622 and rs79400241, respectively), involved in vitamin E metabolism, were associated with the levels of octadecanedioate and vitamin E metabolites (gamma-CEHC and gamma-CEHC glucuronide); MR analysis showed that genetically high levels of these metabolites were associated with lower odds of CHD. Our findings document the genetic architecture of circulating metabolites in an underrepresented Hispanic/Latino community, shedding light on disease etiology.

人类代谢组水平的变化反映了体内平衡的变化，为了解健康和疾病提供了一个窗口。西班牙裔人群是心脏代谢疾病负担较高的人群，其循环代谢物的遗传影响在很大程度上尚不清楚。我们对 3,926 名西班牙裔社区健康研究/拉丁裔参与者研究中的 640 种循环代谢物进行了全基因组关联分析。640 种代谢物的估计遗传力范围在 0%–54% 之间，中位数为 2.5%。我们发现了 46 个变异代谢物对（p 值 < 1.2 × 10 ⁻¹⁰，次要等位基因频率 ≥ 1%，解释的方差比例 [PEV] 平均值 = 3.4%，PEV_范围= 1%–22%），对两个变量具有普遍影响基于人群的研究证实了 301 个已知的位点-代谢物关联。已识别的具有普遍效应的变体中有一半位于基因中，其中包括五个非同义变体。我们在 105 个已发现的基因座和 151 个已知的基因座代谢物组中确定了与表达数量性状基因座的共定位。rs5855544 位于SLC51A的上游，与三种类固醇硫酸盐的较高水平相关，并且与几种组织中SLC51A的表达水平共定位。孟德尔随机化 (MR) 分析确定了几种与冠心病 (CHD) 和 2 型糖尿病相关的代谢物。例如，位于CYP4F2内或附近的两个变异体（分别为rs2108622和rs79400241）参与维生素E代谢，与十八烷二酸和维生素E代谢物（γ-CEHC和γ-CEHC葡萄糖醛酸苷）的水平相关；MR 分析表明，这些代谢物在遗传上的高水平与较低的冠心病发病率相关。我们的研究结果记录了代表性不足的西班牙裔/拉丁裔社区循环代谢物的遗传结构，揭示了疾病的病因学。