Circulating metabolite levels are biomarkers for cardiovascular disease (CVD). Here we studied, association of rare variants and 226 serum lipoproteins, lipids and amino acids in 7,142 (discovery plus follow-up) healthy participants. We leveraged the information from multiple metabolite measurements on the same participants to improve discovery in rare variant association analyses for gene-based and gene-set tests by incorporating correlated metabolites as covariates in the validation stage. Gene-based analysis corrected for the effective number of tests performed, confirmed established associations at APOB, APOC3, PAH, HAL and PCSK (p<1.32x10^-7) and identified novel gene-trait associations at a lower stringency threshold with ACSL1, MYCN, FBXO36 and B4GALNT3 (p<2.5x10^-6). Regulation of the pyruvate dehydrogenase (PDH) complex was associated for the first time, in gene-set analyses also corrected for effective number of tests, with IDL and LDL parameters, as well as circulating cholesterol (p_METASKAT<2.41x10^-6). In conclusion, using an approach that leverages metabolite measurements obtained in the same participants, we identified novel loci and pathways involved in the regulation of these important metabolic biomarkers. As large-scale biobanks continue to amass sequencing and phenotypic information, analytical approaches such as ours will be useful to fully exploit the copious amounts of biological data generated in these efforts.

循环代谢物水平是心血管疾病（CVD）的生物标志物。在这里，我们研究了7,142名（发现加随访）健康参与者中的罕见变异与226种血清脂蛋白，脂质和氨基酸的关联。我们利用来自相同参与者的多种代谢物测量结果中的信息，通过将相关代谢物作为协变量纳入验证阶段，来改善基于基因和基因组测试的稀有变异关联分析的发现。基于基因的分析校正了执行的有效测试次数，确认在APOB，APOC3，PAH，HAL和PCSK上建立了关联（p <1.32x10 ^-7），并在较低的严格性阈值下鉴定出了与ACSL1，MYCN，FBXO36和B4GALNT3相关的新型基因-性状关联（p < 2.5x10 ^-6）。丙酮酸脱氢酶（PDH）复合物的调节首次涉及，在基因组分析中还校正了有效测试次数，IDL和LDL参数以及循环胆固醇（p _METASKAT <2.41x10 ^-6）。总之，使用一种利用在相同参与者中获得的代谢物测量值的方法，我们确定了涉及这些重要代谢生物标记物调控的新型基因座和途径。随着大型生物库不断积累测序和表型信息，诸如我们的分析方法将对充分利用这些努力中产生的大量生物数据很有用。