Untargeted Metabolome- and Transcriptome-Wide Association Study Suggests Causal Genes Modulating Metabolite Concentrations in Urine.
Untargeted Metabolome- and Transcriptome-Wide Association Study Suggests Causal Genes Modulating Metabolite Concentrations in Urine.
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非靶向代谢物组和转录组关联研究表明调节尿液中代谢物浓度的因果基因。
DOI：
10.1021/acs.jproteome.1c00585
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发表时间：
2021-11-05
影响因子：
4.4
通讯作者：
Bergmann, Sven
中科院分区：
文献类型：
--
作者：
Flitman, Reyhan Sonmez;Khalili, Bita;Kutalik, Zoltan;Rueedi, Rico;Bruemmer, Anneke;Bergmann, Sven
关键词：
基因产物可以影响小分子（又名“代谢物”）的浓度，相反，一些代谢物可以调节基因转录物的浓度。虽然这种相互作用的许多具体实例已经被揭示，但系统地揭示人类基因-代谢物相互作用的全球方法仍然缺乏。我们进行了一项代谢组和转录组全范围的关联研究，利用从尿液样本的1H核磁共振波谱（NMR）中提取的非靶向代谢组特征，以及从555名健康个体的淋巴母细胞样细胞系（LCL）的RNA-Seq中量化的基因表达水平，来鉴定影响人类代谢组的基因。我们确定了20个研究范围内的显著关联，对应15个基因，其中5个关联（包含2个基因）通过后续NMR数据得到证实。通过代谢匹配，我们确定了与这些基因相关的代谢组特征对应的代谢物，即与ALMS1相关的n -乙酰化化合物和与HPS1相关的三甲胺（TMA）。最后，孟德尔随机化分析支持了ALMS1-和hps1基因座的基因表达与其相关代谢物浓度之间的潜在因果关系。在HPS1的情况下，我们还观察到TMA浓度可能对HPS1表达水平表现出反向因果效应，表明存在负反馈回路。我们的研究强调了如何整合代谢组学、基因表达和遗传数据来确定调节代谢物浓度的因果基因。
Gene products can affect the concentrations of small molecules (aka “metabolites”), and conversely, some metabolites can modulate the concentrations of gene transcripts. While many specific instances of this interplay have been revealed, a global approach to systematically uncover human gene-metabolite interactions is still lacking. We performed a metabolome- and transcriptome-wide association study to identify genes influencing the human metabolome using untargeted metabolome features, extracted from 1H nuclear magnetic resonance spectroscopy (NMR) of urine samples, and gene expression levels, quantified from RNA-Seq of lymphoblastoid cell lines (LCL) from 555 healthy individuals. We identified 20 study-wide significant associations corresponding to 15 genes, of which 5 associations (with 2 genes) were confirmed with follow-up NMR data. Using metabomatching, we identified the metabolites corresponding to metabolome features associated with the genes, namely, N-acetylated compounds with ALMS1 and trimethylamine (TMA) with HPS1. Finally, Mendelian randomization analysis supported a potential causal link between the expression of genes in both the ALMS1- and HPS1-loci and their associated metabolite concentrations. In the case of HPS1, we additionally observed that TMA concentration likely exhibits a reverse causal effect on HPS1 expression levels, indicating a negative feedback loop. Our study highlights how the integration of metabolomics, gene expression, and genetic data can pinpoint causal genes modulating metabolite concentrations.
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基因发现和多基因预测，从基因组全基因组协会的教育程度研究中，有110万个人。
影响因子：
30.8
作者：
Lee JJ;Wedow R;Okbay A;Kong E;Maghzian O;Zacher M;Nguyen-Viet TA;Bowers P;Sidorenko J;Karlsson Linnér R;Fontana MA;Kundu T;Lee C;Li H;Li R;Royer R;Timshel PN;Walters RK;Willoughby EA;Yengo L;23andMe Research Team;COGENT (Cognitive Genomics Consortium);Social Science Genetic Association Consortium;Alver M;Bao Y;Clark DW;Day FR;Furlotte NA;Joshi PK;Kemper KE;Kleinman A;Langenberg C;Mägi R;Trampush JW;Verma SS;Wu Y;Lam M;Zhao JH;Zheng Z;Boardman JD;Campbell H;Freese J;Harris KM;Hayward C;Herd P;Kumari M;Lencz T;Luan J;Malhotra AK;Metspalu A;Milani L;Ong KK;Perry JRB;Porteous DJ;Ritchie MD;Smart MC;Smith BH;Tung JY;Wareham NJ;Wilson JF;Beauchamp JP;Conley DC;Esko T;Lehrer SF;Magnusson PKE;Oskarsson S;Pers TH;Robinson MR;Thom K;Watson C;Chabris CF;Meyer MN;Laibson DI;Yang J;Johannesson M;Koellinger PD;Turley P;Visscher PM;Benjamin DJ;Cesarini D
通讯作者：
Cesarini D
COLAUS研究：一项基于人群的研究，旨在研究心血管危险因素和代谢综合征的流行病学和遗传决定因素。
影响因子：
2.1
作者：
Firmann, Mathieu;Mayor, Vladimir;Vidal, Pedro Marques;Bochud, Murielle;Pecoud, Alain;Hayoz, Daniel;Paccaud, Fred;Preisig, Martin;Song, Kijoung S.;Yuan, Xin;Danoff, Theodore M.;Stirnadel, Heide A.;Waterworth, Dawn;Mooser, Vincent;Waeber, Gerard;Vollenweider, Peter
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Vollenweider, Peter
影响因子：
3.5
作者：
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通讯作者：
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影响因子：
14.9
作者：
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通讯作者：
Parkinson, Helen
影响因子：
9.8
作者：
Lloyd-Jones, Luke R.;Holloway, Alexander;Powell, Joseph E.
通讯作者：
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