Genome-wide association study of metabolic traits reveals novel gene-metabolite-disease links.
Genome-wide association study of metabolic traits reveals novel gene-metabolite-disease links.
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DOI：
10.1371/journal.pgen.1004132
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发表时间：
2014-02
期刊：
影响因子：
4.5
通讯作者：
Kutalik Z
中科院分区：
文献类型：
--
作者：
Rueedi R;Ledda M;Nicholls AW;Salek RM;Marques-Vidal P;Morya E;Sameshima K;Montoliu I;Da Silva L;Collino S;Martin FP;Rezzi S;Steinbeck C;Waterworth DM;Waeber G;Vollenweider P;Beckmann JS;Le Coutre J;Mooser V;Bergmann S;Genick UK;Kutalik Z
代谢性状是可以驱动临床表型并可以预测疾病进展的分子表型。在这里，我们报告的结果，从代谢组和全基因组的关联研究1H-NMR尿代谢谱。该研究是在一种非靶向方法中进行的，采用了一种新的化合物鉴定方法。从我们参与CoLaus研究的835名高加索人的发现队列中，我们确定了139个显著（P<5×10−8）的单核苷酸多态性（SNP）和代谢组学特征之间的独立关联。这些关联中的五十六个在TasteSensomics队列中得到了复制，该队列由来自圣保罗的601名种族背景各异的个体组成。它们对应于11个基因-代谢物关联，其中6个先前已在尿液代谢组中鉴定，3个在血清代谢组中鉴定。我们的关键新发现是两个SNP与NMR光谱特征的关联，分别指向岩藻糖（rs 492602，P = 6.9×10−44）和赖氨酸（rs 8101881，P = 1.2×10−33）。 第一个基因座的精细定位确定了FUT 2基因，该基因编码岩藻糖基转移酶，以前与克罗恩病有关。这意味着岩藻糖是一种潜在的预后疾病标记物，已经有来自小鼠模型的已发表证据。第二个SNP位于SLC 7A 9基因内，该基因的罕见突变与严重的肾损伤有关。先前关联的复制和我们的新发现证明了非靶向代谢组学GWAS强大地识别分子疾病标志物的潜力。被称为代谢物的小分子的浓度在所有生物体中都受到严格的调节。总的来说，代谢物浓度构成代谢物组，代谢物组因个体的环境和遗传组成而异。在我们的研究中，我们进一步开发了一种非靶向方法来识别影响人体代谢的遗传因素。在这种方法中，我们首先确定与大量个体中任何测量的代谢组学特征相关的所有遗传变异。对于这些变体，我们然后计算与所有特征相关的显著性特征，生成有助于专家或计算识别其浓度最有可能受手头遗传变体影响的代谢物的特征。我们的研究复制了许多先前报道的人类代谢中的遗传驱动变异，并揭示了两个新的惊人的遗传变异的例子，对尿液代谢组产生了相当大的影响。有趣的是，在这两个基因-代谢物对中，基因和受影响的代谢物都与人类疾病有关-第一种情况是克罗恩病，第二种情况是肾脏疾病。这突出了遗传易感性、受影响的代谢物和人类健康之间的联系。
Metabolic traits are molecular phenotypes that can drive clinical phenotypes and may predict disease progression. Here, we report results from a metabolome- and genome-wide association study on 1H-NMR urine metabolic profiles. The study was conducted within an untargeted approach, employing a novel method for compound identification. From our discovery cohort of 835 Caucasian individuals who participated in the CoLaus study, we identified 139 suggestively significant (P<5×10−8) and independent associations between single nucleotide polymorphisms (SNP) and metabolome features. Fifty-six of these associations replicated in the TasteSensomics cohort, comprising 601 individuals from São Paulo of vastly diverse ethnic background. They correspond to eleven gene-metabolite associations, six of which had been previously identified in the urine metabolome and three in the serum metabolome. Our key novel findings are the associations of two SNPs with NMR spectral signatures pointing to fucose (rs492602, P = 6.9×10−44) and lysine (rs8101881, P = 1.2×10−33), respectively. Fine-mapping of the first locus pinpointed the FUT2 gene, which encodes a fucosyltransferase enzyme and has previously been associated with Crohn's disease. This implicates fucose as a potential prognostic disease marker, for which there is already published evidence from a mouse model. The second SNP lies within the SLC7A9 gene, rare mutations of which have been linked to severe kidney damage. The replication of previous associations and our new discoveries demonstrate the potential of untargeted metabolomics GWAS to robustly identify molecular disease markers. The concentrations of small molecules known as metabolites, are subject to tight regulation in all organisms. Collectively, the metabolite concentrations make up the metabolome, which differs amongst individuals as a function of their environment and genetic makeup. In our study, we have further developed an untargeted approach to identify genetic factors affecting human metabolism. In this approach, we first identify all genetic variants that correlate with any of the measured metabolome features in a large set of individuals. For these variants, we then compute a profile of significance for association with all features, generating a signature that facilitates the expert or computational identification of the metabolite whose concentration is most likely affected by the genetic variant at hand. Our study replicated many of the previously reported genetically driven variations in human metabolism and revealed two new striking examples of genetic variations with a sizeable effect on the urine metabolome. Interestingly, in these two gene-metabolite pairs both the gene and the affected metabolite are related to human diseases – Crohn's disease in the first case, and kidney disease in the second. This highlights the connection between genetic predispositions, affected metabolites, and human health.
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影响因子：
30.8
作者：
Kettunen, Johannes;Tukiainen, Taru;Sarin, Antti-Pekka;Ortega-Alonso, Alfredo;Tikkanen, Emmi;Lyytikainen, Leo-Pekka;Kangas, Antti J.;Soininen, Pasi;Wuertz, Peter;Silander, Kaisa;Dick, Danielle M.;Rose, Richard J.;Savolainen, Markku J.;Viikari, Jorma;Kahonen, Mika;Lehtimaki, Terho;Pietilainen, Kirsi H.;Inouye, Michael;McCarthy, Mark I.;Jula, Antti;Eriksson, Johan;Raitakari, Olli T.;Salomaa, Veikko;Kaprio, Jaakko;Jarvelin, Marjo-Riitta;Peltonen, Leena;Perola, Markus;Freimer, Nelson B.;Ala-Korpela, Mika;Palotie, Aarno;Ripatti, Samuli
通讯作者：
Ripatti, Samuli
影响因子：
3.6
作者：
Kohl, Stefanie M.;Klein, Matthias S.;Hochrein, Jochen;Oefner, Peter J.;Spang, Rainer;Gronwald, Wolfram
通讯作者：
Gronwald, Wolfram
影响因子：
30.8
作者：
Barrett, Jeffrey C.;Clayton, David G.;Concannon, Patrick;Akolkar, Beena;Cooper, Jason D.;Erlich, Henry A.;Julier, Cecile;Morahan, Grant;Nerup, Jorn;Nierras, Concepcion;Plagnol, Vincent;Pociot, Flemming;Schuilenburg, Helen;Smyth, Deborah J.;Stevens, Helen;Todd, John A.;Walker, Neil M.;Rich, Stephen S.
通讯作者：
Rich, Stephen S.
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
Ehret, Georg B.;Munroe, Patricia B.;Rice, Kenneth M.;Bochud, Murielle;Johnson, Andrew D.;Chasman, Daniel I.;Smith, Albert V.;Tobin, Martin D.;Verwoert, Germaine C.;Hwang, Shih-Jen;Pihur, Vasyl;Vollenweider, Peter;O'Reilly, Paul F.;Amin, Najaf;Bragg-Gresham, Jennifer L.;Teumer, Alexander;Glazer, Nicole L.;Launer, Lenore;Zhao, Jing Hua;Aulchenko, Yurii;Heath, Simon;Sober, Siim;Parsa, Afshin;Luan, Jian'an;Arora, Pankaj;Dehghan, Abbas;Zhang, Feng;Lucas, Gavin;Hicks, Andrew A.;Jackson, Anne U.;Peden, John F.;Tanaka, Toshiko;Wild, Sarah H.;Rudan, Igor;Igl, Wilmar;Milaneschi, Yuri;Parker, Alex N.;Fava, Cristiano;Chambers, John C.;Fox, Ervin R.;Kumari, Meena;Go, Min Jin;van der Harst, Pim;Kao, Wen Hong Linda;Sjogren, Marketa;Vinay, D. G.;Alexander, Myriam;Tabara, Yasuharu;Shaw-Hawkins, Sue;Whincup, Peter H.;Liu, Yongmei;Shi, Gang;Kuusisto, Johanna;Tayo, Bamidele;Seielstad, Mark;Sim, Xueling;Khanh-Dung Hoang Nguyen;Lehtimaki, Terho;Matullo, Giuseppe;Wu, Ying;Gaunt, Tom R.;Onland-Moret, N. Charlotte;Cooper, Matthew N.;Platou, Carl G. P.;Org, Elin;Hardy, Rebecca;Dahgam, Santosh;Palmen, Jutta;Vitart, Veronique;Braund, Peter S.;Kuznetsova, Tatiana;Uiterwaal, Cuno S. P. M.;Adeyemo, Adebowale;Palmas, Walter;Campbell, Harry;Ludwig, Barbara;Tomaszewski, Maciej;Tzoulaki, Ioanna;Palmer, Nicholette D.;Aspelund, Thor;Garcia, Melissa;Chang, Yen-Pei C.;O'Connell, Jeffrey R.;Steinle, Nanette I.;Grobbee, Diederick E.;Arking, Dan E.;Kardia, Sharon L.;Morrison, Alanna C.;Hernandez, Dena;Najjar, Samer;McArdle, Wendy L.;Hadley, David;Brown, Morris J.;Connell, John M.;Hingorani, Aroon D.;Day, Ian N. M.;Lawlor, Debbie A.;Beilby, John P.;Lawrence, Robert W.;Clarke, Robert;Hopewell, Jemma C.;Ongen, Halit;Dreisbach, Albert W.;Li, Yali;Young, J. Hunter;Bis, Joshua C.;Kahonen, Mika;Viikari, Jorma;Adair, Linda S.;Lee, Nanette R.;Chen, Ming-Huei;Olden, Matthias;Pattaro, Cristian;Bolton, Judith A. Hoffman;Koettgen, Anna;Bergmann, Sven;Mooser, Vincent;Chaturvedi, Nish;Frayling, Timothy M.;Islam, Muhammad;Jafar, Tazeen H.;Erdmann, Jeanette;Kulkarni, Smita R.;Bornstein, Stefan R.;Graessler, Juergen;Groop, Leif;Voight, Benjamin F.;Kettunen, Johannes;Howard, Philip;Taylor, Andrew;Guarrera, Simonetta;Ricceri, Fulvio;Emilsson, Valur;Plump, Andrew;Barroso, Ine S.;Khaw, Kay-Tee;Weder, Alan B.;Hunt, Steven C.;Sun, Yan V.;Bergman, Richard N.;Collins, Francis S.;Bonnycastle, Lori L.;Scott, Laura J.;Stringham, Heather M.;Peltonen, Leena;Perola, Markus;Vartiainen, Erkki;Brand, Stefan-Martin;Staessen, Jan A.;Wang, Thomas J.;Burton, Paul R.;Artigas, Maria Soler;Dong, Yanbin;Snieder, Harold;Wang, Xiaoling;Zhu, Haidong;Lohman, Kurt K.;Rudock, Megan E.;Heckbert, Susan R.;Smith, Nicholas L.;Wiggins, Kerri L.;Doumatey, Ayo;Shriner, Daniel;Veldre, Gudrun;Viigimaa, Margus;Kinra, Sanjay;Prabhakaran, Dorairaj;Tripathy, Vikal;Langefeld, Carl D.;Rosengren, Annika;Thelle, Dag S.;Corsi, Anna Maria;Singleton, Andrew;Forrester, Terrence;Hilton, Gina;McKenzie, Colin A.;Salako, Tunde;Iwai, Naoharu;Kita, Yoshikuni;Ogihara, Toshio;Ohkubo, Takayoshi;Okamura, Tomonori;Ueshima, Hirotsugu;Umemura, Satoshi;Eyheramendy, Susana;Meitinger, Thomas;Wichmann, H. -Erich;Cho, Yoon Shin;Kim, Hyung-Lae;Lee, Jong-Young;Scott, James;Sehmi, Joban S.;Zhang, Weihua;Hedblad, Bo;Nilsson, Peter;Smith, George Davey;Wong, Andrew;Narisu, Narisu;Stancakova, Alena;Raffel, Leslie J.;Yao, Jie;Kathiresan, Sekar;O'Donnell, Christopher J.;Schwartz, Stephen M.;Ikram, M. Arfan;Longstreth, W. T., Jr.;Mosley, Thomas H.;Seshadri, Sudha;Shrine, Nick R. G.;Wain, Louise V.;Morken, Mario A.;Swift, Amy J.;Laitinen, Jaana;Prokopenko, Inga;Zitting, Paavo;Cooper, Jackie A.;Humphries, Steve E.;Danesh, John;Rasheed, Asif;Goel, Anuj;Hamsten, Anders;Watkins, Hugh;Bakker, Stephan J. L.;van Gilst, Wiek H.;Janipalli, Charles S.;Mani, K. Radha;Yajnik, Chittaranjan S.;Hofman, Albert;Mattace-Raso, Francesco U. S.;Oostra, Ben A.;Demirkan, Ayse;Isaacs, Aaron;Rivadeneira, Fernando;Lakatta, Edward G.;Orru, Marco;Scuteri, Angelo;Ala-Korpela, Mika;Kangas, Antti J.;Lyytikainen, Leo-Pekka;Soininen, Pasi;Tukiainen, Taru;Wurtz, Peter;Ong, Rick Twee-Hee;Doerr, Marcus;Kroemer, Heyo K.;Voelker, Uwe;Voelzke, Henry;Galan, Pilar;Hercberg, Serge;Lathrop, Mark;Zelenika, Diana;Deloukas, Panos;Mangino, Massimo;Spector, Tim D.;Zhai, Guangju;Meschia, James F.;Nalls, Michael A.;Sharma, Pankaj;Terzic, Janos;Kumar, M. V. Kranthi;Denniff, Matthew;Zukowska-Szczechowska, Ewa;Wagenknecht, Lynne E.;Fowkes, F. Gerald R.;Charchar, Fadi J.;Schwarz, Peter E. H.;Hayward, Caroline;Guo, Xiuqing;Rotimi, Charles;Bots, Michiel L.;Brand, Eva;Samani, Nilesh J.;Polasek, Ozren;Talmud, Philippa J.;Nyberg, Fredrik;Kuh, Diana;Laan, Maris;Hveem, Kristian;Palmer, Lyle J.;van der Schouw, Yvonne T.;Casas, Juan P.;Mohlke, Karen L.;Vineis, Paolo;Raitakari, Olli;Ganesh, Santhi K.;Wong, Tien Y.;Tai, E. Shyong;Cooper, Richard S.;Laakso, Markku;Rao, Dabeeru C.;Harris, Tamara B.;Morris, Richard W.;Dominiczak, Anna F.;Kivimaki, Mika;Marmot, Michael G.;Miki, Tetsuro;Saleheen, Danish;Chandak, Giriraj R.;Coresh, Josef;Navis, Gerjan;Salomaa, Veikko;Han, Bok-Ghee;Zhu, Xiaofeng;Kooner, Jaspal S.;Melander, Olle;Ridker, Paul M.;Bandinelli, Stefania;Gyllensten, Ulf B.;Wright, Alan F.;Wilson, James F.;Ferrucci, Luigi;Farrall, Martin;Tuomilehto, Jaakko;Pramstaller, Peter P.;Elosua, Roberto;Soranzo, Nicole;Sijbrands, Eric J. 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通讯作者：
Johnson, Toby