Integrative polygenic analysis of the protective effects of fatty acid metabolism on disease as modified by obesity.
Integrative polygenic analysis of the protective effects of fatty acid metabolism on disease as modified by obesity.
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DOI：
10.3389/fnut.2023.1308622
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发表时间：
2023
影响因子：
5
通讯作者：
Gibson, Greg
中科院分区：
文献类型：
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作者：
Astore, Courtney;Gibson, Greg
脂肪酸代谢物的失调可以在复杂疾病如心血管疾病、消化系统疾病和代谢性疾病的进展中起关键作用。代谢物对疾病既可以有保护作用，也可以有风险作用;然而，这种关联的细节仍然存在争议。在这项研究中，我们证明了一种综合的PheWAS方法，以建立高置信度，因果关系提示三种脂肪酸代谢物，即omega-3脂肪酸，omega-6脂肪酸和二十二碳六烯酸，对于1，254种疾病终点的代谢物-疾病关联。如果代谢物水平和代谢物遗传风险评分的作用方向和显著性一致，则确定代谢物-疾病相关性。ω-3脂肪酸与呼吸系统疾病、ω-6脂肪酸与循环系统和内分泌系统疾病、二十二碳六烯酸与消化系统疾病之间存在代谢物富集关系。在对结果的子集进行孟德尔随机化后，我们分别确定了3、6和15种与omega-3脂肪酸、omega-6脂肪酸和二十二碳六烯酸相关的显著疾病。然后，我们证明了一类患病率-风险关系，表明在高和低脂肪酸代谢物水平下疾病的（去）渠道化。最后，我们表明，代谢产物和肥胖之间的相互作用表明，由脂肪酸代谢产物提供的保护程度是强烈调制的基础代谢健康。本研究评估了三种多不饱和脂肪酸（PUFA）的疾病结构，这些结构通过几种PheWAS支持模式进行了验证。我们的研究结果不仅突出了与每种代谢物相关的特定疾病，而且还丰富了疾病组。此外，我们还展示了一种综合的PheWAS方法，该方法可应用于人类代谢组的其他组分或其他感兴趣的性状。这项研究的结果可以作为一个地图集，交叉比较遗传与非遗传性疾病的关联，为三个PUFA调查。这些发现可以通过我们的R shiny应用程序在https://pufa.biosci.gatech.edu上进行探索。
Dysregulation of fatty acid metabolites can play a crucial role in the progression of complex diseases, such as cardiovascular disease, digestive diseases, and metabolic diseases. Metabolites can have either protective or risk effects on a disease; however, the details of such associations remain contentious. In this study, we demonstrate an integrative PheWAS approach to establish high confidence, causally suggestive of metabolite–disease associations for three fatty acid metabolites, namely, omega-3 fatty acids, omega-6 fatty acids, and docosahexaenoic acid, for 1,254 disease endpoints. Metabolite–disease associations were established if there was a concordant direction of effect and significance for metabolite level and genetic risk score for the metabolite. There was enrichment for metabolite associations with diseases of the respiratory system for omega-3 fatty acids, diseases of the circulatory system and endocrine system for omega-6 fatty acids, and diseases of the digestive system for docosahexaenoic acid. Upon performing Mendelian randomization on a subset of the outcomes, we identified 3, 6, and 15 significant diseases associated with omega-3 fatty acids, omega-6 fatty acids, and docosahexaenoic acid, respectively. We then demonstrate a class of prevalence-risk relationships indicative of (de)canalization of disease under high and low fatty acid metabolite levels. Finally, we show that the interaction between the metabolites and obesity demonstrates that the degree of protection afforded by fatty acid metabolites is strongly modulated by underlying metabolic health. This study evaluated the disease architectures of three polyunsaturated fatty acids (PUFAs), which were validated by several PheWAS modes of support. Our results not only highlight specific diseases associated with each metabolite but also disease group enrichments. In addition, we demonstrate an integrative PheWAS methodology that can be applied to other components of the human metabolome or other traits of interest. The results of this study can be used as an atlas to cross-compare genetic with non-genetic disease associations for the three PUFAs investigated. The findings can be explored through our R shiny app at https://pufa.biosci.gatech.edu.
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影响因子：
64.8
作者：
Kurki, Mitja, I;Karjalainen, Juha;Palta, Priit;Sipila, Timo P.;Kristiansson, Kati;Donner, Kati M.;Reeve, Mary P.;Laivuori, Hannele;Aavikko, Mervi;Kaunisto, Mari A.;Loukola, Anu;Lahtela, Elisa;Mattsson, Hannele;Laiho, Paivi;Parolo, Pietro Della Briotta;Lehisto, Arto A.;Kanai, Masahiro;Mars, Nina;Ramo, Joel;Kiiskinen, Tuomo;Heyne, Henrike O.;Veerapen, Kumar;Rueger, Sina;Lemmela, Susanna;Zhou, Wei;Ruotsalainen, Sanni;Parn, Kalle;Hiekkalinna, Tero;Koskelainen, Sami;Paajanen, Teemu;Llorens, Vincent;Gracia-Tabuenca, Javier;Siirtola, Harri;Reis, Kadri;Elnahas, Abdelrahman G.;Sun, Benjamin;Foley, Christopher N.;Aalto-Setala, Katriina;Alasoo, Kaur;Arvas, Mikko;Auro, Kirsi;Biswas, Shameek;Bizaki-Vallaskangas, Argyro;Carpen, Olli;Chen, Chia-Yen;Dada, Oluwaseun A.;Ding, Zhihao;Ehm, Margaret G.;Eklund, Kari;Farkkila, Martti;Finucane, Hilary;Ganna, Andrea;Ghazal, Awaisa;Graham, Robert R.;Green, Eric M.;Hakanen, Antti;Hautalahti, Marco;Hedman, Asa K.;Hiltunen, Mikko;Hinttala, Reetta;Hovatta, Iiris;Hu, Xinli;Huertas-Vazquez, Adriana;Huilaja, Laura;Hunkapiller, Julie;Jacob, Howard;Jensen, Jan-Nygaard;Joensuu, Heikki;John, Sally;Julkunen, Valtteri;Jung, Marc;Junttila, Juhani;Kaarniranta, Kai;Kahonen, Mika;Kajanne, Risto;Kallio, Lila;Kalviainen, Reetta;Kaprio, Jaakko;Kerimov, Nurlan;Kettunen, Johannes;Kilpelainen, Elina;Kilpi, Terhi;Klinger, Katherine;Kosma, Veli-Matti;Kuopio, Teijo;Kurra, Venla;Laisk, Triin;Laukkanen, Jari;Lawless, Nathan;Liu, Aoxing;Longerich, Simonne;Magi, Reedik;Makela, Johanna;Makitie, Antti;Malarstig, Anders;Mannermaa, Arto;Maranville, Joseph;Matakidou, Athena;Meretoja, Tuomo;Mozaffari, Sahar, V;Niemi, Mari E. K.;Niemi, Marianna;Niiranen, Teemu;Okafo, George;Ollila, Hanna M.;Palomaki, Antti;Palotie, Tuula;Partanen, Jukka;Paul, Dirk S.;Pelkonen, Margit;Pendergrass, Rion K.;Petrovski, Slave;Pitkaranta, Anne;Platt, Adam;Pulford, David;Punkka, Eero;Pussinen, Pirkko;Raghavan, Neha;Rahimov, Fedik;Rajpal, Deepak;Renaud, Nicole A.;Riley-Gillis, Bridget;Rodosthenous, Rodosthenis;Saarentaus, Elmo;Salminen, Aino;Salminen, Eveliina;Salomaa, Veikko;Schleutker, Johanna;Serpi, Raisa;Shen, Huei-yi;Siegel, Richard;Silander, Kaisa;Siltanen, Sanna;Soini, Sirpa;Soininen, Hilkka;Sul, Jae Hoon;Tachmazidou, Ioanna;Tasanen, Kaisa;Tienari, Pentti;Toppila-Salmi, Sanna;Tukiainen, Taru;Tuomi, Tiinamaija;Turunen, Joni A.;Ulirsch, Jacob C.;Vaura, Felix;Virolainen, Petri;Waring, Jeffrey;Waterworth, Dawn;Yang, Robert;Nelis, Mari;Reigo, Anu;Metspalu, Andres;Milani, Lili;Esko, Tonu;Fox, Caroline;Havulinna, Aki S.;Perola, Markus;Ripatti, Samuli;Jalanko, Anu;Laitinen, Tarja;Makela, Tomi P.;Plenge, Robert;McCarthy, Mark;Runz, Heiko;Daly, Mark J.;Palotie, Aarno
通讯作者：
Palotie, Aarno
影响因子：
16.6
作者：
Gallois, Apolline;Mefford, Joel;Aschard, Hugues
通讯作者：
Aschard, Hugues
影响因子：
5.9
作者：
He, Jian;Luo, Xiaobei;Xin, Hongjie;Lai, Qianwei;Zhou, Yuanping;Bai, Yang
通讯作者：
Bai, Yang
DOI：
10.1038/s41576-021-00414-z
发表时间：
2022-03
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
Loos RJF;Yeo GSH
通讯作者：
Yeo GSH
影响因子：
5.6
作者：
通讯作者：
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