Genome analyses of > 200,000 individuals identify 58 loci for chronic inflammation and highlight pathways that link inflammation and complex disorders
Journal article
Vaez, Ahmad, Võsa, Urmo, Stathopoulou, Maria G., de Vries, Paul S., Prins, Bram P., Van der Most, Peter J., Tanaka, Toshiko, Naderi, Elnaz, Rose, Lynda M., Wu, Ying, Karlsson, Robert, Barbalic, Maja, Lin, Honghuang, Pool, René, Zhu, Gu, Macé, Aurélien, Sidore, Carlo, Trompet, Stella, Mangino, Massimo, ... Alizadeh, Behrooz Z.. (2018). Genome analyses of > 200,000 individuals identify 58 loci for chronic inflammation and highlight pathways that link inflammation and complex disorders. American Journal of Human Genetics. 103(5), pp. 691-706. https://doi.org/10.1016/j.ajhg.2018.09.009
| Authors | Vaez, Ahmad, Võsa, Urmo, Stathopoulou, Maria G., de Vries, Paul S., Prins, Bram P., Van der Most, Peter J., Tanaka, Toshiko, Naderi, Elnaz, Rose, Lynda M., Wu, Ying, Karlsson, Robert, Barbalic, Maja, Lin, Honghuang, Pool, René, Zhu, Gu, Macé, Aurélien, Sidore, Carlo, Trompet, Stella, Mangino, Massimo, Sabater-Lleal, Maria, Kemp, John P., Abbasi, Ali, Kacprowski, Tim, Verweij, Niek, Smith, Albert V., Huang, Tao, Marzi, Carola, Feitosa, Mary F., Lohman, Kurt K., Kleber, Marcus E., Milaneschi, Yuri, Mueller, Christian, Huq, Mahmudul, Vlachopoulou, Efthymia, Lyytikäinen, Leo-Pekka, Oldmeadow, Christopher, Deelen, Joris, Perola, Markus, Zhao, Jing Hua, Feenstra, Bjarke, Alizadeh, Behrooz Z., Boezen, H. Marike, Franke, Lude, van der Harst, Pim, Navis, Gerjan, Rots, Marianne, Snieder, Harold, Swertz, Morris, Wolffenbuttel, Bruce H. R., Wijmenga, Cisca, Amini, Marzyeh, Benjamin, Emelia, Chasman, Daniel I., Dehghan, Abbas, Ahluwalia, Tarunveer Singh, Meigs, James, Tracy, Russell, Alizadeh, Behrooz Z., Ligthart, Symen, Bis, Josh, Eiriksdottir, Gudny, Pankratz, Nathan, Gross, Myron, Rainer, Alex, Snieder, Harold, Wilson, James G., Psaty, Bruce M., Dupuis, Josee, Prins, Bram, Vaso, Urmo, Stathopoulou, Maria, Franke, Lude, Lehtimaki, Terho, Koenig, Wolfgang, Jamshidi, Yalda, Siest, Sophie, Abbasi, Ali, Uitterlinden, Andre G., Abdollahi, Mohammadreza, Schnabel, Renate, Schick, Ursula M., Nolte, Ilja M., Kraja, Aldi, Hsu, Yi-Hsiang, Tylee, Daniel S., Zwicker, Alyson, Uher, Rudolf, Davey-Smith, George, Morrison, Alanna C., Hicks, Andrew, van Duijn, Cornelia M., Ward-Caviness, Cavin, Boerwinkle, Eric, Rotter, J., Rice, Ken, Lange, Leslie, Perola, Markus, de Geus, Eco, Morris, Andrew P., Makela, Kari Matti, Stacey, David, Eriksson, Johan, Frayling, Tim M., Slagboom, Eline P., Lahti, Jari, Schraut, Katharina E., Fornage, Myriam, Suktitipat, Bhoom, Chen, Wei-Min, Li, Xiaohui, Nutile, Teresa, Malerba, Giovanni, Luan, Jian’an, Bak, Tom, Schork, Nicholas, Del Greco M, Fabiola, Thiering, Elisabeth, Mahajan, Anubha, Marioni, Riccardo E., Mihailov, Evelin, Eriksson, Joel, Ozel, Ayse Bilge, Zhang, Weihua, Nethander, Maria, Cheng, Yu-Ching, Aslibekyan, Stella, Ang, Wei, Gandin, Ilaria, Yengo, Loïc, Portas, Laura, Kooperberg, Charles, Hofer, Edith, Rajan, Kumar B., Schurmann, Claudia, den Hollander, Wouter, Ahluwalia, Tarunveer S., Zhao, Jing, Draisma, Harmen H. M., Ford, Ian, Timpson, Nicholas, Teumer, Alexander, Huang, Hongyan, Wahl, Simone, Liu, YongMei, Huang, Jie, Uh, Hae-Won, Geller, Frank, Joshi, Peter K., Yanek, Lisa R., Trabetti, Elisabetta, Lehne, Benjamin, Vozzi, Diego, Verbanck, Marie, Biino, Ginevra, Saba, Yasaman, Meulenbelt, Ingrid, O’Connell, Jeff R., Laakso, Markku, Giulianini, Franco, Magnusson, Patrik K. E., Ballantyne, Christie M., Hottenga, Jouke Jan, Montgomery, Grant W., Rivadineira, Fernando, Rueedi, Rico, Steri, Maristella, Herzig, Karl-Heinz, Stott, David J., Menni, Cristina, Frånberg, Mattias, St. Pourcain, Beate, Felix, Stephan B., Pers, Tune H., Bakker, Stephan J. L., Kraft, Peter, Peters, Annette, Vaidya, Dhananjay, Delgado, Graciela, Smit, Johannes H., Großmann, Vera, Sinisalo, Juha, Seppälä, Ilkka, Williams, Stephen R., Holliday, Elizabeth G., Moed, Matthijs, Langenberg, Claudia, Räikkönen, Katri, Ding, Jingzhong, Campbell, Harry, Sale, Michele M., Chen, Yii-Der I., James, Alan L., Ruggiero, Daniela, Soranzo, Nicole, Hartman, Catharina A., Smith, Erin N., Berenson, Gerald S., Fuchsberger, Christian, Hernandez, Dena, Tiesler, Carla M. T., Giedraitis, Vilmantas, Liewald, David, Fischer, Krista, Mellström, Dan, Larsson, Anders, Wang, Yunmei, Scott, William R., Lorentzon, Matthias, Beilby, John, Ryan, Kathleen A., Pennell, Craig E., Vuckovic, Dragana, Balkau, Beverly, Concas, Maria Pina, Schmidt, Reinhold, Mendes de Leon, Carlos F., Bottinger, Erwin P., Kloppenburg, Margreet, Paternoster, Lavinia, Boehnke, Michael, Musk, A. W., Willemsen, Gonneke, Evans, David M., Madden, Pamela A. F., Kähönen, Mika, Kutalik, Zoltán, Zoledziewska, Magdalena, Karhunen, Ville, Kritchevsky, Stephen B., Sattar, Naveed, Lachance, Genevieve, Clarke, Robert, Harris, Tamara B., Raitakari, Olli T., Attia, John R., van Heemst, Diana, Kajantie, Eero, Sorice, Rossella, Gambaro, Giovanni, Scott, Robert A., Hicks, Andrew A., Ferrucci, Luigi, Standl, Marie, Lindgren, Cecilia M., Starr, John M., Karlsson, Magnus, Lind, Lars, Li, Jun Z., Chambers, John C., Mori, Trevor A., de Geus, Eco J. C. N., Heath, Andrew C., Martin, Nicholas G., Auvinen, Juha, Buckley, Brendan M., de Craen, Anton J. M., Waldenberger, Melanie, Strauch, Konstantin, Meitinger, Thomas, Scott, Rodney J., McEvoy, Mark, Beekman, Marian, Bombieri, Cristina, Ridker, Paul M., Mohlke, Karen L., Pedersen, Nancy L., Morrison, Alanna C., Boomsma, Dorret I., Whitfield, John B., Strachan, David P., Hofman, Albert, Vollenweider, Peter, Cucca, Francesco, Jarvelin, Marjo-Riitta, Jukema, J. Wouter, Spector, Tim D., Hamsten, Anders, Zeller, Tanja, Uitterlinden, André G., Nauck, Matthias, Gudnason, Vilmundur, Qi, Lu, Grallert, Harald, Borecki, Ingrid B., Rotter, Jerome I., März, Winfried, Wild, Philipp S., Lokki, Marja-Liisa, Boyle, Michael, Salomaa, Veikko, Melbye, Mads, Eriksson, Johan G., Wilson, James F., Penninx, Brenda W. J. H., Becker, Diane M., Worrall, Bradford B., Gibson, Greg, Krauss, Ronald M., Ciullo, Marina, Zaza, Gianluigi, Wareham, Nicholas J., Oldehinkel, Albertine J., Palmer, Lyle J., Murray, Sarah S., Pramstaller, Peter P., Bandinelli, Stefania, Heinrich, Joachim, Ingelsson, Erik, Deary, Ian J., Mägi, Reedik, Vandenput, Liesbeth, van der Harst, Pim, Desch, Karl C., Kooner, Jaspal S., Ohlsson, Claes, Hayward, Caroline, Lehtimäki, Terho, Shuldiner, Alan R., Arnett, Donna K., Beilin, Lawrence J., Robino, Antonietta, Froguel, Philippe, Pirastu, Mario, Jess, Tine, Koenig, Wolfgang, Loos, Ruth J. F., Evans, Denis A., Schmidt, Helena, Smith, George Davey, Slagboom, P. Eline, Eiriksdottir, Gudny, Morris, Andrew P., Psaty, Bruce M., Tracy, Russell P., Nolte, Ilja M., Boerwinkle, Eric, Visvikis-Siest, Sophie, Reiner, Alex P., Gross, Myron, Bis, Joshua C., Franke, Lude, Franco, Oscar H., Benjamin, Emelia J., Chasman, Daniel I., Dupuis, Josée, Snieder, Harold, Dehghan, Abbas and Alizadeh, Behrooz Z. |
|---|---|
| Abstract | C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10−8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences. |
| Keywords | C-reactive protein; genome-wide association study; inflammation; Mendelian randomization; inflammatory disorders; DEPICT; coronary artery disease; schizophrenia; system biology |
| Year | 2018 |
| Journal | American Journal of Human Genetics |
| Journal citation | 103 (5), pp. 691-706 |
| Publisher | Cell Press |
| ISSN | 0002-9297 |
| Digital Object Identifier (DOI) | https://doi.org/10.1016/j.ajhg.2018.09.009 |
| PubMed ID | 30388399 |
| Scopus EID | 2-s2.0-85055557317 |
| PubMed Central ID | PMC6218410 |
| Page range | 691-706 |
| Funder | Australian Research Council (ARC) |
| National Health and Medical Research Council (NHMRC) | |
| Publisher's version | License All rights reserved File Access Level Controlled |
| Output status | Published |
| Publication dates | |
| Online | 01 Nov 2018 |
| Publication process dates | |
| Accepted | 20 Sep 2018 |
| Deposited | 23 Jan 2023 |
| ARC Funded Research | This output has been funded, wholly or partially, under the Australian Research Council Act 2001 |
| Grant ID | FT130101709 |
| 572613 | |
| 1021105 | |
| 403981 | |
| 003209 | |
| Additional information | A complete list of study-specific acknowledgments and funding information are provided in the Supplemental Data: https://www.sciencedirect.com/science/article/pii/S0002929718303203?... |
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