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Genome analyses of > 200,000 individuals identify 58 loci for chronic inflammation and highlight pathways that link inflammation and complex disorders
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
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
Author
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
Alizadeh, Behrooz Z.
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
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
Date
2018
Type
Journal article
Journal
American Journal of Human Genetics
Book
Volume
103
Issue
5
Page Range
691-706
Article Number
ACU Department
Mary MacKillop Institute for Health Research
Faculty of Health Sciences
Faculty of Health Sciences
Collections
Relation URI
Source URL
Event URL
Open Access Status
License
All rights reserved
File Access
Controlled
Notes
A complete list of study-specific acknowledgments and funding information are provided in the Supplemental Data: https://www.sciencedirect.com/science/article/pii/S0002929718303203?via%3Dihub#app3