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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.

TitleGenome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders.
Publication TypeJournal Article
Year of Publication2018
AuthorsLigthart, S, Vaez, A, Võsa, U, Stathopoulou, MG, de Vries, PS, Prins, BP, van der Most, PJ, Tanaka, T, Naderi, E, Rose, LM, Wu, Y, Karlsson, R, Barbalic, M, Lin, H, Pool, R, Zhu, G, Mace, A, Sidore, C, Trompet, S, Mangino, M, Sabater-Lleal, M, Kemp, JP, Abbasi, A, Kacprowski, T, Verweij, N, Smith, AV, Huang, T, Marzi, C, Feitosa, MF, Lohman, KK, Kleber, ME, Milaneschi, Y, Mueller, C, Huq, M, Vlachopoulou, E, Lyytikäinen, L-P, Oldmeadow, C, Deelen, J, Perola, M, Zhao, JH, Feenstra, B, Amini, M, Lahti, J, Schraut, KE, Fornage, M, Suktitipat, B, Chen, W-M, Li, X, Nutile, T, Malerba, G, Luan, J'an, Bak, T, Schork, N, M, Fdel Greco, Thiering, E, Mahajan, A, Marioni, RE, Mihailov, E, Eriksson, J, Ozel, ABilge, Zhang, W, Nethander, M, Cheng, Y-C, Aslibekyan, S, Ang, W, Gandin, I, Yengo, L, Portas, L, Kooperberg, C, Hofer, E, Rajan, KB, Schurmann, C, Hollander, Wden, Ahluwalia, TS, Zhao, J, Draisma, HHM, Ford, I, Timpson, N, Teumer, A, Huang, H, Wahl, S, Liu, Y, Huang, J, Uh, H-W, Geller, F, Joshi, PK, Yanek, LR, Trabetti, E, Lehne, B, Vozzi, D, Verbanck, M, Biino, G, Saba, Y, Meulenbelt, I, O'Connell, JR, Laakso, M, Giulianini, F, Magnusson, PKE, Ballantyne, CM, Hottenga, JJ, Montgomery, GW, Rivadineira, F, Rueedi, R, Steri, M, Herzig, K-H, Stott, DJ, Menni, C, Frånberg, M, St Pourcain, B, Felix, SB, Pers, TH, Bakker, SJL, Kraft, P, Peters, A, Vaidya, D, Delgado, G, Smit, JH, Großmann, V, Sinisalo, J, Seppälä, I, Williams, SR, Holliday, EG, Moed, M, Langenberg, C, Räikkönen, K, Ding, J, Campbell, H, Sale, MM, Chen, Y-derI, James, AL, Ruggiero, D, Soranzo, N, Hartman, CA, Smith, EN, Berenson, GS, Fuchsberger, C, Hernandez, D, Tiesler, CMT, Giedraitis, V, Liewald, D, Fischer, K, Mellström, D, Larsson, A, Wang, Y, Scott, WR, Lorentzon, M, Beilby, J, Ryan, KA, Pennell, CE, Vuckovic, D, Balkau, B, Concas, MPina, Schmidt, R, de Leon, CFMendes, Bottinger, EP, Kloppenburg, M, Paternoster, L, Boehnke, M, Musk, AW, Willemsen, G, Evans, DM, Madden, PAF, Kähönen, M, Kutalik, Z, Zoledziewska, M, Karhunen, V, Kritchevsky, SB, Sattar, N, Lachance, G, Clarke, R, Harris, TB, Raitakari, OT, Attia, JR, van Heemst, D, Kajantie, E, Sorice, R, Gambaro, G, Scott, RA, Hicks, AA, Ferrucci, L, Standl, M, Lindgren, CM, Starr, JM, Karlsson, M, Lind, L, Li, JZ, Chambers, JC, Mori, TA, de Geus, EJCN, Heath, AC, Martin, NG, Auvinen, J, Buckley, BM, de Craen, AJM, Waldenberger, M, Strauch, K, Meitinger, T, Scott, RJ, McEvoy, M, Beekman, M, Bombieri, C, Ridker, PM, Mohlke, KL, Pedersen, NL, Morrison, AC, Boomsma, DI, Whitfield, JB, Strachan, DP, Hofman, A, Vollenweider, P, Cucca, F, Jarvelin, M-R, J Jukema, W, Spector, TD, Hamsten, A, Zeller, T, Uitterlinden, AG, Nauck, M, Gudnason, V, Qi, L, Grallert, H, Borecki, IB, Rotter, JI, März, W, Wild, PS, Lokki, M-L, Boyle, M, Salomaa, V, Melbye, M, Eriksson, JG, Wilson, JF, Penninx, BWJH, Becker, DM, Worrall, BB, Gibson, G, Krauss, RM, Ciullo, M, Zaza, G, Wareham, NJ, Oldehinkel, AJ, Palmer, LJ, Murray, SS, Pramstaller, PP, Bandinelli, S, Heinrich, J, Ingelsson, E, Deary, IJ, Mägi, R, Vandenput, L, van der Harst, P, Desch, KC, Kooner, JS, Ohlsson, C, Hayward, C, Lehtimäki, T, Shuldiner, AR, Arnett, DK, Beilin, LJ, Robino, A, Froguel, P, Pirastu, M, Jess, T, Koenig, W, Loos, RJF, Evans, DA, Schmidt, H, Smith, GD, P Slagboom, E, Eiriksdottir, G, Morris, AP, Psaty, BM, Tracy, RP, Nolte, IM, Boerwinkle, E, Visvikis-Siest, S, Reiner, AP, Gross, M, Bis, JC, Franke, L, Franco, OH, Benjamin, EJ, Chasman, DI, Dupuis, J, Snieder, H, Dehghan, A, Alizadeh, BZ
Corporate/Institutional AuthorsLifeLines Cohort Study,, CHARGE Inflammation Working Group
JournalAm J Hum Genet
Volume103
Issue5
Pagination691-706
Date Published2018 Nov 01
ISSN1537-6605
Abstract<p>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). 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.</p>
DOI10.1016/j.ajhg.2018.09.009
Alternate JournalAm. J. Hum. Genet.
PubMed ID30388399
PubMed Central IDPMC6218410
Grant ListR01 HL141399 / HL / NHLBI NIH HHS / United States
ePub date: 
18/11