Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders.

TitreGenome 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, Macé, 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, Lyytikainen, L-P, Oldmeadow, C, Deelen, J, Perola, M, Zhao, JHua, 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, JJan, 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, Kahonen, 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, Lehtimaki, T, Shuldiner, AR, Arnett, DK, Beilin, LJ, Robino, A, Froguel, P, Pirastu, M, Jess, T, Koenig, W, Loos, RJF, Evans, DA, Schmidt, H, Smith, GDavey, 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 AuthorsLifeLines Cohort Study, CHARGE inflammation working group
JournalAmerican Journal of Human Genetics
Volume103
Issue5
Pagination691-706
Date Published11/2018
DOI10.1016/j.ajhg.2018.09.009
ISSN1537-6605
Mots-clés80 and over, Adolescent, Adult, Aged, Biomarkers/metabolism, Bipolar Disorder/genetics, Bipolar Disorder/metabolism, Body Mass Index, C-Reactive Protein, C-Reactive Protein/genetics, Child, Coronary Artery Disease, DEPICT, Female, Genetic Loci/genetics, Genome-Wide Association Study, Genome-Wide Association Study/methods, Humans, Inflammation, Inflammation/genetics, Inflammation/metabolism, inflammatory disorders, Liver/metabolism, Liver/pathology, Male, Mendelian randomization, Mendelian Randomization Analysis/methods, Metabolic Networks and Pathways/genetics, Middle Aged, Schizophrenia, Schizophrenia/genetics, Schizophrenia/metabolism, system biology, Young Adult
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). 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.

Alternate URL

http://www.ncbi.nlm.nih.gov/pubmed/30388399?dopt=Abstract

WOS ID (UT)

000448942100006

Alternate JournalAm. J. Hum. Genet.
Citation Key / SERVAL ID9225
Peer reviewRefereed
PubMed ID30388399
PubMed Central IDPMC6218410

                         

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