Genome analyses of >200,000 individuals identify 58 loci for chronic inflammation and highlight pathways that link inflammation and complex disorders

Ligthart, S. et al. (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. (doi: 10.1016/j.ajhg.2018.09.009) (PMID:30388399) (PMCID:PMC6218410)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Stott J, Professor David and Sattar, Professor Naveed and Ford, Professor Ian
• Authors: Ligthart, S., Vaez, A., Võsa, U., Stathopoulou, M. G., de Vries, P. S., Prins, B. P., Van der Most, P. J., Tanaka, T., Naderi, E., Rose, L. M., Wu, Y., Karlsson, R., Barbalic, M., Lin, H., Pool, R., Zhu, G., Macé, A., Sidore, C., Trompet, S., Mangino, M., Sabater-Lleal, M., Kemp, J. P., Abbasi, A., Kacprowski, T., Verweij, N., Smith, A. V., Huang, T., Marzi, C., Feitosa, M. F., Lohman, K. K., Kleber, M. E., Milaneschi, Y., Mueller, C., Huq, M., Vlachopoulou, E., Lyytikäinen, L.-P., Oldmeadow, C., Deelen, J., Perola, M., Zhao, J. H., Feenstra, B., Amini, M., Lahti, J., Schraut, K. E., Fornage, M., Suktitipat, B., Chen, W.-M., Li, X., Nutile, T., Malerba, G., Luan, J.’a., Bak, T., Schork, N., Del Greco M., F., Thiering, E., Mahajan, A., Marioni, R. E., Mihailov, E., Eriksson, J., Ozel, A. B., Zhang, W., Nethander, M., Cheng, Y.-C., Aslibekyan, S., Ang, W., Gandin, I., Yengo, L., Portas, L., Kooperberg, C., Hofer, E., Rajan, K. B., Schurmann, C., den Hollander, W., Ahluwalia, T. S., Zhao, J., Draisma, H. H.M., Ford, I., Timpson, N., Teumer, A., Huang, H., Wahl, S., Liu, Y., Huang, J., Uh, H.-W., Geller, F., Joshi, P. K., Yanek, L. R., Trabetti, E., Lehne, B., Vozzi, D., Verbanck, M., Biino, G., Saba, Y., Meulenbelt, I., O’Connell, J. R., Laakso, M., Giulianini, F., Magnusson, P. K.E., Ballantyne, C. M., Hottenga, J. J., Montgomery, G. W., Rivadineira, F., Rueedi, R., Steri, M., Herzig, K.-H., Stott, D. J., Menni, C., Frånberg, M., St. Pourcain, B., Felix, S. B., Pers, T. H., Bakker, S. J.L., Kraft, P., Peters, A., Vaidya, D., Delgado, G., Smit, J. H., Großmann, V., Sinisalo, J., Seppälä, I., Williams, S. R., Holliday, E. G., Moed, M., Langenberg, C., Räikkönen, K., Ding, J., Campbell, H., Sale, M. M., Chen, Y.-D. I., James, A. L., Ruggiero, D., Soranzo, N., Hartman, C. A., Smith, E. N., Berenson, G. S., Fuchsberger, C., Hernandez, D., Tiesler, C. M.T., Giedraitis, V., Liewald, D., Fischer, K., Mellström, D., Larsson, A., Wang, Y., Scott, W. R., Lorentzon, M., Beilby, J., Ryan, K. A., Pennell, C. E., Vuckovic, D., Balkau, B., Concas, M. P., Schmidt, R., Mendes de Leon, C. F., Bottinger, E. P., Kloppenburg, M., Paternoster, L., Boehnke, M., Musk, A.W., Willemsen, G., Evans, D. M., Madden, P. A.F., Kähönen, M., Kutalik, Z., Zoledziewska, M., Karhunen, V., Kritchevsky, S. B., Sattar, N., Lachance, G., Clarke, R., Harris, T. B., Raitakari, O. T., Attia, J. R., van Heemst, D., Kajantie, E., Sorice, R., Gambaro, G., Scott, R. A., Hicks, A. A., Ferrucci, L., Standl, M., Lindgren, C. M., Starr, J. M., Karlsson, M., Lind, L., Li, J. Z., Chambers, J. C., Mori, T. A., de Geus, E. J.C.N., Heath, A. C., Martin, N. G., Auvinen, J., Buckley, B. M., de Craen, A. J.M., Waldenberger, M., Strauch, K., Meitinger, T., Scott, R. J., McEvoy, M., Beekman, M., Bombieri, C., Ridker, P. M., Mohlke, K. L., Pedersen, N. L., Morrison, A. C., Boomsma, D. I., Whitfield, J. B., Strachan, D. P., Hofman, A., Vollenweider, P., Cucca, F., Jarvelin, M.-R., Jukema, J. W., Spector, T. D., Hamsten, A., Zeller, T., Uitterlinden, A. G., Nauck, M., Gudnason, V., Qi, L., Grallert, H., Borecki, I. B., Rotter, J. I., März, W., Wild, P. S., Lokki, M.-L., Boyle, M., Salomaa, V., Melbye, M., Eriksson, J. G., Wilson, J. F., Penninx, B. W.J.H., Becker, D. M., Worrall, B. B., Gibson, G., Krauss, R. M., Ciullo, M., Zaza, G., Wareham, N. J., Oldehinkel, A. J., Palmer, L. J., Murray, S. S., Pramstaller, P. P., Bandinelli, S., Heinrich, J., Ingelsson, E., Deary, I. J., Mägi, R., Vandenput, L., van der Harst, P., Desch, K. C., Kooner, J. S., Ohlsson, C., Hayward, C., Lehtimäki, T., Shuldiner, A. R., Arnett, D. K., Beilin, L. J., Robino, A., Froguel, P., Pirastu, M., Jess, T., Koenig, W., Loos, R. J.F., Evans, D. A., Schmidt, H., Smith, G. D., Slagboom, P. E., Eiriksdottir, G., Morris, A. P., Psaty, B. M., Tracy, R. P., Nolte, I. M., Boerwinkle, E., Visvikis-Siest, S., Reiner, A. P., Gross, M., Bis, J. C., Franke, L., Franco, O. H., Benjamin, E. J., Chasman, D. I., Dupuis, J., Snieder, H., Dehghan, A., Alizadeh, B. Z., Alizadeh, B. Z., Boezen, H. M., Franke, L., van der Harst, P., Navis, G., Rots, M., Snieder, H., Swertz, M., Wolffenbuttel, B. H.R., Wijmenga, C., Benjamin, E., Chasman, D. I., Dehghan, A., Ahluwalia, T. S., Meigs, J., Tracy, R., Alizadeh, B. Z., Ligthart, S., Bis, J., Eiriksdottir, G., Pankratz, N., Gross, M., Rainer, A., Snieder, H., Wilson, J. G., Psaty, B. M., Dupuis, J., Prins, B., Vaso, U., Stathopoulou, M., Franke, L., Lehtimaki, T., Koenig, W., Jamshidi, Y., Siest, S., Abbasi, A., Uitterlinden, A. G., Abdollahi, M., Schnabel, R., Schick, U. M., Nolte, I. M., Kraja, A., Hsu, Y.-H., Tylee, D. S., Zwicker, A., Uher, R., Davey-Smith, G., Morrison, A. C., Hicks, A., van Duijn, C. M., Ward-Caviness, C., Boerwinkle, E., Rotter, J., Rice, K., Lange, L., Perola, M., de Geus, E., Morris, A. P., Makela, K. M., Stacey, D., Eriksson, J., Frayling, T. M., and Slagboom, E. P.
• Subjects: R Medicine > R Medicine (General)
• College/School: College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Robertson Centre; College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: American Journal of Human Genetics
• Publisher: Elsevier (Cell Press)
• ISSN: 0002-9297
• ISSN (Online): 1537-6605