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

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.; 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, HHM; 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, PKE; 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, SJL; 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.I.; James, A.L.; Ruggiero, D.; Soranzo, N.; Hartman, C.A.; Smith, E.N.; Berenson, G.S.; Fuchsberger, C.; Hernandez, D.; Tiesler, CMT; 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, PAF; 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, EJCN; Heath, A.C.; Martin, N.G.; Auvinen, J.; Buckley, B.M.; de Craen, AJM; 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, BWJH; 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, RJF; 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.

doi:10.1016/j.ajhg.2018.09.009

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

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Serval ID

serval:BIB_26357D5FDD21

Type

Article: article from journal or magazin.

Collection

Publications

Institution

UNIL/CHUV

Title

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

Journal

American journal of human genetics

Author(s)

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., 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 HHM, 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 PKE, 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 SJL, 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.I., James A.L., Ruggiero D., Soranzo N., Hartman C.A., Smith E.N., Berenson G.S., Fuchsberger C., Hernandez D., Tiesler CMT, 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 PAF, 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 EJCN, Heath A.C., Martin N.G., Auvinen J., Buckley B.M., de Craen AJM, 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 BWJH, 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 RJF, 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.

Working group(s)

LifeLines Cohort Study, CHARGE Inflammation Working Group

Contributor(s)

Alizadeh B.Z., Boezen H.M., Franke L., van der Harst P., Navis G., Rots M., Snieder H., Swertz M., Wolffenbuttel BHR, 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., Slagboom E.P.

ISSN

1537-6605 (Electronic)

ISSN-L

0002-9297

Publication state

Published

Issued date

01/11/2018

Peer-reviewed

Oui

Volume

103

Number

Pages

691-706

Language

english

Notes

Publication types: Journal Article ; Meta-Analysis ; Research Support, Non-U.S. Gov't
Publication Status: ppublish

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 <sup>-8</sup> ). 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

Adolescent, Adult, Aged, Aged, 80 and over, Biomarkers/metabolism, Bipolar Disorder/genetics, Bipolar Disorder/metabolism, Body Mass Index, C-Reactive Protein/genetics, Child, Female, Genetic Loci/genetics, Genome-Wide Association Study/methods, Humans, Inflammation/genetics, Inflammation/metabolism, Liver/metabolism, Liver/pathology, Male, Mendelian Randomization Analysis/methods, Metabolic Networks and Pathways/genetics, Middle Aged, Schizophrenia/genetics, Schizophrenia/metabolism, Young Adult, C-reactive protein, DEPICT, Mendelian randomization, coronary artery disease, genome-wide association study, inflammation, inflammatory disorders, schizophrenia, system biology

OAI-PMH

oai:serval.unil.ch:BIB_26357D5FDD21

DOI

10.1016/j.ajhg.2018.09.009

Pubmed

30388399

Web of science

000448942100006

Open Access

Yes

Create date

15/11/2018 11:16