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

CHARGE Inflammation Working Group; LifeLines Cohort Study; L.M. Rose; Y. Wu; H. Lin; A. Macé; A. Abbasi; A.V. Smith; C. Mueller; J.H. Zhao; M. Amini; J.F. Wilson; Y. Jamshidi; R. Uher; A. Hicks; A.P. Morris; D. Stacey; J. Eriksson; W.-M. Chen; X. Li; Y.-C. Cheng; J.H. Zhao; H. Huang; Y. Liu; J. Huang; P.K. Joshi; B. Lehne; D.J. Stott; C. Menni; A. Peters; J.H. Smit; S.R. Williams; H. Campbell; Y.-D.I. Chen; A.L. James; E.N. Smith; A. Larsson; Y. Wang; W.R. Scott; D.M. Evans; P.A.F. Madden; G. Lachance; R. Clarke; T.B. Harris; R.A. Scott; A. Hicks; J.Z. Li; J.C. Chambers; N.G. Martin; R.A. Scott; J.B. Whitfield; T.D. Spector; J. Eriksson; J.F. Wilson; L.J. Palmer; S.S. Murray; D.M. Evans; H. Schmidt; G.D. Smith

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

CHARGE Inflammation Working Group, LifeLines Cohort Study, L.M. Rose, Y. Wu, H. Lin, A. Macé, A. Abbasi, A.V. Smith, C. Mueller, J.H. Zhao, M. Amini, J.F. Wilson, Y. Jamshidi, R. Uher, A. Hicks, A.P. Morris, D. Stacey, J. Eriksson, W.-M. Chen, X. LiY.-C. Cheng, J.H. Zhao, H. Huang, Y. Liu, J. Huang, P.K. Joshi, B. Lehne, D.J. Stott, C. Menni, A. Peters, J.H. Smit, S.R. Williams, H. Campbell, Y.-D.I. Chen, A.L. James, E.N. Smith, A. Larsson, Y. Wang, W.R. Scott, D.M. Evans, P.A.F. Madden, G. Lachance, R. Clarke, T.B. Harris, R.A. Scott, A. Hicks, J.Z. Li, J.C. Chambers, N.G. Martin, R.A. Scott, J.B. Whitfield, T.D. Spector, J. Eriksson, J.F. Wilson, L.J. Palmer, S.S. Murray, D.M. Evans, H. Schmidt, G.D. Smith

Twin Research & Genetic Epidemiology

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266 Citations (Scopus)

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. © 2018 American Society of Human Genetics

Original language	English
Pages (from-to)	691-706
Number of pages	16
Journal	American Journal of Human Genetics
Volume	103
Issue number	5
Early online date	1 Nov 2018
DOIs	https://doi.org/10.1016/j.ajhg.2018.09.009
Publication status	Published - 1 Nov 2018

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CHARGE Inflammation Working Group, LifeLines Cohort Study, Rose, L. M., Wu, Y., Lin, H., Macé, A., Abbasi, A., Smith, A. V., Mueller, C., Zhao, J. H., Amini, M., Wilson, J. F., Jamshidi, Y., Uher, R., Hicks, A., Morris, A. P., Stacey, D., Eriksson, J., Chen, W.-M., ... Smith, G. D. (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), 691-706. https://doi.org/10.1016/j.ajhg.2018.09.009

@article{94fedafe318c4177a84f0d67ca37e254,

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

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. {\textcopyright} 2018 American Society of Human Genetics",

author = "{CHARGE Inflammation Working Group} and {LifeLines Cohort Study} and L.M. Rose and Y. Wu and H. Lin and A. Mac{\'e} and A. Abbasi and A.V. Smith and C. Mueller and J.H. Zhao and M. Amini and J.F. Wilson and Y. Jamshidi and R. Uher and A. Hicks and A.P. Morris and D. Stacey and J. Eriksson and W.-M. Chen and X. Li and Y.-C. Cheng and J.H. Zhao and H. Huang and Y. Liu and J. Huang and P.K. Joshi and B. Lehne and D.J. Stott and C. Menni and A. Peters and J.H. Smit and S.R. Williams and H. Campbell and Y.-D.I. Chen and A.L. James and E.N. Smith and A. Larsson and Y. Wang and W.R. Scott and D.M. Evans and P.A.F. Madden and G. Lachance and R. Clarke and T.B. Harris and R.A. Scott and A. Hicks and J.Z. Li and J.C. Chambers and N.G. Martin and R.A. Scott and J.B. Whitfield and T.D. Spector and J. Eriksson and J.F. Wilson and L.J. Palmer and S.S. Murray and D.M. Evans and H. Schmidt and G.D. Smith",

year = "2018",

month = nov,

day = "1",

doi = "10.1016/j.ajhg.2018.09.009",

language = "English",

volume = "103",

pages = "691--706",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Elsevier",

number = "5",

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CHARGE Inflammation Working Group, LifeLines Cohort Study, Rose, LM, Wu, Y, Lin, H, Macé, A, Abbasi, A, Smith, AV, Mueller, C, Zhao, JH, Amini, M, Wilson, JF, Jamshidi, Y, Uher, R, Hicks, A, Morris, AP, Stacey, D, Eriksson, J, Chen, W-M, Li, X, Cheng, Y-C, Zhao, JH, Huang, H, Liu, Y, Huang, J, Joshi, PK, Lehne, B, Stott, DJ, Menni, C, Peters, A, Smit, JH, Williams, SR, Campbell, H, Chen, Y-DI, James, AL, Smith, EN, Larsson, A, Wang, Y, Scott, WR, Evans, DM, Madden, PAF, Lachance, G, Clarke, R, Harris, TB, Scott, RA, Hicks, A, Li, JZ, Chambers, JC, Martin, NG, Scott, RA, Whitfield, JB, Spector, TD, Eriksson, J, Wilson, JF, Palmer, LJ, Murray, SS, Evans, DM, Schmidt, H & Smith, GD 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, vol. 103, no. 5, pp. 691-706. https://doi.org/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. / CHARGE Inflammation Working Group; LifeLines Cohort Study; Rose, L.M. et al.
In: American Journal of Human Genetics, Vol. 103, No. 5, 01.11.2018, p. 691-706.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders

AU - CHARGE Inflammation Working Group

AU - LifeLines Cohort Study

AU - Rose, L.M.

AU - Wu, Y.

AU - Lin, H.

AU - Macé, A.

AU - Abbasi, A.

AU - Smith, A.V.

AU - Mueller, C.

AU - Zhao, J.H.

AU - Amini, M.

AU - Wilson, J.F.

AU - Jamshidi, Y.

AU - Uher, R.

AU - Hicks, A.

AU - Morris, A.P.

AU - Stacey, D.

AU - Eriksson, J.

AU - Chen, W.-M.

AU - Li, X.

AU - Cheng, Y.-C.

AU - Zhao, J.H.

AU - Huang, H.

AU - Liu, Y.

AU - Huang, J.

AU - Joshi, P.K.

AU - Lehne, B.

AU - Stott, D.J.

AU - Menni, C.

AU - Peters, A.

AU - Smit, J.H.

AU - Williams, S.R.

AU - Campbell, H.

AU - Chen, Y.-D.I.

AU - James, A.L.

AU - Smith, E.N.

AU - Larsson, A.

AU - Wang, Y.

AU - Scott, W.R.

AU - Evans, D.M.

AU - Madden, P.A.F.

AU - Lachance, G.

AU - Clarke, R.

AU - Harris, T.B.

AU - Scott, R.A.

AU - Hicks, A.

AU - Li, J.Z.

AU - Chambers, J.C.

AU - Martin, N.G.

AU - Scott, R.A.

AU - Whitfield, J.B.

AU - Spector, T.D.

AU - Eriksson, J.

AU - Wilson, J.F.

AU - Palmer, L.J.

AU - Murray, S.S.

AU - Evans, D.M.

AU - Schmidt, H.

AU - Smith, G.D.

PY - 2018/11/1

Y1 - 2018/11/1

N2 - 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. © 2018 American Society of Human Genetics

AB - 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. © 2018 American Society of Human Genetics

U2 - 10.1016/j.ajhg.2018.09.009

DO - 10.1016/j.ajhg.2018.09.009

M3 - Article

SN - 0002-9297

VL - 103

SP - 691

EP - 706

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 5

ER -

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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