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 - Lifelines Cohort Study
AU - CHARGE Inflammation working group
AU - Ligthart, Symen
AU - Vaez, Ahmad
AU - Võsa, Urmo
AU - Stathopoulou, Maria G.
AU - de Vries, Paul S.
AU - Prins, Bram P.
AU - Van der Most, Peter J.
AU - Tanaka, Toshiko
AU - Naderi, Elnaz
AU - Rose, Lynda M.
AU - Wu, Ying
AU - Karlsson, Robert
AU - Barbalic, Maja
AU - Lin, Honghuang
AU - Pool, René
AU - Zhu, Gu
AU - Macé, Aurélien
AU - Sidore, Carlo
AU - Trompet, Stella
AU - Mangino, Massimo
AU - Sabater-Lleal, Maria
AU - Kemp, John P.
AU - Abbasi, Ali
AU - Kacprowski, Tim
AU - Verweij, Niek
AU - Smith, Albert V.
AU - Huang, Tao
AU - Marzi, Carola
AU - Feitosa, Mary F.
AU - Lohman, Kurt K.
AU - Kleber, Marcus E.
AU - Milaneschi, Yuri
AU - Mueller, Christian
AU - Huq, Mahmudul
AU - Vlachopoulou, Efthymia
AU - Lyytikäinen, Leo Pekka
AU - Oldmeadow, Christopher
AU - Deelen, Joris
AU - Perola, Markus
AU - Zhao, Jing Hua
AU - Feenstra, Bjarke
AU - Alizadeh, Behrooz Z.
AU - Boezen, H. Marike
AU - Franke, Lude
AU - van der Harst, Pim
AU - Navis, Gerjan
AU - Rots, Marianne
AU - Snieder, Harold
AU - Pankratz, Nathan D
AU - Gross, Myron D
N1 - Funding Information:
O.H.F. works at ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec Ltd.), Metagenics Inc., and AXA. Nestec Ltd., Metagenics Inc., and AXA had no role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review or approval of the manuscript. Bruce M. Psaty serves on the data and safety monitoring board of a clinical trial funded by Zoll LifeCor and on the steering committee of the Yale Open Data Access Project, funded by Johnson & Johnson.
Publisher Copyright:
© 2018 American Society of Human Genetics
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.
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.
KW - C-reactive protein
KW - DEPICT
KW - Mendelian randomization
KW - coronary artery disease
KW - genome-wide association study
KW - inflammation
KW - inflammatory disorders
KW - schizophrenia
KW - system biology
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U2 - 10.1016/j.ajhg.2018.09.009
DO - 10.1016/j.ajhg.2018.09.009
M3 - Article
C2 - 30388399
AN - SCOPUS:85055557317
SN - 0002-9297
VL - 103
SP - 691
EP - 706
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
ER -
