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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| 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. |
| Year of Publication | 2018
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| Journal | Am J Hum Genet
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| Volume | 103
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| Issue | 5
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| Pages | 691-706
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| Date Published | 2018 Nov 01
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| ISSN | 1537-6605
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| DOI | 10.1016/j.ajhg.2018.09.009
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| PubMed ID | 30388399
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| PubMed Central ID | PMC6218410
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| Grant list | R01 HL120393 / HL / NHLBI NIH HHS / United States
U01 HL130114 / HL / NHLBI NIH HHS / United States
MC_UU_00011/1 / MRC_ / Medical Research Council / United Kingdom
P30 AG049638 / AG / NIA NIH HHS / United States
MR/K002414/1 / MRC_ / Medical Research Council / United Kingdom
MC_UP_1605/7 / MRC_ / Medical Research Council / United Kingdom
G9815508 / MRC_ / Medical Research Council / United Kingdom
MC_UU_12013/4 / MRC_ / Medical Research Council / United Kingdom
BB/F019394/1 / BB_ / Biotechnology and Biological Sciences Research Council / United Kingdom
MR/J012165/1 / MRC_ / Medical Research Council / United Kingdom
MC_UU_12015/1 / MRC_ / Medical Research Council / United Kingdom
U01 HL120393 / HL / NHLBI NIH HHS / United States
R01 DK072193 / DK / NIDDK NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
MC_PC_15018 / MRC_ / Medical Research Council / United Kingdom
MC_UU_00007/10 / MRC_ / Medical Research Council / United Kingdom
U01 DK062370 / DK / NIDDK NIH HHS / United States
P30 DK020572 / DK / NIDDK NIH HHS / United States
S10 OD020069 / OD / NIH HHS / United States
P30 AG010129 / AG / NIA NIH HHS / United States
R01 HL141399 / HL / NHLBI NIH HHS / United States
MR/K026992/1 / MRC_ / Medical Research Council / United Kingdom
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