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

Ligthart, Symen; Vaez, Ahmad; Võsa, Urmo; Stathopoulou, Maria G; de Vries, Paul S; Prins, Bram P; Van der Most, Peter J; Tanaka, Toshiko; Naderi, Elnaz; Rose, Lynda M; Wu, Ying; Karlsson, Robert; Barbalic, Maja; Lin, Honghuang; Pool, René; Zhu, Gu; Macé, Aurélien; Sidore, Carlo; Trompet, Stella; Mangino, Massimo; ... (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. Cell Press 10.1016/j.ajhg.2018.09.009

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Social and Preventive Medicine

UniBE Contributor:

Franco Duran, Oscar Horacio

Subjects:

600 Technology > 610 Medicine & health
300 Social sciences, sociology & anthropology > 360 Social problems & social services

ISSN:

0002-9297

Publisher:

Cell Press

Language:

English

Submitter:

Tanya Karrer

Date Deposited:

16 Nov 2018 00:36

Last Modified:

19 Nov 2018 15:48

Publisher DOI:

10.1016/j.ajhg.2018.09.009

PubMed ID:

30388399

Uncontrolled Keywords:

C-reactive protein DEPICT Mendelian randomization coronary artery disease genome-wide association study inflammation inflammatory disorders schizophrenia system biology

BORIS DOI:

10.7892/boris.121276

URI:

https://boris.unibe.ch/id/eprint/121276

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