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Genome-wide association study identifies 16 genomic regions associated with circulating cytokines at birth

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Vis graf over relationer

Circulating inflammatory markers are essential to human health and disease, and they are often dysregulated or malfunctioning in cancers as well as in cardiovascular, metabolic, immunologic and neuropsychiatric disorders. However, the genetic contribution to the physiological variation of levels of circulating inflammatory markers is largely unknown. Here we report the results of a genome-wide genetic study of blood concentration of ten cytokines, including the hitherto unexplored calcium-binding protein (S100B). The study leverages a unique sample of neonatal blood spots from 9,459 Danish subjects from the iPSYCH initiative. We estimate the SNP-heritability of marker levels as ranging from essentially zero for Erythropoietin (EPO) up to 73% for S100B. We identify and replicate 16 associated genomic regions (p < 5 x 10 −9), of which four are novel. We show that the associated variants map to enhancer elements, suggesting a possible transcriptional effect of genomic variants on the cytokine levels. The identification of the genetic architecture underlying the basic levels of cytokines is likely to prompt studies investigating the relationship between cytokines and complex disease. Our results also suggest that the genetic architecture of cytokines is stable from neonatal to adult life.

TidsskriftPlos Genetics
Udgave nummer11
Sider (fra-til)e1009163
StatusUdgivet - nov. 2020

Bibliografisk note

Funding Information:
This study was supported by The Lundbeck Foundation (grant numbers R102-A9118, R155-2014-1724 and R268-2016-3925 and 278-2018-1411), Denmark, the Independent Research Fund Denmark (grant number 7025-00078B), the Stanley Medical Research Institute, an Advanced Grant from the European Research Council (project number 294838) and the Stanley Center for Psychiatric Research at Broad Institute and Centre for Integrated Register-based Research at Aarhus University (MEB,KS, iPSYCH-BROAD, DMH,PBM, TFH, and TW). WKT was in part supported by NIH grant R01GM104400. DL and SF were supported by a grant from LifeMap Sciences Inc. (Calfornia, USA). This research has been conducted using the Danish National Biobank resource, supported by the Novo Nordisk Foundation (SK and DMH). YW and OAA are supported by the Research Council of Norway (Dr. Wang through a FRIPRO Young Talented Grant (#302854) and a FRIPRO Mobility grant scheme (#251134)) and the UiO:Life Science Convergence Environment (4MENT). The FRIPRO Mobility grant scheme (FRICON) is co-funded by the European Union's Seventh Framework Programme for research, technological development and demonstration under Marie Curie grant agreement No. 608695. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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