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Brown, A.A.* ; Fernandez-Tajes, J.J.* ; Hong, M.G.* ; Brorsson, C.A.* ; Koivula, R.W.* ; Davtian, D.* ; Dupuis, T.* ; Sartori, A.* ; Michalettou, T.D.* ; Forgie, I.M.* ; Adam, J. ; Allin, K.H.* ; Caiazzo, R.* ; Cederberg, H.* ; De Masi, F.* ; Elders, P.J.M.* ; Giordano, G.N.* ; Haid, M. ; Hansen, T.* ; Hansen, T.H.* ; Hattersley, A.T.* ; Heggie, A.J.* ; Howald, C.* ; Jones, A.G.* ; Kokkola, T.* ; Laakso, M.* ; Mahajan, A.* ; Mari, A.* ; McDonald, T.J.* ; McEvoy, D.* ; Mourby, M.* ; Musholt, P.B.* ; Nilsson, B.* ; Pattou, F.* ; Penet, D.* ; Raverdy, V.* ; Ridderstråle, M.* ; Romano, L.* ; Rutters, F.* ; Sharma, S. ; Teare, H.* ; 't Hart, L.* ; Tsirigos, K.D.* ; Vangipurapu, J.* ; Vestergaard, H.* ; Brunak, S.* ; Franks, P.W.* ; Frost, G.* ; Grallert, H. ; Jablonka, B.* ; McCarthy, M.I.* ; Pavo, I.* ; Pedersen, O.* ; Ruetten, H.* ; Walker, M.* ; Adamski, J. ; Schwenk, J.M.* ; Pearson, E.R.* ; Dermitzakis, E.T.* ; Viñuela, A.* ; DIRECT Consortium (Thorand, B. ; Fritsche, A. ; Artati, A. ; Prehn, C.)

Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits.

Nat. Commun. 14:5062 (2023)

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Open Access Gold as soon as Publ. Version/Full Text is submitted to ZB.

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We evaluate the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant associates with multiple molecular phenotypes over multiple genomic regions. The highest proportion of share genetic regulation is detected between gene expression and proteins (66.6%), with a further median shared genetic associations across 49 different tissues of 78.3% and 62.4% between plasma proteins and gene expression. We represent the genetic and molecular associations in networks including 2828 known GWAS variants, showing that GWAS variants are more often connected to gene expression in trans than other molecular phenotypes in the network. Our work provides a roadmap to understanding molecular networks and deriving the underlying mechanism of action of GWAS variants using different molecular phenotypes in an accessible tissue.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Multi-omics; Variants; Disease; Associations; Expression; Discovery; Thousands; Tissues; Models; Mapper

ISSN (print) / ISBN 2041-1723

e-ISSN 2041-1723

Journal Nature Communications

Quellenangaben Volume: 14, Issue: 1, Article Number: 5062

Publisher Nature Publishing Group

Publishing Place London

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Epidemiology II (EPI2)
CF Metabolomics & Proteomics (CF-MPC)
Institute of Experimental Genetics (IEG)
Institute of Diabetes Research and Metabolic Diseases (IDM)

Grants European Union
Innovative Medicines Initiative Joint Undertaking