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Lookup NU author(s): Dafni Michalettou, Dr Alison Heggie, Donna McEvoy, Professor Mark Walker, Dr Harshal Deshmukh, Dr Ana ViñuelaORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2023, Springer Nature Limited.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.
Author(s): Brown AA, Fernandez-Tajes JJ, Hong M-G, Brorsson CA, Koivula RW, Davtian D, Dupuis T, Sartori A, Michalettou T-D, Forgie IM, Adam J, Allin KH, Caiazzo R, Cederberg H, De Masi F, Elders PJM, Giordano GN, Haid M, Hansen T, Hansen TH, Hattersley AT, Heggie AJ, Howald C, Jones AG, Kokkola T, Laakso M, Mahajan A, Mari A, McDonald TJ, McEvoy D, Mourby M, Musholt PB, Nilsson B, Pattou F, Penet D, Raverdy V, Ridderstrale M, Romano L, Rutters F, Sharma S, Teare H, 't Hart L, Tsirigos KD, Vangipurapu J, Vestergaard H, Brunak S, Franks PW, Frost G, Grallert H, Jablonka B, McCarthy MI, Pavo I, Pedersen O, Ruetten H, Walker M, Adragni K, Allesoe RLL, Artati AA, Arumugam M, Atabaki-Pasdar N, Baltauss T, Banasik K, Barnett AL, Baum P, Bell JD, Beulens JW, Bianzano SB, Bizzotto R, Bonnefond A, Cabrelli L, Dale M, Dawed AY, de Preville N, Dekkers KF, Deshmukh HA, Dings C, Donnelly L, Dutta A, Ehrhardt B, Engelbrechtsen L, Eriksen R, Fan Y, Ferrer J, Fitipaldi H, Forman A, Fritsche A, Froguel P, Gassenhuber J, Gough S, Graefe-Mody U, Grempler R, Groeneveld L, Groop L, Gudmundsdottir V, Gupta R, Hennige AMH, Hill AV, Holl RW, Hudson M, Jacobsen UP, Jennison C, Johansen J, Jonsson A, Karaderi T, Kaye J, Kennedy G, Klintenberg M, Kuulasmaa T, Lehr T, Loftus H, Lundgaard ATT, Mazzoni G, McRobert N, McVittie I, Nice R, Nicolay C, Nijpels G, Palmer CN, Pedersen HK, Perry MH, Pomares-Millan H, Prehn CP, Ramisch A, Rasmussen S, Robertson N, Rodriquez M, Sackett P, Scherer N, Shah N, Sihinevich I, Slieker RC, Sondertoft NB, Steckel-Hamann B, Thomas MK, Thomas CEE, Thomas ELL, Thorand B, Thorne CE, Tillner J, Tura A, Uhlen M, van Leeuwen N, van Oort S, Verkindt H, Vogt J, Wad Sackett PW, Wesolowska-Andersen A, Whitcher B, White MW, Adamski J, Schwenk JM, Pearson ER, Dermitzakis ET, Vinuela A
Publication type: Article
Publication status: Published
Journal: Nature Communications
Year: 2023
Volume: 14
Issue: 1
Print publication date: 01/12/2023
Online publication date: 21/08/2023
Acceptance date: 02/08/2023
Date deposited: 25/09/2023
ISSN (electronic): 2041-1723
Publisher: Nature Research
URL: https://doi.org/10.1038/s41467-023-40569-3
DOI: 10.1038/s41467-023-40569-3
Data Access Statement: The molecular and clinical raw data as well as the processed are available under restricted access due to the informed consent given by study participants, the various national ethical approvals for the present study, and the European General Data Protection Regulation (GDPR), individual-level clinical and molecular data cannot be transferred from the centralized IMI-DIRECT repository. Requests for access will be informed on how data can be accessed via the DIRECT secure analysis platform following submission of an appropriate application. The IMI-DIRECT data access policy is available at https://directdiabetes.org. [Remainder of statement at https://doi.org/10.1038/s41467-023-40569-3]
PubMed id: 37604891
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