Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits
Authors: Brown Andrew A. , Fernandez-Tajes Juan J. , Hong Mun-gwan , Brorsson Caroline A. , Koivula Robert W. , Davtian David , Dupuis Théo , Sartori Ambra , Michalettou Theodora-Dafni , Forgie Ian M. , Adam Jonathan , Allin Kristine H. , Caiazzo Robert , Cederberg Henna , De Masi Federico , Elders Petra J. M. , Giordano Giuseppe N. , Haid Mark , Hansen Torben , Hansen Tue H. , Hattersley Andrew T. , Heggie Alison J. , Howald Cédric , Jones Angus G. , Kokkola Tarja , Laakso Markku , Mahajan Anubha , Mari Andrea , McDonald Timothy J. , McEvoy Donna , Mourby Miranda , Musholt Petra B. , Nilsson Birgitte , Pattou Francois , Penet Deborah , Raverdy Violeta , Ridderstråle Martin , Romano Luciana , Rutters Femke , Sharma Sapna , Teare Harriet , ‘t Hart Leen , Tsirigos Konstantinos D. , Vangipurapu Jagadish , Vestergaard Henrik , Brunak Søren , Franks Paul W. , Frost Gary , Grallert Harald , Jablonka Bernd , McCarthy Mark I. , Pavo Imre , Pedersen Oluf , Ruetten Hartmut , Walker Mark ,   The DIRECT Consortium, Adragni Kofi , Allesøe Rosa Lundbye L. , Artati Anna A. , Arumugam Manimozhiyan , Atabaki-Pasdar Naeimeh , Baltauss Tania , Banasik Karina , Barnett Anna L. , Baum Patrick , Bell Jimmy D. , Beulens Joline W. , Bianzano Susanna B. , Bizzotto Roberto , Bonnefond Amelie , Cabrelli Louise , Dale Matilda , Dawed Adem Y. , de Preville Nathalie , Dekkers Koen F. , Deshmukh Harshal A. , Dings Christiane , Donnelly Louise , Dutta Avirup , Ehrhardt Beate , Engelbrechtsen Line , Eriksen Rebeca , Fan Yong , Ferrer Jorge , Fitipaldi Hugo , Forman Annemette , Fritsche Andreas , Froguel Philippe , Gassenhuber Johann , Gough Stephen , Graefe-Mody Ulrike , Grempler Rolf , Groeneveld Lenka , Groop Leif , Gudmundsdóttir Valborg , Gupta Ramneek , Hennige Anita M. H. , Hill Anita V. , Holl Reinhard W. , Hudson Michelle , Jacobsen Ulrik Plesner , Jennison Christopher , Johansen Joachim , Jonsson Anna , Karaderi Tugce , Kaye Jane , Kennedy Gwen , Klintenberg Maria , Kuulasmaa Teemu , Lehr Thorsten , Loftus Heather , Lundgaard Agnete Troen T. , Mazzoni Gianluca , McRobert Nicky , McVittie Ian , Nice Rachel , Nicolay Claudia , Nijpels Giel , Palmer Colin N. , Pedersen Helle K. , Perry Mandy H. , Pomares-Millan Hugo , Prehn Cornelia P. , Ramisch Anna , Rasmussen Simon , Robertson Neil , Rodriquez Marianne , Sackett Peter , Scherer Nina , Shah Nisha , Sihinevich Iryna , Slieker Roderick C. , Sondertoft Nadja B. , Steckel-Hamann Birgit , Thomas Melissa K. , Thomas Cecilia Engel E. , Thomas Elizabeth Louise L. , Thorand Barbara , Thorne Claire E. , Tillner Joachim , Tura Andrea , Uhlen Mathias , van Leeuwen Nienke , van Oort Sabine , Verkindt Helene , Vogt Josef , Wad Sackett Peter W. , Wesolowska-Andersen Agata , Whitcher Brandon , White Margaret W. , Adamski Jerzy , Schwenk Jochen M. , Pearson Ewan R. , Dermitzakis Emmanouil T. , Viñuela Ana 
Published: August 2023

AbstractWe 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.