Abstract
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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 5062 |
| Tidsskrift | Nature Communications |
| Vol/bind | 14 |
| Antal sider | 17 |
| ISSN | 2041-1723 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:We are grateful to IMI-DIRECT study participants who volunteered for phenotyping, and clinical and technical staff across involved European study centres who contributed to recruitment and clinical assessment of study participants. The work leading to this publication has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement 115317 (DIRECT), resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. Information on the initiatives and activities of the IMI-DIRECT research consortium is available at https://directdiabetes.org .
Publisher Copyright:
© 2023, Springer Nature Limited.
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Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits. / 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; 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.
I: Nature Communications, Bind 14, 5062, 2023.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review
}
TY - JOUR
T1 - Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits
AU - Brown, Andrew A.
AU - Fernandez-Tajes, Juan J.
AU - Hong, Mun gwan
AU - Brorsson, Caroline A.
AU - Koivula, Robert W.
AU - Davtian, David
AU - Dupuis, Théo
AU - Sartori, Ambra
AU - Michalettou, Theodora Dafni
AU - Forgie, Ian M.
AU - Adam, Jonathan
AU - Allin, Kristine H.
AU - Caiazzo, Robert
AU - Cederberg, Henna
AU - De Masi, Federico
AU - Elders, Petra J.M.
AU - Giordano, Giuseppe N.
AU - Haid, Mark
AU - Hansen, Torben
AU - Hansen, Tue H.
AU - Hattersley, Andrew T.
AU - Heggie, Alison J.
AU - Howald, Cédric
AU - Jones, Angus G.
AU - Kokkola, Tarja
AU - Laakso, Markku
AU - Mahajan, Anubha
AU - Mari, Andrea
AU - McDonald, Timothy J.
AU - McEvoy, Donna
AU - Mourby, Miranda
AU - Musholt, Petra B.
AU - Nilsson, Birgitte
AU - Pattou, Francois
AU - Penet, Deborah
AU - Raverdy, Violeta
AU - Ridderstråle, Martin
AU - Romano, Luciana
AU - Rutters, Femke
AU - Sharma, Sapna
AU - Teare, Harriet
AU - ‘t Hart, Leen
AU - Tsirigos, Konstantinos D.
AU - Vangipurapu, Jagadish
AU - Vestergaard, Henrik
AU - Brunak, Søren
AU - Franks, Paul W.
AU - Frost, Gary
AU - Grallert, Harald
AU - Jablonka, Bernd
AU - McCarthy, Mark I.
AU - Pavo, Imre
AU - Pedersen, Oluf
AU - Ruetten, Hartmut
AU - Walker, Mark
AU - Adragni, Kofi
AU - Allesøe, Rosa Lundbye L.
AU - Artati, Anna A.
AU - Arumugam, Manimozhiyan
AU - Atabaki-Pasdar, Naeimeh
AU - Baltauss, Tania
AU - Banasik, Karina
AU - Barnett, Anna L.
AU - Baum, Patrick
AU - Bell, Jimmy D.
AU - Beulens, Joline W.
AU - Bianzano, Susanna B.
AU - Bizzotto, Roberto
AU - Bonnefond, Amelie
AU - Cabrelli, Louise
AU - Dale, Matilda
AU - Dawed, Adem Y.
AU - de Preville, Nathalie
AU - Dekkers, Koen F.
AU - Deshmukh, Harshal A.
AU - Dings, Christiane
AU - Donnelly, Louise
AU - Dutta, Avirup
AU - Ehrhardt, Beate
AU - Engelbrechtsen, Line
AU - Eriksen, Rebeca
AU - Fan, Yong
AU - Ferrer, Jorge
AU - Fitipaldi, Hugo
AU - Forman, Annemette
AU - Fritsche, Andreas
AU - Froguel, Philippe
AU - Gassenhuber, Johann
AU - Gough, Stephen
AU - Graefe-Mody, Ulrike
AU - Grempler, Rolf
AU - Groeneveld, Lenka
AU - Groop, Leif
AU - Gudmundsdóttir, Valborg
AU - Gupta, Ramneek
AU - Hennige, Anita M.H.
AU - Hill, Anita V.
AU - Holl, Reinhard W.
AU - Hudson, Michelle
AU - Jacobsen, Ulrik Plesner
AU - Jennison, Christopher
AU - Johansen, Joachim
AU - Jonsson, Anna
AU - Karaderi, Tugce
AU - Kaye, Jane
AU - Kennedy, Gwen
AU - Klintenberg, Maria
AU - Kuulasmaa, Teemu
AU - Lehr, Thorsten
AU - Loftus, Heather
AU - Lundgaard, Agnete Troen T.
AU - Mazzoni, Gianluca
AU - McRobert, Nicky
AU - McVittie, Ian
AU - Nice, Rachel
AU - Nicolay, Claudia
AU - Nijpels, Giel
AU - Palmer, Colin N.
AU - Pedersen, Helle K.
AU - Perry, Mandy H.
AU - Pomares-Millan, Hugo
AU - Prehn, Cornelia P.
AU - Ramisch, Anna
AU - Rasmussen, Simon
AU - Robertson, Neil
AU - Rodriquez, Marianne
AU - Sackett, Peter
AU - Scherer, Nina
AU - Shah, Nisha
AU - Sihinevich, Iryna
AU - Slieker, Roderick C.
AU - Sondertoft, Nadja B.
AU - Steckel-Hamann, Birgit
AU - Thomas, Melissa K.
AU - Thomas, Cecilia Engel E.
AU - Thomas, Elizabeth Louise L.
AU - Thorand, Barbara
AU - Thorne, Claire E.
AU - Tillner, Joachim
AU - Tura, Andrea
AU - Uhlen, Mathias
AU - van Leeuwen, Nienke
AU - van Oort, Sabine
AU - Verkindt, Helene
AU - Vogt, Josef
AU - Wad Sackett, Peter W.
AU - Wesolowska-Andersen, Agata
AU - Whitcher, Brandon
AU - White, Margaret W.
AU - Adamski, Jerzy
AU - Schwenk, Jochen M.
AU - Pearson, Ewan R.
AU - Dermitzakis, Emmanouil T.
AU - Viñuela, Ana
N1 - Publisher Copyright: © 2023, Springer Nature Limited.
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-023-40569-3
DO - 10.1038/s41467-023-40569-3
M3 - Journal article
C2 - 37604891
AN - SCOPUS:85168454423
VL - 14
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 5062
ER -