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

Andrew A. Brown; Juan J. Fernandez-Tajes; Mun-Gwan Hong; Caroline A. Brorsson; Robert W. Koivula; David Davtian; Théo Dupuis; Ambra Sartori; Theodora-Dafni Michalettou; Ian M. Forgie; Jonathan Adam; Kristine H. Allin; Robert Caiazzo; Henna Cederberg; Federico De Masi; Petra J. M. Elders; Giuseppe N. Giordano; Mark Haid; Torben Hansen; Tue H. Hansen; Andrew T. Hattersley; Alison J. Heggie; Cédric Howald; Angus G. Jones; Tarja Kokkola; Markku Laakso; Anubha Mahajan; Andrea Mari; Timothy J. McDonald; Donna McEvoy; Miranda Mourby; Petra B. Musholt; Birgitte Nilsson; Francois Pattou; Deborah Penet; Violeta Raverdy; Martin Ridderstråle; Luciana Romano; Femke Rutters; Sapna Sharma; Harriet Teare; Leen't Hart; Konstantinos D. Tsirigos; Jagadish Vangipurapu; Henrik Vestergaard; Søren Brunak; Paul W. Franks; Gary Frost; Harald Grallert; Bernd Jablonka; Mark McCarthy; Imre Pavo; Oluf Pedersen; Hartmut Ruetten; Mark Walker; The DIRECT consortium; Ewan R. Pearson; Emmanouil T. Dermitzakis; Ana Viñuela

doi:10.1038/s41467-023-40569-3

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

Andrew A. Brown, Juan J. Fernandez-Tajes, Mun-Gwan Hong, Caroline A. Brorsson, Robert W. Koivula, David Davtian, Théo Dupuis, Ambra Sartori, Theodora-Dafni Michalettou, Ian M. Forgie, Jonathan Adam, Kristine H. Allin, Robert Caiazzo, Henna Cederberg, Federico De Masi, Petra J. M. Elders, Giuseppe N. Giordano, Mark Haid, Torben Hansen, Tue H. HansenAndrew T. Hattersley, Alison J. Heggie, Cédric Howald, Angus G. Jones, Tarja Kokkola, Markku Laakso, Anubha Mahajan, Andrea Mari, Timothy J. McDonald, Donna McEvoy, Miranda Mourby, Petra B. Musholt, Birgitte Nilsson, Francois Pattou, Deborah Penet, Violeta Raverdy, Martin Ridderstråle, Luciana Romano, Femke Rutters, Sapna Sharma, Harriet Teare, Leen't Hart, Konstantinos D. Tsirigos, Jagadish Vangipurapu, Henrik Vestergaard, Søren Brunak, Paul W. Franks, Gary Frost, Harald Grallert, Bernd Jablonka, Mark McCarthy, Imre Pavo, Oluf Pedersen, Hartmut Ruetten, Mark Walker, The DIRECT consortium, Ewan R. Pearson, Emmanouil T. Dermitzakis (Lead / Corresponding author), Ana Viñuela (Lead / Corresponding author)

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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.

Original language	English
Article number	5062
Number of pages	17
Journal	Nature Communications
Volume	14
DOIs	https://doi.org/10.1038/s41467-023-40569-3
Publication status	Published - 21 Aug 2023

Keywords

Data integration
Genetics
Genetics research

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10.1038/s41467-023-40569-3Licence: CC BY

Final published versionFinal published version, 4.46 MBLicence: CC BY

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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., ... Viñuela, A. (2023). Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits. Nature Communications, 14, Article 5062. https://doi.org/10.1038/s41467-023-40569-3

@article{15d0cb91deb54f72bff5cb1cf931c6fa,

title = "Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits",

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.",

keywords = "Data integration, Genetics, Genetics research",

author = "Brown, {Andrew A.} and Fernandez-Tajes, {Juan J.} and Mun-Gwan Hong and Brorsson, {Caroline A.} and Koivula, {Robert W.} and David Davtian and Th{\'e}o Dupuis and Ambra Sartori and Theodora-Dafni Michalettou and Forgie, {Ian M.} and Jonathan Adam and Allin, {Kristine H.} and Robert Caiazzo and Henna Cederberg and {De Masi}, Federico and Elders, {Petra J. M.} and Giordano, {Giuseppe N.} and Mark Haid and Torben Hansen and Hansen, {Tue H.} and Hattersley, {Andrew T.} and Heggie, {Alison J.} and C{\'e}dric Howald and Jones, {Angus G.} and Tarja Kokkola and Markku Laakso and Anubha Mahajan and Andrea Mari and McDonald, {Timothy J.} and Donna McEvoy and Miranda Mourby and Musholt, {Petra B.} and Birgitte Nilsson and Francois Pattou and Deborah Penet and Violeta Raverdy and Martin Ridderstr{\aa}le and Luciana Romano and Femke Rutters and Sapna Sharma and Harriet Teare and Leen't Hart and Tsirigos, {Konstantinos D.} and Jagadish Vangipurapu and Henrik Vestergaard and S{\o}ren Brunak and Franks, {Paul W.} and Gary Frost and Harald Grallert and Bernd Jablonka and Mark McCarthy and Imre Pavo and Oluf Pedersen and Hartmut Ruetten and Mark Walker and {The DIRECT consortium} and Barnett, {Anna I.} and Louise Cabrelli and Dawed, {Adem Y.} and Louise Donnelly and Gwen Kennedy and Heather Loftus and Palmer, {Colin N.} and Pearson, {Ewan R.} and Dermitzakis, {Emmanouil T.} and Ana Vi{\~n}uela",

note = "Funding Information: 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{\textquoteright}s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies{\textquoteright} in kind contribution. Copyright: {\textcopyright} 2023 The Author(s).",

year = "2023",

month = aug,

day = "21",

doi = "10.1038/s41467-023-40569-3",

language = "English",

volume = "14",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

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, Ridderstråle, M, Romano, L, Rutters, F, Sharma, S, Teare, H, Hart, L, Tsirigos, KD, Vangipurapu, J, Vestergaard, H, Brunak, S, Franks, PW, Frost, G, Grallert, H, Jablonka, B, McCarthy, M, Pavo, I, Pedersen, O, Ruetten, H, Walker, M, The DIRECT consortium, Pearson, ER, Dermitzakis, ET & Viñuela, A 2023, 'Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits', Nature Communications, vol. 14, 5062. https://doi.org/10.1038/s41467-023-40569-3

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 - Hart, Leen't

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

AU - Pavo, Imre

AU - Pedersen, Oluf

AU - Ruetten, Hartmut

AU - Walker, Mark

AU - The DIRECT consortium

AU - Barnett, Anna I.

AU - Cabrelli, Louise

AU - Dawed, Adem Y.

AU - Donnelly, Louise

AU - Kennedy, Gwen

AU - Loftus, Heather

AU - Palmer, Colin N.

AU - Pearson, Ewan R.

AU - Dermitzakis, Emmanouil T.

AU - Viñuela, Ana

N1 - Funding Information: 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. Copyright: © 2023 The Author(s).

PY - 2023/8/21

Y1 - 2023/8/21

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.

KW - Data integration

KW - Genetics

KW - Genetics research

UR - http://www.scopus.com/inward/record.url?scp=85168454423&partnerID=8YFLogxK

U2 - 10.1038/s41467-023-40569-3

DO - 10.1038/s41467-023-40569-3

M3 - Article

C2 - 37604891

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

M1 - 5062

ER -

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

Abstract

Keywords

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DIRECT: Diabetes Research on Patient Stratification (joint with 25 other partners)

Cite this

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

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Projects

DIRECT: Diabetes Research on Patient Stratification (joint with 25 other partners)

Cite this