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; C. dric 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; S. ren Brunak; Paul W. Franks; Gary Frost; Harald Grallert; Bernd Jablonka; Mark I. McCarthy; Imre Pavo; Oluf Pedersen; Hartmut Ruetten; Mark Walker; Kofi Adragni; Rosa Lundbye L. Allesøe; Anna A. Artati; Manimozhiyan Arumugam; Naeimeh Atabaki-Pasdar; Tania Baltauss; Karina Banasik; Anna L. Barnett; Patrick Baum; Jimmy D. Bell; Joline W. Beulens; Susanna B. Bianzano; Roberto Bizzotto; Amelie Bonnefond; Louise Cabrelli; Matilda Dale; Adem Y. Dawed; Nathalie de Preville; Koen F. Dekkers; Harshal A. Deshmukh; Christiane Dings; Louise Donnelly; Avirup Dutta; Beate Ehrhardt; Line Engelbrechtsen; Rebeca Eriksen; Yong Fan; Jorge Ferrer; Hugo Fitipaldi; Annemette Forman; Andreas Fritsche; Philippe Froguel; Johann Gassenhuber; Stephen Gough; Ulrike Graefe-Mody; Rolf Grempler; Lenka Groeneveld; Leif Groop; Valborg Gudmundsdóttir; Ramneek Gupta; Anita M. H. Hennige; Anita V. Hill; Reinhard W. Holl; Michelle Hudson; Ulrik Plesner Jacobsen; Christopher Jennison; Joachim Johansen; Anna Jonsson; Tugce Karaderi; Jane Kaye; Gwen Kennedy; Maria Klintenberg; Teemu Kuulasmaa; Thorsten Lehr; Heather Loftus; Agnete Troen T. Lundgaard; Gianluca Mazzoni; Nicky McRobert; Ian McVittie; Rachel Nice; Claudia Nicolay; Giel Nijpels; Colin N. Palmer; Helle K. Pedersen; Mandy H. Perry; Hugo Pomares-Millan; Cornelia P. Prehn; Anna Ramisch; Simon Rasmussen; Neil Robertson; Marianne Rodriquez; Peter Sackett; Nina Scherer; Nisha Shah; Iryna Sihinevich; Roderick C. Slieker; Nadja B. Sondertoft; Birgit Steckel-Hamann; Melissa K. Thomas; Cecilia Engel E. Thomas; Elizabeth Louise L. Thomas; Barbara Thorand; Claire E. Thorne; Joachim Tillner; Andrea Tura; Mathias Uhlen; Nienke van Leeuwen; Sabine van Oort; Helene Verkindt; Josef Vogt; Peter W. Wad Sackett; Agata Wesolowska-Andersen; Brandon Whitcher; Margaret W. White; Jerzy Adamski; Jochen M. Schwenk; Ewan R. Pearson; Emmanouil T. Dermitzakis; Ana Viñuela

doi:https://doi.org/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, C. dric 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, S. ren Brunak, Paul W. Franks, Gary Frost, Harald Grallert, Bernd Jablonka, Mark I. McCarthy, Imre Pavo, Oluf Pedersen, Hartmut Ruetten, Mark Walker, Kofi Adragni, Rosa Lundbye L. Allesøe, Anna A. Artati, Manimozhiyan Arumugam, Naeimeh Atabaki-Pasdar, Tania Baltauss, Karina Banasik, Anna L. Barnett, Patrick Baum, Jimmy D. Bell, Joline W. Beulens, Susanna B. Bianzano, Roberto Bizzotto, Amelie Bonnefond, Louise Cabrelli, Matilda Dale, Adem Y. Dawed, Nathalie de Preville, Koen F. Dekkers, Harshal A. Deshmukh, Christiane Dings, Louise Donnelly, Avirup Dutta, Beate Ehrhardt, Line Engelbrechtsen, Rebeca Eriksen, Yong Fan, Jorge Ferrer, Hugo Fitipaldi, Annemette Forman, Andreas Fritsche, Philippe Froguel, Johann Gassenhuber, Stephen Gough, Ulrike Graefe-Mody, Rolf Grempler, Lenka Groeneveld, Leif Groop, Valborg Gudmundsdóttir, Ramneek Gupta, Anita M. H. Hennige, Anita V. Hill, Reinhard W. Holl, Michelle Hudson, Ulrik Plesner Jacobsen, Christopher Jennison, Joachim Johansen, Anna Jonsson, Tugce Karaderi, Jane Kaye, Gwen Kennedy, Maria Klintenberg, Teemu Kuulasmaa, Thorsten Lehr, Heather Loftus, Agnete Troen T. Lundgaard, Gianluca Mazzoni, Nicky McRobert, Ian McVittie, Rachel Nice, Claudia Nicolay, Giel Nijpels, Colin N. Palmer, Helle K. Pedersen, Mandy H. Perry, Hugo Pomares-Millan, Cornelia P. Prehn, Anna Ramisch, Simon Rasmussen, Neil Robertson, Marianne Rodriquez, Peter Sackett, Nina Scherer, Nisha Shah, Iryna Sihinevich, Roderick C. Slieker, Nadja B. Sondertoft, Birgit Steckel-Hamann, Melissa K. Thomas, Cecilia Engel E. Thomas, Elizabeth Louise L. Thomas, Barbara Thorand, Claire E. Thorne, Joachim Tillner, Andrea Tura, Mathias Uhlen, Nienke van Leeuwen, Sabine van Oort, Helene Verkindt, Josef Vogt, Peter W. Wad Sackett, Agata Wesolowska-Andersen, Brandon Whitcher, Margaret W. White, Jerzy Adamski, Jochen M. Schwenk, Ewan R. Pearson, Emmanouil T. Dermitzakis, Ana Viñuela

Research output: Contribution to journal › Article › Academic › peer-review

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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
Journal	Nature communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-40569-3
Publication status	Published - 1 Dec 2023

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https://doi.org/10.1038/s41467-023-40569-3

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Brown, A. A., Fernandez-Tajes, J. J., Hong, M., 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(1), Article 5062. https://doi.org/10.1038/s41467-023-40569-3

@article{2cf16c4276604a408f4008414a829d87,

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.",

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 Howald, {C. dric} 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 {{\textquoteleft}t Hart}, Leen and Tsirigos, {Konstantinos D.} and Jagadish Vangipurapu and Henrik Vestergaard and Brunak, {S. ren} and Franks, {Paul W.} and Gary Frost and Harald Grallert and Bernd Jablonka and McCarthy, {Mark I.} and Imre Pavo and Oluf Pedersen and Hartmut Ruetten and Mark Walker and Kofi Adragni and Alles{\o}e, {Rosa Lundbye L.} and Artati, {Anna A.} and Manimozhiyan Arumugam and Naeimeh Atabaki-Pasdar and Tania Baltauss and Karina Banasik and Barnett, {Anna L.} and Patrick Baum and Bell, {Jimmy D.} and Beulens, {Joline W.} and Bianzano, {Susanna B.} and Roberto Bizzotto and Amelie Bonnefond and Louise Cabrelli and Matilda Dale and Dawed, {Adem Y.} and {de Preville}, Nathalie and Dekkers, {Koen F.} and Deshmukh, {Harshal A.} and Christiane Dings and Louise Donnelly and Avirup Dutta and Beate Ehrhardt and Line Engelbrechtsen and Rebeca Eriksen and Yong Fan and Jorge Ferrer and Hugo Fitipaldi and Annemette Forman and Andreas Fritsche and Philippe Froguel and Johann Gassenhuber and Stephen Gough and Ulrike Graefe-Mody and Rolf Grempler and Lenka Groeneveld and Leif Groop and Valborg Gudmundsd{\'o}ttir and Ramneek Gupta and Hennige, {Anita M. H.} and Hill, {Anita V.} and Holl, {Reinhard W.} and Michelle Hudson and Jacobsen, {Ulrik Plesner} and Christopher Jennison and Joachim Johansen and Anna Jonsson and Tugce Karaderi and Jane Kaye and Gwen Kennedy and Maria Klintenberg and Teemu Kuulasmaa and Thorsten Lehr and Heather Loftus and Lundgaard, {Agnete Troen T.} and Gianluca Mazzoni and Nicky McRobert and Ian McVittie and Rachel Nice and Claudia Nicolay and Giel Nijpels and Palmer, {Colin N.} and Pedersen, {Helle K.} and Perry, {Mandy H.} and Hugo Pomares-Millan and Prehn, {Cornelia P.} and Anna Ramisch and Simon Rasmussen and Neil Robertson and Marianne Rodriquez and Peter Sackett and Nina Scherer and Nisha Shah and Iryna Sihinevich and Slieker, {Roderick C.} and Sondertoft, {Nadja B.} and Birgit Steckel-Hamann and Thomas, {Melissa K.} and Thomas, {Cecilia Engel E.} and Thomas, {Elizabeth Louise L.} and Barbara Thorand and Thorne, {Claire E.} and Joachim Tillner and Andrea Tura and Mathias Uhlen and {van Leeuwen}, Nienke and {van Oort}, Sabine and Helene Verkindt and Josef Vogt and {Wad Sackett}, {Peter W.} and Agata Wesolowska-Andersen and Brandon Whitcher and White, {Margaret W.} and Jerzy Adamski and Schwenk, {Jochen M.} and Pearson, {Ewan R.} and Dermitzakis, {Emmanouil T.} and Ana Vi{\~n}uela",

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{\textquoteright}s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies{\textquoteright} in kind contribution. Information on the initiatives and activities of the IMI-DIRECT research consortium is available at https://directdiabetes.org . Publisher Copyright: {\textcopyright} 2023, Springer Nature Limited.",

year = "2023",

month = dec,

day = "1",

doi = "https://doi.org/10.1038/s41467-023-40569-3",

language = "English",

volume = "14",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Brown, AA, Fernandez-Tajes, JJ, Hong, M, 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, CD, 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, ‘t Hart, L, Tsirigos, KD, Vangipurapu, J, Vestergaard, H, Brunak, SR, Franks, PW, Frost, G, Grallert, H, Jablonka, B, McCarthy, MI, Pavo, I, Pedersen, O, Ruetten, H, Walker, M, Adragni, K, Allesøe, 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, Gudmundsdóttir, 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 & Viñuela, A 2023, 'Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits', Nature communications, vol. 14, no. 1, 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, C. dric

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, S. ren

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 - 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.

PY - 2023/12/1

Y1 - 2023/12/1

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.

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

U2 - https://doi.org/10.1038/s41467-023-40569-3

DO - https://doi.org/10.1038/s41467-023-40569-3

M3 - Article

C2 - 37604891

SN - 2041-1723

VL - 14

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 5062

ER -

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

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