Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation

Josine L. Min; Jenny van Dongen; Jouke Jan Hottenga; Gonneke Willemsen; Eco J.C. de Geus; Dorret I. Boomsma; Caroline L. Relton; BIOS Consortium

doi:10.1038/s41588-021-00923-x

Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation

Josine L. Min^*, Jenny van Dongen, Jouke Jan Hottenga, Gonneke Willemsen, Eco J.C. de Geus, Dorret I. Boomsma, Caroline L. Relton, BIOS Consortium

^*Corresponding author for this work

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

31 Downloads (Pure)

Abstract

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15–17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype–phenotype map than previously anticipated.

Original language	English
Pages (from-to)	1311-1321
Number of pages	11
Journal	Nature genetics
Volume	53
Issue number	9
Early online date	6 Sept 2021
DOIs	https://doi.org/10.1038/s41588-021-00923-x
Publication status	Published - Sept 2021

Bibliographical note

Funding Information:
C.L.R., G.D.S., G.S., J.L.M., K.B., M. Suderman, T.G.R. and T.R.G. are supported by the UK Medical Research Council (MRC) Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/1, MC_UU_00011/4, MC_UU_00011/5). C.L.R. receives support from a Cancer Research UK Programme grant (no. C18281/A191169). G.H. is funded by the Wellcome Trust and the Royal Society (208806/Z/17/Z). E.H. and J.M. were supported by MRC project grants (nos. MR/K013807/1 and MR/R005176/1 to J.M.) and an MRC Clinical Infrastructure award (no. MR/M008924/1 to J.M.). B.T.H. is supported by the Netherlands CardioVascular Research Initiative (the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development, and the Royal Netherlands Academy of Sciences) for the GENIUS project ‘Generating the best evidence-based pharmaceutical targets for atherosclerosis’ (CVON2011-19, CVON2017-20). J.T.B. was supported by the Economic and Social Research Council (grant no. ES/N000404/1). The present study was also supported by JPI HDHL-funded DIMENSION project (administered by the BBSRC UK, grant no. BB/S020845/1 to J.T.B., and by ZonMW the Netherlands, grant no. 529051021 to B.T.H). A.D.B. has been supported by a Wellcome Trust PhD Training Fellowship for Clinicians and the Edinburgh Clinical Academic Track programme (204979/Z/16/Z). J. Klughammer was supported by a DOC fellowship of the Austrian Academy of Sciences. Cohort-specific acknowledgements and funding are presented in the Supplementary Note.

Funding Information:
T.R.G. receives funding from GlaxoSmithKline and Biogen for unrelated research. The other authors declare no competing interests.

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

Funding

C.L.R., G.D.S., G.S., J.L.M., K.B., M. Suderman, T.G.R. and T.R.G. are supported by the UK Medical Research Council (MRC) Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/1, MC_UU_00011/4, MC_UU_00011/5). C.L.R. receives support from a Cancer Research UK Programme grant (no. C18281/A191169). G.H. is funded by the Wellcome Trust and the Royal Society (208806/Z/17/Z). E.H. and J.M. were supported by MRC project grants (nos. MR/K013807/1 and MR/R005176/1 to J.M.) and an MRC Clinical Infrastructure award (no. MR/M008924/1 to J.M.). B.T.H. is supported by the Netherlands CardioVascular Research Initiative (the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development, and the Royal Netherlands Academy of Sciences) for the GENIUS project ‘Generating the best evidence-based pharmaceutical targets for atherosclerosis’ (CVON2011-19, CVON2017-20). J.T.B. was supported by the Economic and Social Research Council (grant no. ES/N000404/1). The present study was also supported by JPI HDHL-funded DIMENSION project (administered by the BBSRC UK, grant no. BB/S020845/1 to J.T.B., and by ZonMW the Netherlands, grant no. 529051021 to B.T.H). A.D.B. has been supported by a Wellcome Trust PhD Training Fellowship for Clinicians and the Edinburgh Clinical Academic Track programme (204979/Z/16/Z). J. Klughammer was supported by a DOC fellowship of the Austrian Academy of Sciences. Cohort-specific acknowledgements and funding are presented in the Supplementary Note. T.R.G. receives funding from GlaxoSmithKline and Biogen for unrelated research. The other authors declare no competing interests.

Funders	Funder number
BBSRC UK
Dutch Heart Foundation
Netherlands CardioVascular Research Initiative
Koninklijke Nederlandse Akademie van Wetenschappen	CVON2017-20, CVON2011-19
GlaxoSmithKline
Biogen
Wellcome Trust	208806/Z/17/Z, 204979/Z/16/Z
Medical Research Council	MC_UU_00011/4, MC_UU_00011/1, MR/K013807/1, MR/M008924/1, MR/L501529/1, MR/R005176/1, MC_UU_00011/5
Biotechnology and Biological Sciences Research Council	BB/S020845/1
Economic and Social Research Council	ES/N000404/1
Royal Society
Cancer Research UK	C18281/A191169
University of Bristol
Österreichischen Akademie der Wissenschaften	doc fellowship
ZonMw	529051021
Nederlandse Federatie van Universitair Medische Centra

Access to Document

10.1038/s41588-021-00923-x

Genomic and phenotypic insights from an atlas of genetic effects on DNA methylationFinal published version, 10.5 MBLicence: Article 25fa Dutch Copyright Act

Persistent URL (handle)

Persistent link

Cite this

@article{4d409b94e1574dd8ae4af8b4b180320f,

title = "Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation",

abstract = "Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15–17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype–phenotype map than previously anticipated.",

author = "Min, {Josine L.} and Gibran Hemani and Eilis Hannon and Dekkers, {Koen F.} and Juan Castillo-Fernandez and Ren{\'e} Luijk and Elena Carnero-Montoro and Lawson, {Daniel J.} and Kimberley Burrows and Matthew Suderman and Bretherick, {Andrew D.} and Richardson, {Tom G.} and Johanna Klughammer and Valentina Iotchkova and Gemma Sharp and {Al Khleifat}, Ahmad and Aleksey Shatunov and Alfredo Iacoangeli and McArdle, {Wendy L.} and Ho, {Karen M.} and Ashish Kumar and Cilla S{\"o}derh{\"a}ll and Carolina Soriano-T{\'a}rraga and Eva Giralt-Steinhauer and Nabila Kazmi and Dan Mason and McRae, {Allan F.} and Corcoran, {David L.} and Karen Sugden and Silva Kasela and Alexia Cardona and Day, {Felix R.} and Giovanni Cugliari and Clara Viberti and Simonetta Guarrera and Michael Lerro and Richa Gupta and Sailalitha Bollepalli and Pooja Mandaviya and Yanni Zeng and Clarke, {Toni Kim} and Walker, {Rosie M.} and Vanessa Schmoll and Darina Czamara and Carlos Ruiz-Arenas and Rezwan, {Faisal I.} and Marioni, {Riccardo E.} and Tian Lin and Yvonne Awaloff and Marine Germain and Dylan A{\"i}ssi and Ramona Zwamborn and {van Eijk}, Kristel and Annelot Dekker and {van Dongen}, Jenny and Hottenga, {Jouke Jan} and Gonneke Willemsen and Xu, {Cheng Jian} and Guillermo Barturen and Francesc Catal{\`a}-Moll and Martin Kerick and Carol Wang and Phillip Melton and Elliott, {Hannah R.} and Jean Shin and Manon Bernard and Idil Yet and Melissa Smart and Tyler Gorrie-Stone and Chris Shaw and {Al Chalabi}, Ammar and Ring, {Susan M.} and G{\"o}ran Pershagen and Erik Mel{\'e}n and Jordi Jim{\'e}nez-Conde and Jaume Roquer and Lawlor, {Deborah A.} and John Wright and Martin, {Nicholas G.} and Montgomery, {Grant W.} and Moffitt, {Terrie E.} and Richie Poulton and T{\~o}nu Esko and Lili Milani and Andres Metspalu and Perry, {John R.B.} and Ong, {Ken K.} and Wareham, {Nicholas J.} and Giuseppe Matullo and Carlotta Sacerdote and Salvatore Panico and Avshalom Caspi and Louise Arseneault and France Gagnon and Miina Ollikainen and Jaakko Kaprio and Felix, {Janine F.} and Fernando Rivadeneira and Henning Tiemeier and {van IJzendoorn}, {Marinus H.} and Uitterlinden, {Andr{\'e} G.} and Jaddoe, {Vincent W.V.} and Chris Haley and McIntosh, {Andrew M.} and Evans, {Kathryn L.} and Alison Murray and Katri R{\"a}ikk{\"o}nen and Jari Lahti and Nohr, {Ellen A.} and S{\o}rensen, {Thorkild I.A.} and Torben Hansen and Morgen, {Camilla S.} and Binder, {Elisabeth B.} and Susanne Lucae and Gonzalez, {Juan Ramon} and Mariona Bustamante and Jordi Sunyer and Holloway, {John W.} and Wilfried Karmaus and Hongmei Zhang and Deary, {Ian J.} and Wray, {Naomi R.} and Starr, {John M.} and Marian Beekman and {van Heemst}, Diana and Slagboom, {P. Eline} and Morange, {Pierre Emmanuel} and Tr{\'e}gou{\"e}t, {David Alexandre} and Veldink, {Jan H.} and Davies, {Gareth E.} and {de Geus}, {Eco J.C.} and Boomsma, {Dorret I.} and Vonk, {Judith M.} and Bert Brunekreef and Koppelman, {Gerard H.} and Alarc{\'o}n-Riquelme, {Marta E.} and Huang, {Rae Chi} and Pennell, {Craig E.} and {van Meurs}, Joyce and Ikram, {M. Arfan} and Hughes, {Alun D.} and Therese Tillin and Nish Chaturvedi and Zdenka Pausova and Tomas Paus and Spector, {Timothy D.} and Meena Kumari and Schalkwyk, {Leonard C.} and Visscher, {Peter M.} and {Davey Smith}, George and Christoph Bock and Gaunt, {Tom R.} and Bell, {Jordana T.} and Heijmans, {Bastiaan T.} and Jonathan Mill and Relton, {Caroline L.} and {BIOS Consortium}",

note = "Funding Information: C.L.R., G.D.S., G.S., J.L.M., K.B., M. Suderman, T.G.R. and T.R.G. are supported by the UK Medical Research Council (MRC) Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/1, MC_UU_00011/4, MC_UU_00011/5). C.L.R. receives support from a Cancer Research UK Programme grant (no. C18281/A191169). G.H. is funded by the Wellcome Trust and the Royal Society (208806/Z/17/Z). E.H. and J.M. were supported by MRC project grants (nos. MR/K013807/1 and MR/R005176/1 to J.M.) and an MRC Clinical Infrastructure award (no. MR/M008924/1 to J.M.). B.T.H. is supported by the Netherlands CardioVascular Research Initiative (the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development, and the Royal Netherlands Academy of Sciences) for the GENIUS project {\textquoteleft}Generating the best evidence-based pharmaceutical targets for atherosclerosis{\textquoteright} (CVON2011-19, CVON2017-20). J.T.B. was supported by the Economic and Social Research Council (grant no. ES/N000404/1). The present study was also supported by JPI HDHL-funded DIMENSION project (administered by the BBSRC UK, grant no. BB/S020845/1 to J.T.B., and by ZonMW the Netherlands, grant no. 529051021 to B.T.H). A.D.B. has been supported by a Wellcome Trust PhD Training Fellowship for Clinicians and the Edinburgh Clinical Academic Track programme (204979/Z/16/Z). J. Klughammer was supported by a DOC fellowship of the Austrian Academy of Sciences. Cohort-specific acknowledgements and funding are presented in the Supplementary Note. Funding Information: T.R.G. receives funding from GlaxoSmithKline and Biogen for unrelated research. The other authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2021",

month = sep,

doi = "10.1038/s41588-021-00923-x",

language = "English",

volume = "53",

pages = "1311--1321",

journal = "Nature genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "9",

}

TY - JOUR

T1 - Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation

AU - Min, Josine L.

AU - Hemani, Gibran

AU - Hannon, Eilis

AU - Dekkers, Koen F.

AU - Castillo-Fernandez, Juan

AU - Luijk, René

AU - Carnero-Montoro, Elena

AU - Lawson, Daniel J.

AU - Burrows, Kimberley

AU - Suderman, Matthew

AU - Bretherick, Andrew D.

AU - Richardson, Tom G.

AU - Klughammer, Johanna

AU - Iotchkova, Valentina

AU - Sharp, Gemma

AU - Al Khleifat, Ahmad

AU - Shatunov, Aleksey

AU - Iacoangeli, Alfredo

AU - McArdle, Wendy L.

AU - Ho, Karen M.

AU - Kumar, Ashish

AU - Söderhäll, Cilla

AU - Soriano-Tárraga, Carolina

AU - Giralt-Steinhauer, Eva

AU - Kazmi, Nabila

AU - Mason, Dan

AU - McRae, Allan F.

AU - Corcoran, David L.

AU - Sugden, Karen

AU - Kasela, Silva

AU - Cardona, Alexia

AU - Day, Felix R.

AU - Cugliari, Giovanni

AU - Viberti, Clara

AU - Guarrera, Simonetta

AU - Lerro, Michael

AU - Gupta, Richa

AU - Bollepalli, Sailalitha

AU - Mandaviya, Pooja

AU - Zeng, Yanni

AU - Clarke, Toni Kim

AU - Walker, Rosie M.

AU - Schmoll, Vanessa

AU - Czamara, Darina

AU - Ruiz-Arenas, Carlos

AU - Rezwan, Faisal I.

AU - Marioni, Riccardo E.

AU - Lin, Tian

AU - Awaloff, Yvonne

AU - Germain, Marine

AU - Aïssi, Dylan

AU - Zwamborn, Ramona

AU - van Eijk, Kristel

AU - Dekker, Annelot

AU - van Dongen, Jenny

AU - Hottenga, Jouke Jan

AU - Willemsen, Gonneke

AU - Xu, Cheng Jian

AU - Barturen, Guillermo

AU - Català-Moll, Francesc

AU - Kerick, Martin

AU - Wang, Carol

AU - Melton, Phillip

AU - Elliott, Hannah R.

AU - Shin, Jean

AU - Bernard, Manon

AU - Yet, Idil

AU - Smart, Melissa

AU - Gorrie-Stone, Tyler

AU - Shaw, Chris

AU - Al Chalabi, Ammar

AU - Ring, Susan M.

AU - Pershagen, Göran

AU - Melén, Erik

AU - Jiménez-Conde, Jordi

AU - Roquer, Jaume

AU - Lawlor, Deborah A.

AU - Wright, John

AU - Martin, Nicholas G.

AU - Montgomery, Grant W.

AU - Moffitt, Terrie E.

AU - Poulton, Richie

AU - Esko, Tõnu

AU - Milani, Lili

AU - Metspalu, Andres

AU - Perry, John R.B.

AU - Ong, Ken K.

AU - Wareham, Nicholas J.

AU - Matullo, Giuseppe

AU - Sacerdote, Carlotta

AU - Panico, Salvatore

AU - Caspi, Avshalom

AU - Arseneault, Louise

AU - Gagnon, France

AU - Ollikainen, Miina

AU - Kaprio, Jaakko

AU - Felix, Janine F.

AU - Rivadeneira, Fernando

AU - Tiemeier, Henning

AU - van IJzendoorn, Marinus H.

AU - Uitterlinden, André G.

AU - Jaddoe, Vincent W.V.

AU - Haley, Chris

AU - McIntosh, Andrew M.

AU - Evans, Kathryn L.

AU - Murray, Alison

AU - Räikkönen, Katri

AU - Lahti, Jari

AU - Nohr, Ellen A.

AU - Sørensen, Thorkild I.A.

AU - Hansen, Torben

AU - Morgen, Camilla S.

AU - Binder, Elisabeth B.

AU - Lucae, Susanne

AU - Gonzalez, Juan Ramon

AU - Bustamante, Mariona

AU - Sunyer, Jordi

AU - Holloway, John W.

AU - Karmaus, Wilfried

AU - Zhang, Hongmei

AU - Deary, Ian J.

AU - Wray, Naomi R.

AU - Starr, John M.

AU - Beekman, Marian

AU - van Heemst, Diana

AU - Slagboom, P. Eline

AU - Morange, Pierre Emmanuel

AU - Trégouët, David Alexandre

AU - Veldink, Jan H.

AU - Davies, Gareth E.

AU - de Geus, Eco J.C.

AU - Boomsma, Dorret I.

AU - Vonk, Judith M.

AU - Brunekreef, Bert

AU - Koppelman, Gerard H.

AU - Alarcón-Riquelme, Marta E.

AU - Huang, Rae Chi

AU - Pennell, Craig E.

AU - van Meurs, Joyce

AU - Ikram, M. Arfan

AU - Hughes, Alun D.

AU - Tillin, Therese

AU - Chaturvedi, Nish

AU - Pausova, Zdenka

AU - Paus, Tomas

AU - Spector, Timothy D.

AU - Kumari, Meena

AU - Schalkwyk, Leonard C.

AU - Visscher, Peter M.

AU - Davey Smith, George

AU - Bock, Christoph

AU - Gaunt, Tom R.

AU - Bell, Jordana T.

AU - Heijmans, Bastiaan T.

AU - Mill, Jonathan

AU - Relton, Caroline L.

AU - BIOS Consortium

N1 - Funding Information: C.L.R., G.D.S., G.S., J.L.M., K.B., M. Suderman, T.G.R. and T.R.G. are supported by the UK Medical Research Council (MRC) Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/1, MC_UU_00011/4, MC_UU_00011/5). C.L.R. receives support from a Cancer Research UK Programme grant (no. C18281/A191169). G.H. is funded by the Wellcome Trust and the Royal Society (208806/Z/17/Z). E.H. and J.M. were supported by MRC project grants (nos. MR/K013807/1 and MR/R005176/1 to J.M.) and an MRC Clinical Infrastructure award (no. MR/M008924/1 to J.M.). B.T.H. is supported by the Netherlands CardioVascular Research Initiative (the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development, and the Royal Netherlands Academy of Sciences) for the GENIUS project ‘Generating the best evidence-based pharmaceutical targets for atherosclerosis’ (CVON2011-19, CVON2017-20). J.T.B. was supported by the Economic and Social Research Council (grant no. ES/N000404/1). The present study was also supported by JPI HDHL-funded DIMENSION project (administered by the BBSRC UK, grant no. BB/S020845/1 to J.T.B., and by ZonMW the Netherlands, grant no. 529051021 to B.T.H). A.D.B. has been supported by a Wellcome Trust PhD Training Fellowship for Clinicians and the Edinburgh Clinical Academic Track programme (204979/Z/16/Z). J. Klughammer was supported by a DOC fellowship of the Austrian Academy of Sciences. Cohort-specific acknowledgements and funding are presented in the Supplementary Note. Funding Information: T.R.G. receives funding from GlaxoSmithKline and Biogen for unrelated research. The other authors declare no competing interests. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2021/9

Y1 - 2021/9

N2 - Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15–17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype–phenotype map than previously anticipated.

AB - Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15–17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype–phenotype map than previously anticipated.

UR - http://www.scopus.com/inward/record.url?scp=85103124472&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85103124472&partnerID=8YFLogxK

U2 - 10.1038/s41588-021-00923-x

DO - 10.1038/s41588-021-00923-x

M3 - Article

C2 - 34493871

SN - 1061-4036

VL - 53

SP - 1311

EP - 1321

JO - Nature genetics

JF - Nature genetics

IS - 9

ER -

Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation

Abstract

Bibliographical note

Funding

Access to Document

Persistent URL (handle)

Other files and links

Fingerprint

Cite this