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

Josine L. Min; Gibran Hemani; Eilis Hannon; Koen F. Dekkers; Juan Castillo-Fernandez; René Luijk; Elena Carnero-Montoro; Daniel J. Lawson; Kimberley Burrows; Matthew Suderman; Andrew D. Bretherick; Tom G. Richardson; Johanna Klughammer; Valentina Iotchkova; Gemma Sharp; Ahmad Al Khleifat; Aleksey Shatunov; Alfredo Iacoangeli; Wendy L. McArdle; Karen M. Ho; Ashish Kumar; Cilla Söderhäll; Carolina Soriano-Tárraga; Eva Giralt-Steinhauer; Nabila Kazmi; Dan Mason; Allan F. McRae; David L. Corcoran; Karen Sugden; Silva Kasela; Alexia Cardona; Felix R. Day; Giovanni Cugliari; Clara Viberti; Simonetta Guarrera; Michael Lerro; Richa Gupta; Sailalitha Bollepalli; Pooja Mandaviya; Yanni Zeng; Toni Kim Clarke; Rosie M. Walker; Vanessa Schmoll; Darina Czamara; Carlos Ruiz-Arenas; Faisal I. Rezwan; Riccardo E. Marioni; Ellen A. Nohr; Thorkild I.A. Sørensen; Camilla S. Morgen; 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^*
, Gibran Hemani
, Eilis Hannon
, Koen F. Dekkers
, Juan Castillo-Fernandez
, René Luijk
, Elena Carnero-Montoro
, Daniel J. Lawson
, Kimberley Burrows
, Matthew Suderman
, Andrew D. Bretherick
, Tom G. Richardson
, Johanna Klughammer
, Valentina Iotchkova
, Gemma Sharp
, Ahmad Al Khleifat
, Aleksey Shatunov
, Alfredo Iacoangeli
, Wendy L. McArdle
, Karen M. Ho

Ashish Kumar, Cilla Söderhäll, Carolina Soriano-Tárraga, Eva Giralt-Steinhauer, Nabila Kazmi, Dan Mason, Allan F. McRae, David L. Corcoran, Karen Sugden, Silva Kasela, Alexia Cardona, Felix R. Day, Giovanni Cugliari, Clara Viberti, Simonetta Guarrera, Michael Lerro, Richa Gupta, Sailalitha Bollepalli, Pooja Mandaviya, Yanni Zeng, Toni Kim Clarke, Rosie M. Walker, Vanessa Schmoll, Darina Czamara, Carlos Ruiz-Arenas, Faisal I. Rezwan, Riccardo E. Marioni, Ellen A. Nohr, Thorkild I.A. Sørensen, Camilla S. Morgen, BIOS Consortium

^*Corresponding author for this work

KI, OUH, Research unit of Gynaecology and Obstetrics

University of Bristol
University of Exeter
Leiden University
King's College London
University of Granada
The University of Edinburgh
Vienna Biocenter (VBC)
University of Oxford
Maurice Wohl Clinical Neuroscience Institute
Karolinska Institute
Swiss Tropical and Public Health Institute (Swiss TPH)
University of Basel
Hospital del Mar
Bradford Institute for Health Research
The University of Queensland
Duke University
University of Tartu
University of Cambridge
University of Turin
Italian Institute for Genomic Medicine
University of Toronto
University of Helsinki
Erasmus University Medical Center Rotterdam
Sun Yat-sen University
Max Planck Institute of Psychiatry
CREAL
Pompeu Fabra University
CIBER Epidemiologia Y Salud Publica
University of Wales
University of South-Eastern Norway
University of Copenhagen

Research output: Contribution to journal › Journal article › Research › peer-review

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
Journal	Nature Genetics
Volume	53
Issue number	9
Pages (from-to)	1311-1321
ISSN	1061-4036
DOIs	https://doi.org/10.1038/s41588-021-00923-x
Publication status	Published - Sept 2021

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.

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10.1038/s41588-021-00923-x

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7612069/pdf/EMS131971.pdf

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Min, J. L., Hemani, G., Hannon, E., Dekkers, K. F., Castillo-Fernandez, J., Luijk, R., Carnero-Montoro, E., Lawson, D. J., Burrows, K., Suderman, M., Bretherick, A. D., Richardson, T. G., Klughammer, J., Iotchkova, V., Sharp, G., Al Khleifat, A., Shatunov, A., Iacoangeli, A., McArdle, W. L., ... BIOS Consortium (2021). Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation. Nature Genetics, 53(9), 1311-1321. https://doi.org/10.1038/s41588-021-00923-x

@article{091fe9f1ca374f6fa4db177919d46410,

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{\textendash}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{\textendash}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 Nohr, \{Ellen A.\} and S{\o}rensen, \{Thorkild I.A.\} and Morgen, \{Camilla S.\} 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",

}

Min, JL, Hemani, G, Hannon, E, Dekkers, KF, Castillo-Fernandez, J, Luijk, R, Carnero-Montoro, E, Lawson, DJ, Burrows, K, Suderman, M, Bretherick, AD, Richardson, TG, Klughammer, J, Iotchkova, V, Sharp, G, Al Khleifat, A, Shatunov, A, Iacoangeli, A, McArdle, WL, Ho, KM, Kumar, A, Söderhäll, C, Soriano-Tárraga, C, Giralt-Steinhauer, E, Kazmi, N, Mason, D, McRae, AF, Corcoran, DL, Sugden, K, Kasela, S, Cardona, A, Day, FR, Cugliari, G, Viberti, C, Guarrera, S, Lerro, M, Gupta, R, Bollepalli, S, Mandaviya, P, Zeng, Y, Clarke, TK, Walker, RM, Schmoll, V, Czamara, D, Ruiz-Arenas, C, Rezwan, FI, Marioni, RE, Nohr, EA, Sørensen, TIA, Morgen, CS & BIOS Consortium 2021, 'Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation', Nature Genetics, vol. 53, no. 9, pp. 1311-1321. https://doi.org/10.1038/s41588-021-00923-x

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 - Nohr, Ellen A.

AU - Sørensen, Thorkild I.A.

AU - Morgen, Camilla S.

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.

U2 - 10.1038/s41588-021-00923-x

DO - 10.1038/s41588-021-00923-x

M3 - Journal article

C2 - 34493871

AN - SCOPUS:85103124472

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

Funding

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