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

et al.; Josine L Min; Gibran Hemani; Eilis Hannon; Koen  dekkers; Juan Castillo-Fernandez; René Luijk; Elena Carnero-Montoro; Daniel John Lawson; Kimberley Burrows; Matthew J Suderman; Andrew D. Bretherick; Tom G Richardson; Johanna Klughammer; Valentina  Lochkova; Gemma C Sharp; Ahmad  Al Khleifat; Aleksey Shatunov; Alfredo  Lacoangeli; Wendy L Mcardle; Karen M Ho; Ashish Kumar; Cils Soderhall; Carolina  Soriano-Tárraga; Eva  Giralt-Steinhauer; Nabila Kazmi; Dan Mason; Allan F McRae; David L  Corcoran; Hannah R Elliott; Susan M Ring; Debbie A Lawlor; Thorkild I. A. Sørensen; George Davey Smith; Tom R Gaunt; Caroline L Relton

doi:10.1038/s41588-021-00923-x

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

et al., Josine L Min^*, Gibran Hemani, Eilis Hannon, Koen dekkers, Juan Castillo-Fernandez, René Luijk, Elena Carnero-Montoro, Daniel John Lawson, Kimberley Burrows, Matthew J Suderman, Andrew D. Bretherick, Tom G Richardson, Johanna Klughammer, Valentina Lochkova, Gemma C Sharp, Ahmad Al Khleifat, Aleksey Shatunov, Alfredo Lacoangeli, Wendy L McardleKaren M Ho, Ashish Kumar, Cils Soderhall, Carolina Soriano-Tárraga, Eva Giralt-Steinhauer, Nabila Kazmi, Dan Mason, Allan F McRae, David L Corcoran, Hannah R Elliott, Susan M Ring, Debbie A Lawlor, Thorkild I. A. Sørensen, George Davey Smith, Tom R Gaunt, Caroline L Relton

^*Corresponding author for this work

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Abstract

Characterising genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. Here we describe results of DNA methylation-quantitative trait loci (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 mQTL of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We reveal that the genetic architecture of DNAm levels is highly polygenic and DNAm exhibits signatures of negative and positive natural selection. Using shared genetic control between distal DNAm sites we construct networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic factors are associated with both DNAm levels and complex diseases but only in a minority of cases these associations reflect direct 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	E-pub ahead of print - 6 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.

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IEU: MRC Integrative Epidemiology Unit Quinquennial renewal
Gaunt, L. F. (Principal Investigator) & Davey Smith, G. (Principal Investigator)
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Project: Research
8073 MRC IEU - Programme 6
Lawlor, D. A. (Principal Investigator)
1/04/18 → 31/03/23
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- Bristol Medical School (PHS) - Professor in Statistical Genetics
- Bristol Population Health Science Institute
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Cite this

et al., Min, J. L., Hemani, G., Hannon, E., dekkers, K., Castillo-Fernandez, J., Luijk, R., Carnero-Montoro, E., Lawson, D. J., Burrows, K., Suderman, M. J., Bretherick, A. D., Richardson, T. G., Klughammer, J., Lochkova, V., Sharp, G. C., Al Khleifat, A., Shatunov, A., Lacoangeli, A., ... Relton, C. L. (2021). Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation. Nature Genetics, 53(9), 1311-1321. Advance online publication. https://doi.org/10.1038/s41588-021-00923-x

@article{a7b82a056f9c4f67a5afa207862daea0,

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

abstract = "Characterising genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. Here we describe results of DNA methylation-quantitative trait loci (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 mQTL of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We reveal that the genetic architecture of DNAm levels is highly polygenic and DNAm exhibits signatures of negative and positive natural selection. Using shared genetic control between distal DNAm sites we construct networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic factors are associated with both DNAm levels and complex diseases but only in a minority of cases these associations reflect direct causal relationships from DNAm to trait or vice versa indicating a more complex genotype-phenotype map than previously anticipated. ",

author = "{et al.} and Min, {Josine L} and Gibran Hemani and Eilis Hannon and Koen dekkers and Juan Castillo-Fernandez and Ren{\'e} Luijk and Elena Carnero-Montoro and Lawson, {Daniel John} and Kimberley Burrows and Suderman, {Matthew J} and Bretherick, {Andrew D.} and Richardson, {Tom G} and Johanna Klughammer and Valentina Lochkova and Sharp, {Gemma C} and {Al Khleifat}, Ahmad and Aleksey Shatunov and Alfredo Lacoangeli and Mcardle, {Wendy L} and Ho, {Karen M} and Ashish Kumar and Cils Soderhall 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 Elliott, {Hannah R} and Ring, {Susan M} and Lawlor, {Debbie A} and S{\o}rensen, {Thorkild I. A.} and {Davey Smith}, George and Gaunt, {Tom R} and Relton, {Caroline L}",

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.",

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et al., Min, JL , Hemani, G, Hannon, E, dekkers, K, Castillo-Fernandez, J, Luijk, R, Carnero-Montoro, E, Lawson, DJ , Burrows, K , Suderman, MJ, Bretherick, AD, Richardson, TG, Klughammer, J, Lochkova, V, Sharp, GC, Al Khleifat, A, Shatunov, A, Lacoangeli, A, Mcardle, WL, Ho, KM, Kumar, A, Soderhall, C, Soriano-Tárraga, C, Giralt-Steinhauer, E, Kazmi, N, Mason, D, McRae, AF, Corcoran, DL, Elliott, HR , Ring, SM , Lawlor, DA, Sørensen, TIA, Davey Smith, G , Gaunt, TR & Relton, CL 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 - et al.

AU - Min, Josine L

AU - Hemani, Gibran

AU - Hannon, Eilis

AU - dekkers, Koen

AU - Castillo-Fernandez, Juan

AU - Luijk, René

AU - Carnero-Montoro, Elena

AU - Lawson, Daniel John

AU - Burrows, Kimberley

AU - Suderman, Matthew J

AU - Bretherick, Andrew D.

AU - Richardson, Tom G

AU - Klughammer, Johanna

AU - Lochkova, Valentina

AU - Sharp, Gemma C

AU - Al Khleifat, Ahmad

AU - Shatunov, Aleksey

AU - Lacoangeli, Alfredo

AU - Mcardle, Wendy L

AU - Ho, Karen M

AU - Kumar, Ashish

AU - Soderhall, Cils

AU - Soriano-Tárraga, Carolina

AU - Giralt-Steinhauer, Eva

AU - Kazmi, Nabila

AU - Mason, Dan

AU - McRae, Allan F

AU - Corcoran, David L

AU - Elliott, Hannah R

AU - Ring, Susan M

AU - Lawlor, Debbie A

AU - Sørensen, Thorkild I. A.

AU - Davey Smith, George

AU - Gaunt, Tom R

AU - Relton, Caroline L

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 - 2021/9/6

Y1 - 2021/9/6

N2 - Characterising genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. Here we describe results of DNA methylation-quantitative trait loci (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 mQTL of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We reveal that the genetic architecture of DNAm levels is highly polygenic and DNAm exhibits signatures of negative and positive natural selection. Using shared genetic control between distal DNAm sites we construct networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic factors are associated with both DNAm levels and complex diseases but only in a minority of cases these associations reflect direct causal relationships from DNAm to trait or vice versa indicating a more complex genotype-phenotype map than previously anticipated.

AB - Characterising genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. Here we describe results of DNA methylation-quantitative trait loci (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 mQTL of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We reveal that the genetic architecture of DNAm levels is highly polygenic and DNAm exhibits signatures of negative and positive natural selection. Using shared genetic control between distal DNAm sites we construct networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic factors are associated with both DNAm levels and complex diseases but only in a minority of cases these associations reflect direct 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 - Article (Academic Journal)

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

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Projects

IEU: MRC Integrative Epidemiology Unit Quinquennial renewal

8073 MRC IEU - Programme 6

Equipment

HPC (High Performance Computing) and HTC (High Throughput Computing) Facilities

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Professor Gibran Hemani

Cite this