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

J. L. Min; G. Hemani; E. Hannon; K. F. Dekkers; J. Castillo-Fernandez; R. Luijk; E. Carnero-Montoro; D. J. Lawson; K. Burrows; M. Suderman; A. D. Bretherick; T. G. Richardson; J. Klughammer; V. Iotchkova; G. Sharp; Khleifat A. Al; A. Shatunov; A. Iacoangeli; W. L. McArdle; K. M. Ho; A. Kumar; C. Soderhall; C. Soriano-Tarraga; E. Giralt-Steinhauer; N. Kazmi; D. Mason; A. F. McRae; D. L. Corcoran; K. Sugden; S. Kasela; A. Cardona; F. R. Day; G. Cugliari; C. Viberti; S. Guarrera; M. Lerro; R. Gupta; S. Bollepalli; P. Mandaviya; Y. Zeng; Clarke T. -K.; R. M. Walker; V. Schmoll; D. Czamara; C. Ruiz-Arenas; F. I. Rezwan; R. E. Marioni; T. Lin; Y. Awaloff; M. Germain; D. Aissi; R. Zwamborn; K. van Eijk; A. Dekker; J. van Dongen; Hottenga J. -J.; G. Willemsen; Xu C. -J.; G. Barturen; F. Catala-Moll; M. Kerick; C. Wang; P. Melton; H. R. Elliott; J. Shin; M. Bernard; I. Yet; M. Smart; T. Gorrie-Stone; C. Shaw; Chalabi A. Al; S. M. Ring; G. Pershagen; E. Melen; J. Jimenez-Conde; J. Roquer; D. A. Lawlor; J. Wright; N. G. Martin; G. W. Montgomery; T. E. Moffitt; R. Poulton; T. Esko; L. Milani; A. Metspalu; J. R. B. Perry; K. K. Ong; N. J. Wareham; G. Matullo; Carlotta SACERDOTE; S. Panico; A. Caspi; L. Arseneault; F. Gagnon; M. Ollikainen; J. Kaprio; J. F. Felix; F. Rivadeneira; H. Tiemeier; M. H. van IJzendoorn; A. G. Uitterlinden; V. W. V. Jaddoe; C. Haley; A. M. McIntosh; K. L. Evans; A. Murray; K. Raikkonen; J. Lahti; E. A. Nohr; T. I. A. Sorensen; T. Hansen; C. S. Morgen; E. B. Binder; S. Lucae; J. R. Gonzalez; M. Bustamante; J. Sunyer; J. W. Holloway; W. Karmaus; H. Zhang; I. J. Deary; N. R. Wray; J. M. Starr; M. Beekman; D. van Heemst; P. E. Slagboom; Morange P. -E.; Tregouet D. -A.; J. H. Veldink; G. E. Davies; E. J. C. de Geus; D. I. Boomsma; J. M. Vonk; B. Brunekreef; G. H. Koppelman; M. E. Alarcon-Riquelme; Huang R. -C.; C. E. Pennell; J. van Meurs; M. A. Ikram; A. D. Hughes; T. Tillin; N. Chaturvedi; Z. Pausova; T. Paus; T. D. Spector; M. Kumari; L. C. Schalkwyk; P. M. Visscher; Smith G. Davey; C. Bock; T. R. Gaunt; J. T. Bell; B. T. Heijmans; J. Mill; C. L. Relton

doi:10.1038/s41588-021-00923-x

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

J. L. Min, G. Hemani, E. Hannon, K. F. Dekkers, J. Castillo-Fernandez, R. Luijk, E. Carnero-Montoro, D. J. Lawson, K. Burrows, M. Suderman, A. D. Bretherick, T. G. Richardson, J. Klughammer, V. Iotchkova, G. Sharp, Khleifat A. Al, A. Shatunov, A. Iacoangeli, W. L. McArdle, K. M. HoA. Kumar, C. Soderhall, C. Soriano-Tarraga, E. Giralt-Steinhauer, N. Kazmi, D. Mason, A. F. McRae, D. L. Corcoran, K. Sugden, S. Kasela, A. Cardona, F. R. Day, G. Cugliari, C. Viberti, S. Guarrera, M. Lerro, R. Gupta, S. Bollepalli, P. Mandaviya, Y. Zeng, Clarke T. -K., R. M. Walker, V. Schmoll, D. Czamara, C. Ruiz-Arenas, F. I. Rezwan, R. E. Marioni, T. Lin, Y. Awaloff, M. Germain, D. Aissi, R. Zwamborn, K. van Eijk, A. Dekker, J. van Dongen, Hottenga J. -J., G. Willemsen, Xu C. -J., G. Barturen, F. Catala-Moll, M. Kerick, C. Wang, P. Melton, H. R. Elliott, J. Shin, M. Bernard, I. Yet, M. Smart, T. Gorrie-Stone, C. Shaw, Chalabi A. Al, S. M. Ring, G. Pershagen, E. Melen, J. Jimenez-Conde, J. Roquer, D. A. Lawlor, J. Wright, N. G. Martin, G. W. Montgomery, T. E. Moffitt, R. Poulton, T. Esko, L. Milani, A. Metspalu, J. R. B. Perry, K. K. Ong, N. J. Wareham, G. Matullo, Carlotta SACERDOTE, S. Panico, A. Caspi, L. Arseneault, F. Gagnon, M. Ollikainen, J. Kaprio, J. F. Felix, F. Rivadeneira, H. Tiemeier, M. H. van IJzendoorn, A. G. Uitterlinden, V. W. V. Jaddoe, C. Haley, A. M. McIntosh, K. L. Evans, A. Murray, K. Raikkonen, J. Lahti, E. A. Nohr, T. I. A. Sorensen, T. Hansen, C. S. Morgen, E. B. Binder, S. Lucae, J. R. Gonzalez, M. Bustamante, J. Sunyer, J. W. Holloway, W. Karmaus, H. Zhang, I. J. Deary, N. R. Wray, J. M. Starr, M. Beekman, D. van Heemst, P. E. Slagboom, Morange P. -E., Tregouet D. -A., J. H. Veldink, G. E. Davies, E. J. C. de Geus, D. I. Boomsma, J. M. Vonk, B. Brunekreef, G. H. Koppelman, M. E. Alarcon-Riquelme, Huang R. -C., C. E. Pennell, J. van Meurs, M. A. Ikram, A. D. Hughes, T. Tillin, N. Chaturvedi, Z. Pausova, T. Paus, T. D. Spector, M. Kumari, L. C. Schalkwyk, P. M. Visscher, Smith G. Davey, C. Bock, T. R. Gaunt, J. T. Bell, B. T. Heijmans, J. Mill, C. L. Relton

Dipartimento di Scienze della Salute

Risultato della ricerca: Contributo su rivista › Articolo in rivista › 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.

Lingua originale	Inglese
pagine (da-a)	1311-1321
Numero di pagine	11
Rivista	Nature Genetics
Volume	53
Numero di pubblicazione	9
DOI	https://doi.org/10.1038/s41588-021-00923-x
Stato di pubblicazione	Pubblicato - 2021

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10.1038/s41588-021-00923-x

https://hdl.handle.net/11579/198348

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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, K. A., Shatunov, A., Iacoangeli, A., McArdle, W. L., ... Relton, C. L. (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{3e9bf296475449ce9ef4b0b6f14d784a,

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, {J. L.} and G. Hemani and E. Hannon and Dekkers, {K. F.} and J. Castillo-Fernandez and R. Luijk and E. Carnero-Montoro and Lawson, {D. J.} and K. Burrows and M. Suderman and Bretherick, {A. D.} and Richardson, {T. G.} and J. Klughammer and V. Iotchkova and G. Sharp and Al, {Khleifat A.} and A. Shatunov and A. Iacoangeli and McArdle, {W. L.} and Ho, {K. M.} and A. Kumar and C. Soderhall and C. Soriano-Tarraga and E. Giralt-Steinhauer and N. Kazmi and D. Mason and McRae, {A. F.} and Corcoran, {D. L.} and K. Sugden and S. Kasela and A. Cardona and Day, {F. R.} and G. Cugliari and C. Viberti and S. Guarrera and M. Lerro and R. Gupta and S. Bollepalli and P. Mandaviya and Y. Zeng and -K., {Clarke T.} and Walker, {R. M.} and V. Schmoll and D. Czamara and C. Ruiz-Arenas and Rezwan, {F. I.} and Marioni, {R. E.} and T. Lin and Y. Awaloff and M. Germain and D. Aissi and R. Zwamborn and {van Eijk}, K. and A. Dekker and {van Dongen}, J. and -J., {Hottenga J.} and G. Willemsen and -J., {Xu C.} and G. Barturen and F. Catala-Moll and M. Kerick and C. Wang and P. Melton and Elliott, {H. R.} and J. Shin and M. Bernard and I. Yet and M. Smart and T. Gorrie-Stone and C. Shaw and Al, {Chalabi A.} and Ring, {S. M.} and G. Pershagen and E. Melen and J. Jimenez-Conde and J. Roquer and Lawlor, {D. A.} and J. Wright and Martin, {N. G.} and Montgomery, {G. W.} and Moffitt, {T. E.} and R. Poulton and T. Esko and L. Milani and A. Metspalu and Perry, {J. R. B.} and Ong, {K. K.} and Wareham, {N. J.} and G. Matullo and Carlotta SACERDOTE and S. Panico and A. Caspi and L. Arseneault and F. Gagnon and M. Ollikainen and J. Kaprio and Felix, {J. F.} and F. Rivadeneira and H. Tiemeier and {van IJzendoorn}, {M. H.} and Uitterlinden, {A. G.} and Jaddoe, {V. W. V.} and C. Haley and McIntosh, {A. M.} and Evans, {K. L.} and A. Murray and K. Raikkonen and J. Lahti and Nohr, {E. A.} and Sorensen, {T. I. A.} and T. Hansen and Morgen, {C. S.} and Binder, {E. B.} and S. Lucae and Gonzalez, {J. R.} and M. Bustamante and J. Sunyer and Holloway, {J. W.} and W. Karmaus and H. Zhang and Deary, {I. J.} and Wray, {N. R.} and Starr, {J. M.} and M. Beekman and {van Heemst}, D. and Slagboom, {P. E.} and -E., {Morange P.} and -A., {Tregouet D.} and Veldink, {J. H.} and Davies, {G. E.} and {de Geus}, {E. J. C.} and Boomsma, {D. I.} and Vonk, {J. M.} and B. Brunekreef and Koppelman, {G. H.} and Alarcon-Riquelme, {M. E.} and -C., {Huang R.} and Pennell, {C. E.} and {van Meurs}, J. and Ikram, {M. A.} and Hughes, {A. D.} and T. Tillin and N. Chaturvedi and Z. Pausova and T. Paus and Spector, {T. D.} and M. Kumari and Schalkwyk, {L. C.} and Visscher, {P. M.} and Davey, {Smith G.} and C. Bock and Gaunt, {T. R.} and Bell, {J. T.} and Heijmans, {B. T.} and J. Mill and Relton, {C. L.}",

year = "2021",

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, KA, Shatunov, A, Iacoangeli, A, McArdle, WL, Ho, KM, Kumar, A, Soderhall, C, Soriano-Tarraga, 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, -K., CT, Walker, RM, Schmoll, V, Czamara, D, Ruiz-Arenas, C, Rezwan, FI, Marioni, RE, Lin, T, Awaloff, Y, Germain, M, Aissi, D, Zwamborn, R, van Eijk, K, Dekker, A, van Dongen, J, -J., HJ, Willemsen, G, -J., XC, Barturen, G, Catala-Moll, F, Kerick, M, Wang, C, Melton, P, Elliott, HR, Shin, J, Bernard, M, Yet, I, Smart, M, Gorrie-Stone, T, Shaw, C, Al, CA, Ring, SM, Pershagen, G, Melen, E, Jimenez-Conde, J, Roquer, J, Lawlor, DA, Wright, J, Martin, NG, Montgomery, GW, Moffitt, TE, Poulton, R, Esko, T, Milani, L, Metspalu, A, Perry, JRB, Ong, KK, Wareham, NJ, Matullo, G, SACERDOTE, C, Panico, S, Caspi, A, Arseneault, L, Gagnon, F, Ollikainen, M, Kaprio, J, Felix, JF, Rivadeneira, F, Tiemeier, H, van IJzendoorn, MH, Uitterlinden, AG, Jaddoe, VWV, Haley, C, McIntosh, AM, Evans, KL, Murray, A, Raikkonen, K, Lahti, J, Nohr, EA, Sorensen, TIA, Hansen, T, Morgen, CS, Binder, EB, Lucae, S, Gonzalez, JR, Bustamante, M, Sunyer, J, Holloway, JW, Karmaus, W, Zhang, H, Deary, IJ, Wray, NR, Starr, JM, Beekman, M, van Heemst, D, Slagboom, PE, -E., MP, -A., TD, Veldink, JH, Davies, GE, de Geus, EJC, Boomsma, DI, Vonk, JM, Brunekreef, B, Koppelman, GH, Alarcon-Riquelme, ME, -C., HR, Pennell, CE, van Meurs, J, Ikram, MA, Hughes, AD, Tillin, T, Chaturvedi, N, Pausova, Z, Paus, T, Spector, TD, Kumari, M, Schalkwyk, LC, Visscher, PM, Davey, SG, Bock, C, Gaunt, TR, Bell, JT, Heijmans, BT, Mill, J & Relton, CL 2021, 'Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation', Nature Genetics, vol. 53, n. 9, pagg. 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, J. L.

AU - Hemani, G.

AU - Hannon, E.

AU - Dekkers, K. F.

AU - Castillo-Fernandez, J.

AU - Luijk, R.

AU - Carnero-Montoro, E.

AU - Lawson, D. J.

AU - Burrows, K.

AU - Suderman, M.

AU - Bretherick, A. D.

AU - Richardson, T. G.

AU - Klughammer, J.

AU - Iotchkova, V.

AU - Sharp, G.

AU - Al, Khleifat A.

AU - Shatunov, A.

AU - Iacoangeli, A.

AU - McArdle, W. L.

AU - Ho, K. M.

AU - Kumar, A.

AU - Soderhall, C.

AU - Soriano-Tarraga, C.

AU - Giralt-Steinhauer, E.

AU - Kazmi, N.

AU - Mason, D.

AU - McRae, A. F.

AU - Corcoran, D. L.

AU - Sugden, K.

AU - Kasela, S.

AU - Cardona, A.

AU - Day, F. R.

AU - Cugliari, G.

AU - Viberti, C.

AU - Guarrera, S.

AU - Lerro, M.

AU - Gupta, R.

AU - Bollepalli, S.

AU - Mandaviya, P.

AU - Zeng, Y.

AU - -K., Clarke T.

AU - Walker, R. M.

AU - Schmoll, V.

AU - Czamara, D.

AU - Ruiz-Arenas, C.

AU - Rezwan, F. I.

AU - Marioni, R. E.

AU - Lin, T.

AU - Awaloff, Y.

AU - Germain, M.

AU - Aissi, D.

AU - Zwamborn, R.

AU - van Eijk, K.

AU - Dekker, A.

AU - van Dongen, J.

AU - -J., Hottenga J.

AU - Willemsen, G.

AU - -J., Xu C.

AU - Barturen, G.

AU - Catala-Moll, F.

AU - Kerick, M.

AU - Wang, C.

AU - Melton, P.

AU - Elliott, H. R.

AU - Shin, J.

AU - Bernard, M.

AU - Yet, I.

AU - Smart, M.

AU - Gorrie-Stone, T.

AU - Shaw, C.

AU - Al, Chalabi A.

AU - Ring, S. M.

AU - Pershagen, G.

AU - Melen, E.

AU - Jimenez-Conde, J.

AU - Roquer, J.

AU - Lawlor, D. A.

AU - Wright, J.

AU - Martin, N. G.

AU - Montgomery, G. W.

AU - Moffitt, T. E.

AU - Poulton, R.

AU - Esko, T.

AU - Milani, L.

AU - Metspalu, A.

AU - Perry, J. R. B.

AU - Ong, K. K.

AU - Wareham, N. J.

AU - Matullo, G.

AU - SACERDOTE, Carlotta

AU - Panico, S.

AU - Caspi, A.

AU - Arseneault, L.

AU - Gagnon, F.

AU - Ollikainen, M.

AU - Kaprio, J.

AU - Felix, J. F.

AU - Rivadeneira, F.

AU - Tiemeier, H.

AU - van IJzendoorn, M. H.

AU - Uitterlinden, A. G.

AU - Jaddoe, V. W. V.

AU - Haley, C.

AU - McIntosh, A. M.

AU - Evans, K. L.

AU - Murray, A.

AU - Raikkonen, K.

AU - Lahti, J.

AU - Nohr, E. A.

AU - Sorensen, T. I. A.

AU - Hansen, T.

AU - Morgen, C. S.

AU - Binder, E. B.

AU - Lucae, S.

AU - Gonzalez, J. R.

AU - Bustamante, M.

AU - Sunyer, J.

AU - Holloway, J. W.

AU - Karmaus, W.

AU - Zhang, H.

AU - Deary, I. J.

AU - Wray, N. R.

AU - Starr, J. M.

AU - Beekman, M.

AU - van Heemst, D.

AU - Slagboom, P. E.

AU - -E., Morange P.

AU - -A., Tregouet D.

AU - Veldink, J. H.

AU - Davies, G. E.

AU - de Geus, E. J. C.

AU - Boomsma, D. I.

AU - Vonk, J. M.

AU - Brunekreef, B.

AU - Koppelman, G. H.

AU - Alarcon-Riquelme, M. E.

AU - -C., Huang R.

AU - Pennell, C. E.

AU - van Meurs, J.

AU - Ikram, M. A.

AU - Hughes, A. D.

AU - Tillin, T.

AU - Chaturvedi, N.

AU - Pausova, Z.

AU - Paus, T.

AU - Spector, T. D.

AU - Kumari, M.

AU - Schalkwyk, L. C.

AU - Visscher, P. M.

AU - Davey, Smith G.

AU - Bock, C.

AU - Gaunt, T. R.

AU - Bell, J. T.

AU - Heijmans, B. T.

AU - Mill, J.

AU - Relton, C. L.

PY - 2021

Y1 - 2021

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 - https://iris.uniupo.it/handle/11579/198348

U2 - 10.1038/s41588-021-00923-x

DO - 10.1038/s41588-021-00923-x

M3 - Article

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

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