Genetic variation influencing DNA methylation provides insights into molecular mechanisms regulating genomic function

MuTHER Consortium

doi:10.1038/s41588-021-00969-x

Genetic variation influencing DNA methylation provides insights into molecular mechanisms regulating genomic function

MuTHER Consortium

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

58 Citations (Scopus)

Abstract

We determined the relationships between DNA sequence variation and DNA methylation using blood samples from 3,799 Europeans and 3,195 South Asians. We identify 11,165,559 SNP–CpG associations (methylation quantitative trait loci (meQTL), P < 10⁻¹⁴), including 467,915 meQTL that operate in trans. The meQTL are enriched for functionally relevant characteristics, including shared chromatin state, High-throuhgput chromosome conformation interaction, and association with gene expression, metabolic variation and clinical traits. We use molecular interaction and colocalization analyses to identify multiple nuclear regulatory pathways linking meQTL loci to phenotypic variation, including UBASH3B (body mass index), NFKBIE (rheumatoid arthritis), MGA (blood pressure) and COMMD7 (white cell counts). For rs6511961, chromatin immunoprecipitation followed by sequencing (ChIP–seq) validates zinc finger protein (ZNF)333 as the likely trans acting effector protein. Finally, we used interaction analyses to identify population- and lineage-specific meQTL, including rs174548 in FADS1, with the strongest effect in CD8⁺ T cells, thus linking fatty acid metabolism with immune dysregulation and asthma. Our study advances understanding of the potential pathways linking genetic variation to human phenotype.

Original language	English
Pages (from-to)	18-29
Number of pages	12
Journal	Nature genetics
Volume	54
Issue number	1
DOIs	https://doi.org/10.1038/s41588-021-00969-x
Publication status	Published - Jan 2022

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10.1038/s41588-021-00969-x

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@article{2635f71d8aba441e99ee62d641cc6275,

title = "Genetic variation influencing DNA methylation provides insights into molecular mechanisms regulating genomic function",

abstract = "We determined the relationships between DNA sequence variation and DNA methylation using blood samples from 3,799 Europeans and 3,195 South Asians. We identify 11,165,559 SNP–CpG associations (methylation quantitative trait loci (meQTL), P < 10−14), including 467,915 meQTL that operate in trans. The meQTL are enriched for functionally relevant characteristics, including shared chromatin state, High-throuhgput chromosome conformation interaction, and association with gene expression, metabolic variation and clinical traits. We use molecular interaction and colocalization analyses to identify multiple nuclear regulatory pathways linking meQTL loci to phenotypic variation, including UBASH3B (body mass index), NFKBIE (rheumatoid arthritis), MGA (blood pressure) and COMMD7 (white cell counts). For rs6511961, chromatin immunoprecipitation followed by sequencing (ChIP–seq) validates zinc finger protein (ZNF)333 as the likely trans acting effector protein. Finally, we used interaction analyses to identify population- and lineage-specific meQTL, including rs174548 in FADS1, with the strongest effect in CD8+ T cells, thus linking fatty acid metabolism with immune dysregulation and asthma. Our study advances understanding of the potential pathways linking genetic variation to human phenotype.",

author = "{MuTHER Consortium} and Hawe, {Johann S.} and Rory Wilson and Schmid, {Katharina T.} and Li Zhou and Lakshmanan, {Lakshmi Narayanan} and Lehne, {Benjamin C.} and Brigitte K{\"u}hnel and Scott, {William R.} and Matthias Wielscher and Yew, {Yik Weng} and Clemens Baumbach and Lee, {Dominic P.} and Eirini Marouli and Manon Bernard and Liliane Pfeiffer and Mat{\'i}as-Garc{\'i}a, {Pamela R.} and Autio, {Matias I.} and Stephane Bourgeois and Christian Herder and Ville Karhunen and Thomas Meitinger and Holger Prokisch and Wolfgang Rathmann and Michael Roden and Sylvain Sebert and Jean Shin and Konstantin Strauch and Weihua Zhang and Tan, {Wilson L.W.} and Hauck, {Stefanie M.} and Juliane Merl-Pham and Harald Grallert and Barbosa, {Eudes G.V.} and Ahmadi, {Kourosh R.} and Chrysanthi Ainali and Amy Barrett and Veronique Bataille and Bell, {Jordana T.} and Alfonso Buil and Dermitzakis, {Emmanouil T.} and Dimas, {Antigone S.} and Richard Durbin and Daniel Glass and Elin Grundberg and Neelam Hassanali and Eshwar Meduri and {di Meglio}, Paola and Nestle, {Frank O.} and Spector, {Tim D.} and Sophia Tsoka",

note = "Funding Information: The KORA study was initiated and financed by the Helmholtz Zentrum M{\"u}nchen (German Research Center for Environmental Health), which is funded by the German Federal Ministry of Education and Research (BMBF) and by the state of Bavaria. KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universit{\"a}t, as part of LMUinnovativ. The work was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the EU Joint Programming Initiative {\textquoteleft}a Healthy Diet for a Healthy Life{\textquoteright} (DIMENSION grant number 01EA1902A). The work was further supported by the Bavarian State Ministry of Health and Care through the research project DigiMed Bayern (https:// www.digimed-bayern.de/). The German Diabetes Center (DDZ) is supported by the Ministry of Culture and Science of the State of North Rhine–Westphalia and the German Federal Ministry of Health. This study was supported in part by a grant from the German Federal Ministry of Education and Research to the German Center for Diabetes Research (DZD). The LOLIPOP study is supported by the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust, the British Heart Foundation (SP/04/002), the Medical Research Council (G0601966, G0700931), the Wellcome Trust (084723/Z/08/Z), the NIHR (RP-PG-0407-10371), European Union FP7 (EpiMigrant, 279143) and European Union Horizon 2020 (iHealth-T2D, 643774). B.C.L. is supported by the Imperial College Junior Research Fellowship scheme as well as an Academy of Medical Sciences Springboard award. J.C.C. is also supported by the Singapore NMRC (NMRC/ STaR/0028/2017). We thank the participants and research staff who made the study possible. For the Northern Finnish Birth Cohort studies, M. Wielscher was supported by the European Union{\textquoteright}s Horizon 2020 research and innovation program (grant 633212). NFBC1966 received financial support from the Academy of Finland (grants 104781, 120315, 129269, 1114194 and 24300796, Center of Excellence in Complex Disease Genetics and SALVE), University Hospital Oulu, Biocenter, University of Oulu, Finland (75617), NHLBI grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01), the NIH–NIMH (5R01MH63706:02), the ENGAGE project and grant agreement HEALTH-F4-2007-201413, EU FP7 EurHEALTHAgeing (277849), the Medical Research Council, UK (G0500539, G0600705, G1002319, PrevMetSyn/SALVE) and an MRC Centenary Early Career Award. NFBC1986 received financial support from EU QLG1-CT-2000-01643 (EUROBLCS) grant E51560, NorFA grant nos. 731, 20056 and 30167 and USA/NIHH 2000 G DF682 grant 50945. The NFBC programs are also funded by the H2020-633595 DynaHEALTH action, the Academy of Finland Exposomic, Genomic and Epigenomic Approach to Prediction of Metabolic and Cardiorespiratory Function and Ill-Health project (285547) and the EU H2020 ALEC project (grant agreement 633212). The MuTHER study was funded by the WT (081917/Z/07/Z). TwinsUK was funded by the WT and the European Community{\textquoteright}s Seventh Framework Programme (FP7/2007-2013). The study also received support from the NIHR Clinical Research Facility at Guy{\textquoteright}s and St. Thomas{\textquoteright} and King{\textquoteright}s College London. Analysis was funded by British Heart Foundation grant RG/14/5/30893 to P.D. and forms part of the research themes contributing to the translational research portfolio of the Barts Cardiovascular Biomedical Research Unit, which is funded by the NIHR. The Saguenay Youth Study has been funded by the Canadian Institutes of Health Research (T.P., Z.P.), the Heart and Stroke Foundation of Canada (Z.P.) and the Canadian Foundation for Innovation (Z.P.). We acknowledge G. M{\"o}ller and J. Adamski (Helmholtz Center Munich) for their support in the IP–MS transfection experiment. We used data generated by the PCHI-C Consortium31, funded by the UK NIHR, the Medical Research Council (MR/ L007150/1) and the Biotechnology and Biological Research Council (BB/J004480/1). Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2022",

month = jan,

doi = "10.1038/s41588-021-00969-x",

language = "English",

volume = "54",

pages = "18--29",

journal = "Nature genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "1",

}

TY - JOUR

T1 - Genetic variation influencing DNA methylation provides insights into molecular mechanisms regulating genomic function

AU - MuTHER Consortium

AU - Hawe, Johann S.

AU - Wilson, Rory

AU - Schmid, Katharina T.

AU - Zhou, Li

AU - Lakshmanan, Lakshmi Narayanan

AU - Lehne, Benjamin C.

AU - Kühnel, Brigitte

AU - Scott, William R.

AU - Wielscher, Matthias

AU - Yew, Yik Weng

AU - Baumbach, Clemens

AU - Lee, Dominic P.

AU - Marouli, Eirini

AU - Bernard, Manon

AU - Pfeiffer, Liliane

AU - Matías-García, Pamela R.

AU - Autio, Matias I.

AU - Bourgeois, Stephane

AU - Herder, Christian

AU - Karhunen, Ville

AU - Meitinger, Thomas

AU - Prokisch, Holger

AU - Rathmann, Wolfgang

AU - Roden, Michael

AU - Sebert, Sylvain

AU - Shin, Jean

AU - Strauch, Konstantin

AU - Zhang, Weihua

AU - Tan, Wilson L.W.

AU - Hauck, Stefanie M.

AU - Merl-Pham, Juliane

AU - Grallert, Harald

AU - Barbosa, Eudes G.V.

AU - Ahmadi, Kourosh R.

AU - Ainali, Chrysanthi

AU - Barrett, Amy

AU - Bataille, Veronique

AU - Bell, Jordana T.

AU - Buil, Alfonso

AU - Dermitzakis, Emmanouil T.

AU - Dimas, Antigone S.

AU - Durbin, Richard

AU - Glass, Daniel

AU - Grundberg, Elin

AU - Hassanali, Neelam

AU - Meduri, Eshwar

AU - di Meglio, Paola

AU - Nestle, Frank O.

AU - Spector, Tim D.

AU - Tsoka, Sophia

N1 - Funding Information: The KORA study was initiated and financed by the Helmholtz Zentrum München (German Research Center for Environmental Health), which is funded by the German Federal Ministry of Education and Research (BMBF) and by the state of Bavaria. KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. The work was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the EU Joint Programming Initiative ‘a Healthy Diet for a Healthy Life’ (DIMENSION grant number 01EA1902A). The work was further supported by the Bavarian State Ministry of Health and Care through the research project DigiMed Bayern (https:// www.digimed-bayern.de/). The German Diabetes Center (DDZ) is supported by the Ministry of Culture and Science of the State of North Rhine–Westphalia and the German Federal Ministry of Health. This study was supported in part by a grant from the German Federal Ministry of Education and Research to the German Center for Diabetes Research (DZD). The LOLIPOP study is supported by the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust, the British Heart Foundation (SP/04/002), the Medical Research Council (G0601966, G0700931), the Wellcome Trust (084723/Z/08/Z), the NIHR (RP-PG-0407-10371), European Union FP7 (EpiMigrant, 279143) and European Union Horizon 2020 (iHealth-T2D, 643774). B.C.L. is supported by the Imperial College Junior Research Fellowship scheme as well as an Academy of Medical Sciences Springboard award. J.C.C. is also supported by the Singapore NMRC (NMRC/ STaR/0028/2017). We thank the participants and research staff who made the study possible. For the Northern Finnish Birth Cohort studies, M. Wielscher was supported by the European Union’s Horizon 2020 research and innovation program (grant 633212). NFBC1966 received financial support from the Academy of Finland (grants 104781, 120315, 129269, 1114194 and 24300796, Center of Excellence in Complex Disease Genetics and SALVE), University Hospital Oulu, Biocenter, University of Oulu, Finland (75617), NHLBI grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01), the NIH–NIMH (5R01MH63706:02), the ENGAGE project and grant agreement HEALTH-F4-2007-201413, EU FP7 EurHEALTHAgeing (277849), the Medical Research Council, UK (G0500539, G0600705, G1002319, PrevMetSyn/SALVE) and an MRC Centenary Early Career Award. NFBC1986 received financial support from EU QLG1-CT-2000-01643 (EUROBLCS) grant E51560, NorFA grant nos. 731, 20056 and 30167 and USA/NIHH 2000 G DF682 grant 50945. The NFBC programs are also funded by the H2020-633595 DynaHEALTH action, the Academy of Finland Exposomic, Genomic and Epigenomic Approach to Prediction of Metabolic and Cardiorespiratory Function and Ill-Health project (285547) and the EU H2020 ALEC project (grant agreement 633212). The MuTHER study was funded by the WT (081917/Z/07/Z). TwinsUK was funded by the WT and the European Community’s Seventh Framework Programme (FP7/2007-2013). The study also received support from the NIHR Clinical Research Facility at Guy’s and St. Thomas’ and King’s College London. Analysis was funded by British Heart Foundation grant RG/14/5/30893 to P.D. and forms part of the research themes contributing to the translational research portfolio of the Barts Cardiovascular Biomedical Research Unit, which is funded by the NIHR. The Saguenay Youth Study has been funded by the Canadian Institutes of Health Research (T.P., Z.P.), the Heart and Stroke Foundation of Canada (Z.P.) and the Canadian Foundation for Innovation (Z.P.). We acknowledge G. Möller and J. Adamski (Helmholtz Center Munich) for their support in the IP–MS transfection experiment. We used data generated by the PCHI-C Consortium31, funded by the UK NIHR, the Medical Research Council (MR/ L007150/1) and the Biotechnology and Biological Research Council (BB/J004480/1). Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2022/1

Y1 - 2022/1

N2 - We determined the relationships between DNA sequence variation and DNA methylation using blood samples from 3,799 Europeans and 3,195 South Asians. We identify 11,165,559 SNP–CpG associations (methylation quantitative trait loci (meQTL), P < 10−14), including 467,915 meQTL that operate in trans. The meQTL are enriched for functionally relevant characteristics, including shared chromatin state, High-throuhgput chromosome conformation interaction, and association with gene expression, metabolic variation and clinical traits. We use molecular interaction and colocalization analyses to identify multiple nuclear regulatory pathways linking meQTL loci to phenotypic variation, including UBASH3B (body mass index), NFKBIE (rheumatoid arthritis), MGA (blood pressure) and COMMD7 (white cell counts). For rs6511961, chromatin immunoprecipitation followed by sequencing (ChIP–seq) validates zinc finger protein (ZNF)333 as the likely trans acting effector protein. Finally, we used interaction analyses to identify population- and lineage-specific meQTL, including rs174548 in FADS1, with the strongest effect in CD8+ T cells, thus linking fatty acid metabolism with immune dysregulation and asthma. Our study advances understanding of the potential pathways linking genetic variation to human phenotype.

AB - We determined the relationships between DNA sequence variation and DNA methylation using blood samples from 3,799 Europeans and 3,195 South Asians. We identify 11,165,559 SNP–CpG associations (methylation quantitative trait loci (meQTL), P < 10−14), including 467,915 meQTL that operate in trans. The meQTL are enriched for functionally relevant characteristics, including shared chromatin state, High-throuhgput chromosome conformation interaction, and association with gene expression, metabolic variation and clinical traits. We use molecular interaction and colocalization analyses to identify multiple nuclear regulatory pathways linking meQTL loci to phenotypic variation, including UBASH3B (body mass index), NFKBIE (rheumatoid arthritis), MGA (blood pressure) and COMMD7 (white cell counts). For rs6511961, chromatin immunoprecipitation followed by sequencing (ChIP–seq) validates zinc finger protein (ZNF)333 as the likely trans acting effector protein. Finally, we used interaction analyses to identify population- and lineage-specific meQTL, including rs174548 in FADS1, with the strongest effect in CD8+ T cells, thus linking fatty acid metabolism with immune dysregulation and asthma. Our study advances understanding of the potential pathways linking genetic variation to human phenotype.

UR - http://www.scopus.com/inward/record.url?scp=85122284960&partnerID=8YFLogxK

U2 - 10.1038/s41588-021-00969-x

DO - 10.1038/s41588-021-00969-x

M3 - Article

AN - SCOPUS:85122284960

SN - 1061-4036

VL - 54

SP - 18

EP - 29

JO - Nature genetics

JF - Nature genetics

IS - 1

ER -

Genetic variation influencing DNA methylation provides insights into molecular mechanisms regulating genomic function

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