Identification, Heritability, and Relation With Gene Expression of Novel DNA Methylation Loci for Blood Pressure

Yisong Huang; Miina Ollikainen; Maheswary Muniandy; Tao Zhang; Jenny van Dongen; Guang Hao; Peter J. van der Most; Yue Pan; Natalia Pervjakova; Yan V. Sun; Qin Hui; Jari Lahti; Eliza Fraszczyk; Xueling Lu; Dianjianyi Sun; Melissa A. Richard; Gonneke Willemsen; Kauko Heikkila; Irene Mateo Leach; Nina Mononen; Mika Kähönen; Mikko A. Hurme; Olli T. Raitakari; Amanda J. Drake; Markus Perola; Marja Liisa Nuotio; Yunfeng Huang; Batbayar Khulan; Katri Räikkönen; Bruce H.R. Wolffenbuttel; Alexandra Zhernakova; Jingyuan Fu; Haidong Zhu; Yanbin Dong; Jana V. van Vliet-Ostaptchouk; Lude Franke; Johan G. Eriksson; Myriam Fornage; Lili Milani; Terho Lehtimäki; Viola Vaccarino; Dorret I. Boomsma; Pim van der Harst; Eco J.C. de Geus; Veikko Salomaa; Shengxu Li; Wei Chen; Shaoyong Su; James Wilson; Harold Snieder; Jaakko Kaprio; Xiaoling Wang

doi:10.1161/HYPERTENSIONAHA.120.14973

Identification, Heritability, and Relation With Gene Expression of Novel DNA Methylation Loci for Blood Pressure

Yisong Huang, Miina Ollikainen, Maheswary Muniandy, Tao Zhang, Jenny van Dongen, Guang Hao, Peter J. van der Most, Yue Pan, Natalia Pervjakova, Yan V. Sun, Qin Hui, Jari Lahti, Eliza Fraszczyk, Xueling Lu, Dianjianyi Sun, Melissa A. Richard, Gonneke Willemsen, Kauko Heikkila, Irene Mateo Leach, Nina MononenMika Kähönen, Mikko A. Hurme, Olli T. Raitakari, Amanda J. Drake, Markus Perola, Marja Liisa Nuotio, Yunfeng Huang, Batbayar Khulan, Katri Räikkönen, Bruce H.R. Wolffenbuttel, Alexandra Zhernakova, Jingyuan Fu, Haidong Zhu, Yanbin Dong, Jana V. van Vliet-Ostaptchouk, Lude Franke, Johan G. Eriksson, Myriam Fornage, Lili Milani, Terho Lehtimäki, Viola Vaccarino, Dorret I. Boomsma, Pim van der Harst, Eco J.C. de Geus, Veikko Salomaa, Shengxu Li, Wei Chen, Shaoyong Su, James Wilson, Harold Snieder, Jaakko Kaprio, Xiaoling Wang

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

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Abstract

We conducted an epigenome-wide association study meta-analysis on blood pressure (BP) in 4820 individuals of European and African ancestry aged 14 to 69. Genome-wide DNA methylation data from peripheral leukocytes were obtained using the Infinium Human Methylation 450k BeadChip. The epigenome-wide association study meta-analysis identified 39 BP-related CpG sites with P<1×10-5. In silico replication in the CHARGE consortium of 17 010 individuals validated 16 of these CpG sites. Out of the 16 CpG sites, 13 showed novel association with BP. Conversely, out of the 126 CpG sites identified as being associated (P<1×10-7) with BP in the CHARGE consortium, 21 were replicated in the current study. Methylation levels of all the 34 CpG sites that were cross-validated by the current study and the CHARGE consortium were heritable and 6 showed association with gene expression. Furthermore, 9 CpG sites also showed association with BP with P<0.05 and consistent direction of the effect in the meta-analysis of the Finnish Twin Cohort (199 twin pairs and 4 singletons; 61% monozygous) and the Netherlands Twin Register (266 twin pairs and 62 singletons; 84% monozygous). Bivariate quantitative genetic modeling of the twin data showed that a majority of the phenotypic correlations between methylation levels of these CpG sites and BP could be explained by shared unique environmental rather than genetic factors, with 100% of the correlations of systolic BP with cg19693031 (TXNIP) and cg00716257 (JDP2) determined by environmental effects acting on both systolic BP and methylation levels.

Original language	English
Pages (from-to)	195-205
Number of pages	11
Journal	Hypertension
Volume	76
Issue number	1
Early online date	10 Jun 2020
DOIs	https://doi.org/10.1161/HYPERTENSIONAHA.120.14973
Publication status	Published - Jul 2020

Funding

This study was supported by National Institutes of Health (NIH)/ NHLBI (grant HL104125). Funding specific to each cohort was list below. The Bogalusa Heart Study (BHS): The BHS is a joint effort of many investigators and staff members whose contribution is gratefully acknowledged. The current study was supported by grants R01AG016592 and R03AG060619 from National Institute of Aging, and P20GM109036 from the National Institute of General Medical Sciences of the National Institutes of Health. The Georgia Stress and Heart Study (GSH): The GSH has been supported by NIH/NHLBI Grant HL69999. The current study was supported by NIH/NHLBI HL125577 and NIH/NHLBI HL104125. We would like to thank all the participants in the study and the staff at the Georgia Prevention Institute. The Dietary, Lifestyle, and Genetic determinants of Obesity and Metabolic syndrome (DILGOM) Study: The DILGOM study was supported by the Finnish Academy (grant #118065). V. Salomaa was also supported by the Finnish Foundation for Cardiovascular Research. The Emory Twin Study (ETS): The ETS has been supported by NIH R01HL68630, R01AG026255, R01HL125246, R01HL136205 and 2K24 HL077506. The current study was supported by NIH/NHLBI R21 HL106333-01A1. The Estonian Genome Center of the University of Tartu: The EGCUT studies were financed by University of Tartu (grant \u201CCenter of Translational Genomics\u201D), by Estonian Government (grant #SF0180142s08) and by European Commission through the European Regional Development Fund in the frame of grant \u201CCentre of Excellence in Genomics\u201D and Estonian Research Infrastructure\u2019s Roadmap and through FP7 grant #313010. The Finnish Twin Cohort (FTC): The FTC has been supported by the Academy of Finland (grants 265240, 263278, 308248, 312073 to J. Kaprio and 297908 to M. Ollikainen), and the Sigrid Juselius Foundation (to M. Ollikainen). The current DNA methylation study was supported by NIH/NHLBI grant HL104125. The Helsinki Birth Cohort Study (HBCS): The HBCS was supported by Finska L\u00E4kares\u00E4llskapet, the Finnish Special Governmental Subsidy for Health Sciences, Academy of Finland, Samfundet Folkh\u00E4lsan, Liv och H\u00E4lsa, the Signe and Ane Gyllenberg Foundation, EU FP7 (DORIAN) project number 278603. A.J. Drake and B. Khulan were supported by a Scottish Senior Clinical Fellowship SCD/09 (to A.J. Drake). The Jackson Heart Study (JHS): The JHS is supported and conducted in collaboration with Jackson State University (HHSN268201800013I), Tougaloo College (HHSN268201800014I), the Mississippi State Department of Health (HHSN268201800015I/HHSN26800001) and the University of Mississippi Medical Center (HHSN268201800010I, HHSN268201800011I and HHSN268201800012I) contracts from the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute for Minority Health and Health Disparities (NIMHD). The current DNA methylation study was supported by NIH/NHLBI grant HL104125. The authors also wish to thank the staff and participants of the JHS. J. Wilson is supported by U54GM115428 from the National Institute of General Medical Sciences. The Lifelines Cohort Study: This work was supported by the National Consortium for Healthy Ageing (NCHA; NCHA NGI Grant 050-060-810), a grant from the National Institute for Public Health and the Environment (RIVM) and the Ministry of Health, Welfare and Sports of the Netherlands (S/132005), the European Union\u2019s Seventh Framework programme (FP7/2007-2013) through the Biobank Standardisation and Harmonisation for Research Excellence in the European Union (BioSHaRE-EU) project, grant agreement 261433, and by the Dutch Diabetes Foundation (Diabetes Funds Junior Fellowship grant 2013.81.1673 to J.V. van Vliet-Ostaptchouk). The Netherlands Twin Register: Funding for the NTR was obtained from the Netherlands Organization for Scientific Research (NWO) and The Netherlands Organisation for Health Research and Development (ZonMW) grants 904-61-090, 985-10-002, 904-61-193,480-04-004, 400-05-717, Addiction-31160008, 016-115-035, Middelgroot-911-09-032, NWO-Groot 480-15-001/674, Center for Medical Systems Biology (CSMB, NWO Genomics), NBIC/BioAssist/RK(2008.024), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI\u2013NL, 184.021.007 and 184.033.111); Spinozapremie (NWO-56-464-14192), KNAW Academy Professor Award (PAH/6635), and University Research Fellow grant (URF) to DIB; Amsterdam Public Health research institute (former EMGO+); the European Science Foundation (ESF, EU/ QLRT-2001-01254), the European Community\u2019s Seventh Framework Program (FP7-HEALTH-F4-2007-2013, grant 01413: ENGAGE and grant 602768: ACTION); the European Research Council (ERC Starting 284167, ERC Consolidator 771057, ERC Advanced 230374), Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the National Institutes of Health (NIH, R01D0042157-01A1, MH081802, DA018673, R01 DK092127-04, Grand Opportunity grants 1RC2 MH089951); the Avera Institute for Human Genetics, Sioux Falls, South Dakota. Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. Computing was supported by NWO through grant 2018/EW/00408559, BiG Grid, the Dutch e-Science Grid and SURFSARA. The Prevention of Renal and Vascular End stage Disease study: The PREVEND Study was funded by grants from the Dutch Kidney Foundation (grant E.033). The current DNA methylation study was supported by NIH/NHLBI grant HL104125. The Young Finns Study has been financially supported by the Academy of Finland: grants 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi); the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals (grant X51001); Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research; Finnish Cultural Foundation; The Sigrid Juselius Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrj\u00F6 Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; The Finnish Cultural Foundation\u2014The Pirkanmaa Regional Fund; Diabetes Research Foundation of Finnish Diabetes Association; EU Horizon 2020 (grant 755320 for TAXINOMISIS and grant 848146 for To-AiTION); European Research Council (grant 742927 for MULTIEPIGEN project); Academy of Finland grant no. 322098; and Tampere University Hospital Supporting Foundation. The Epigenetic basis of Obesity induced cardiovascular disease and type 2 diabetes study: The EpiGO study was supported by NIH/NHLBI grant HL105689. The Lifestyle, Adiposity, and Cardiovascular Health in Youth study: The LACHY study was supported by NIH/NHLBI grant HL64157. The current DNA methylation study was supported by NIH/NHLBI grant HL105689 and AHA grant GRNT20480211. The Lifelines Deep Cohort: this project was funded by the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL) grant RP3 to L. Franke. L. Franke receives Nederlands Organisation for Scentific Research (NWO) ZonMW-VIDI 917.14.374, European Research Council ERC Starting grant Immrisk 637640 and financial support from Oncode Institute. A. Zhernakova is supported by ERC Starting Grant 715772, NWO-VIDI grant 016.178.056, and NWO Gravitation grant ExposomeNL. J. Fu is supported by NWO Gravitation Netherlands Organ-on-Chip Initiative (024.003.001) and the Netherlands Heart Foundation CVON grant 2018-27.

Funders	Funder number
National Heart, Lung, and Blood Institute	R03AG060619, R01AG016592, HL104125
National Heart, Lung, and Blood Institute
Paavo Nurmen Säätiö
Sigrid Juséliuksen Säätiö
Diabetes Fonds	2013.81.1673
Diabetes Fonds
BBMRI-NL	RP3, 917.14.374
Seventh Framework Programme
Seventh Framework Programme	313010
Seventh Framework Programme
Suomen Akatemia	263278, 312073, 265240, 308248, 297908
Suomen Akatemia
Netherlands Heart Foundation CVON	2018-27
NBIC/BioAssist/RK	2008.024
National Consortium for Healthy Ageing
Nierstichting	126925, 121584, 129378, 117787, E.033, 41071, 286284, 134309, 124282
Nierstichting
European Regional Development Fund
Seventh Framework Programme
Estonian Genome Center of the University of Tartu
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
European Research Council	637640
European Research Council
National Institute on Aging	P20GM109036
National Institute on Aging
National Heart, Lung, and Blood Institute
Juho Vainion Säätiö
National Institute of General Medical Sciences	HL125577, HL69999
National Institute of General Medical Sciences
Suomen Kulttuurirahasto
National Institutes of Health
European Commission	261433
European Commission
ENGAGE	602768
Emil Aaltosen Säätiö
Samfundet Folkhälsan, Liv och Hälsa
NWO-VIDI	016.178.056, 024.003.001
National Institute for Public Health and the Environment
Turun Yliopistollinen Keskussairaala	X51001
Turun Yliopistollinen Keskussairaala
DORIAN	278603
Oncode Institute	715772
ZonMw
Rijksinstituut voor Volksgezondheid en Milieu
Amsterdam Public Health Research Institute
National Institute of Mental Health	1RC2 MH089951, R01 DK092127-04, DA018673, U24 MH068457-06, R01D0042157-01A1, MH081802
National Institute of Mental Health
Suomen Akatemia	118065
Suomen Akatemia
Ministerie van Volksgezondheid, Welzijn en Sport	S/132005
Ministerie van Volksgezondheid, Welzijn en Sport
Centre for Medical Systems Biology
American Heart Association	GRNT20480211
American Heart Association
European Commission
BBMRI	184.033.111, 184.021.007, NWO-56-464-14192
Signe ja Ane Gyllenbergin Säätiö
Avera Institute for Human Genetics	2018/EW/00408559
European Science Foundation	EU/ QLRT-2001-01254
European Science Foundation
Engineering Research Centers	230374, 284167
Engineering Research Centers
Mississippi State Department of Health	HHSN268201800015I/HHSN26800001
SURFsara
Estonian Government	0180142s08
Tartu Ülikool
Jackson State University	HHSN268201800013I
Jackson State University
Seventh Framework Programme
National Institute on Minority Health and Health Disparities	U54GM115428
National Institute on Minority Health and Health Disparities
NWO-Groot	480-15-001/674
Tampere University Hospital Supporting Foundation	HL64157, HL105689
Horizon 2020	848146, 322098, 755320, 742927
Horizon 2020
Sydäntutkimussäätiö	R01HL68630, R01HL125246, R01HL136205, 2K24 HL077506, R21 HL106333-01A1, R01AG026255
Sydäntutkimussäätiö
Biobanking and Biomolecular Resources Research Infrastructure
Finska Läkaresällskapet
University of Mississippi Medical Center	HHSN268201800012I, HHSN268201800011I, HHSN268201800010I
NCHA NGI	050-060-810
Koninklijke Nederlandse Akademie van Wetenschappen	PAH/6635
Koninklijke Nederlandse Akademie van Wetenschappen
Tougaloo College	HHSN268201800014I
European Research Council
ZonMw	016-115-035, 904-61-090, 904-61-193,480-04-004, 400-05-717, 985-10-002
ZonMw
Tampereen Tuberkuloosisäätiö
Yrjö Jahnssonin Säätiö
FP7-HEALTH-F4-2007-2013	01413

Keywords

blood pressure
DNA methylation
epigenome
hypertension
Twin study

Cohort Studies

Netherlands Twin Register (NTR)

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10.1161/HYPERTENSIONAHA.120.14973

Identification, Heritability, and Relation With Gene Expression of Novel DNA Methylation Loci for Blood PressureFinal published version, 256 KBLicence: Article 25fa Dutch Copyright Act

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Huang, Y., Ollikainen, M., Muniandy, M., Zhang, T., van Dongen, J., Hao, G., van der Most, P. J., Pan, Y., Pervjakova, N., Sun, Y. V., Hui, Q., Lahti, J., Fraszczyk, E., Lu, X., Sun, D., Richard, M. A., Willemsen, G., Heikkila, K., Mateo Leach, I., ... Wang, X. (2020). Identification, Heritability, and Relation With Gene Expression of Novel DNA Methylation Loci for Blood Pressure. Hypertension, 76(1), 195-205. https://doi.org/10.1161/HYPERTENSIONAHA.120.14973

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title = "Identification, Heritability, and Relation With Gene Expression of Novel DNA Methylation Loci for Blood Pressure",

abstract = "We conducted an epigenome-wide association study meta-analysis on blood pressure (BP) in 4820 individuals of European and African ancestry aged 14 to 69. Genome-wide DNA methylation data from peripheral leukocytes were obtained using the Infinium Human Methylation 450k BeadChip. The epigenome-wide association study meta-analysis identified 39 BP-related CpG sites with P<1×10-5. In silico replication in the CHARGE consortium of 17 010 individuals validated 16 of these CpG sites. Out of the 16 CpG sites, 13 showed novel association with BP. Conversely, out of the 126 CpG sites identified as being associated (P<1×10-7) with BP in the CHARGE consortium, 21 were replicated in the current study. Methylation levels of all the 34 CpG sites that were cross-validated by the current study and the CHARGE consortium were heritable and 6 showed association with gene expression. Furthermore, 9 CpG sites also showed association with BP with P<0.05 and consistent direction of the effect in the meta-analysis of the Finnish Twin Cohort (199 twin pairs and 4 singletons; 61% monozygous) and the Netherlands Twin Register (266 twin pairs and 62 singletons; 84% monozygous). Bivariate quantitative genetic modeling of the twin data showed that a majority of the phenotypic correlations between methylation levels of these CpG sites and BP could be explained by shared unique environmental rather than genetic factors, with 100% of the correlations of systolic BP with cg19693031 (TXNIP) and cg00716257 (JDP2) determined by environmental effects acting on both systolic BP and methylation levels.",

keywords = "blood pressure, DNA methylation, epigenome, hypertension, Twin study",

author = "Yisong Huang and Miina Ollikainen and Maheswary Muniandy and Tao Zhang and {van Dongen}, Jenny and Guang Hao and {van der Most}, {Peter J.} and Yue Pan and Natalia Pervjakova and Sun, {Yan V.} and Qin Hui and Jari Lahti and Eliza Fraszczyk and Xueling Lu and Dianjianyi Sun and Richard, {Melissa A.} and Gonneke Willemsen and Kauko Heikkila and {Mateo Leach}, Irene and Nina Mononen and Mika K{\"a}h{\"o}nen and Hurme, {Mikko A.} and Raitakari, {Olli T.} and Drake, {Amanda J.} and Markus Perola and Nuotio, {Marja Liisa} and Yunfeng Huang and Batbayar Khulan and Katri R{\"a}ikk{\"o}nen and Wolffenbuttel, {Bruce H.R.} and Alexandra Zhernakova and Jingyuan Fu and Haidong Zhu and Yanbin Dong and {van Vliet-Ostaptchouk}, {Jana V.} and Lude Franke and Eriksson, {Johan G.} and Myriam Fornage and Lili Milani and Terho Lehtim{\"a}ki and Viola Vaccarino and Boomsma, {Dorret I.} and {van der Harst}, Pim and {de Geus}, {Eco J.C.} and Veikko Salomaa and Shengxu Li and Wei Chen and Shaoyong Su and James Wilson and Harold Snieder and Jaakko Kaprio and Xiaoling Wang",

year = "2020",

month = jul,

doi = "10.1161/HYPERTENSIONAHA.120.14973",

language = "English",

volume = "76",

pages = "195--205",

journal = "Hypertension",

issn = "0194-911X",

publisher = "Lippincott Williams and Wilkins",

number = "1",

}

Huang, Y, Ollikainen, M, Muniandy, M, Zhang, T, van Dongen, J, Hao, G, van der Most, PJ, Pan, Y, Pervjakova, N, Sun, YV, Hui, Q, Lahti, J, Fraszczyk, E, Lu, X, Sun, D, Richard, MA, Willemsen, G, Heikkila, K, Mateo Leach, I, Mononen, N, Kähönen, M, Hurme, MA, Raitakari, OT, Drake, AJ, Perola, M, Nuotio, ML, Huang, Y, Khulan, B, Räikkönen, K, Wolffenbuttel, BHR, Zhernakova, A, Fu, J, Zhu, H, Dong, Y, van Vliet-Ostaptchouk, JV, Franke, L, Eriksson, JG, Fornage, M, Milani, L, Lehtimäki, T, Vaccarino, V, Boomsma, DI, van der Harst, P, de Geus, EJC, Salomaa, V, Li, S, Chen, W, Su, S, Wilson, J, Snieder, H, Kaprio, J & Wang, X 2020, 'Identification, Heritability, and Relation With Gene Expression of Novel DNA Methylation Loci for Blood Pressure', Hypertension, vol. 76, no. 1, pp. 195-205. https://doi.org/10.1161/HYPERTENSIONAHA.120.14973

TY - JOUR

T1 - Identification, Heritability, and Relation With Gene Expression of Novel DNA Methylation Loci for Blood Pressure

AU - Huang, Yisong

AU - Ollikainen, Miina

AU - Muniandy, Maheswary

AU - Zhang, Tao

AU - van Dongen, Jenny

AU - Hao, Guang

AU - van der Most, Peter J.

AU - Pan, Yue

AU - Pervjakova, Natalia

AU - Sun, Yan V.

AU - Hui, Qin

AU - Lahti, Jari

AU - Fraszczyk, Eliza

AU - Lu, Xueling

AU - Sun, Dianjianyi

AU - Richard, Melissa A.

AU - Willemsen, Gonneke

AU - Heikkila, Kauko

AU - Mateo Leach, Irene

AU - Mononen, Nina

AU - Kähönen, Mika

AU - Hurme, Mikko A.

AU - Raitakari, Olli T.

AU - Drake, Amanda J.

AU - Perola, Markus

AU - Nuotio, Marja Liisa

AU - Huang, Yunfeng

AU - Khulan, Batbayar

AU - Räikkönen, Katri

AU - Wolffenbuttel, Bruce H.R.

AU - Zhernakova, Alexandra

AU - Fu, Jingyuan

AU - Zhu, Haidong

AU - Dong, Yanbin

AU - van Vliet-Ostaptchouk, Jana V.

AU - Franke, Lude

AU - Eriksson, Johan G.

AU - Fornage, Myriam

AU - Milani, Lili

AU - Lehtimäki, Terho

AU - Vaccarino, Viola

AU - Boomsma, Dorret I.

AU - van der Harst, Pim

AU - de Geus, Eco J.C.

AU - Salomaa, Veikko

AU - Li, Shengxu

AU - Chen, Wei

AU - Su, Shaoyong

AU - Wilson, James

AU - Snieder, Harold

AU - Kaprio, Jaakko

AU - Wang, Xiaoling

PY - 2020/7

Y1 - 2020/7

N2 - We conducted an epigenome-wide association study meta-analysis on blood pressure (BP) in 4820 individuals of European and African ancestry aged 14 to 69. Genome-wide DNA methylation data from peripheral leukocytes were obtained using the Infinium Human Methylation 450k BeadChip. The epigenome-wide association study meta-analysis identified 39 BP-related CpG sites with P<1×10-5. In silico replication in the CHARGE consortium of 17 010 individuals validated 16 of these CpG sites. Out of the 16 CpG sites, 13 showed novel association with BP. Conversely, out of the 126 CpG sites identified as being associated (P<1×10-7) with BP in the CHARGE consortium, 21 were replicated in the current study. Methylation levels of all the 34 CpG sites that were cross-validated by the current study and the CHARGE consortium were heritable and 6 showed association with gene expression. Furthermore, 9 CpG sites also showed association with BP with P<0.05 and consistent direction of the effect in the meta-analysis of the Finnish Twin Cohort (199 twin pairs and 4 singletons; 61% monozygous) and the Netherlands Twin Register (266 twin pairs and 62 singletons; 84% monozygous). Bivariate quantitative genetic modeling of the twin data showed that a majority of the phenotypic correlations between methylation levels of these CpG sites and BP could be explained by shared unique environmental rather than genetic factors, with 100% of the correlations of systolic BP with cg19693031 (TXNIP) and cg00716257 (JDP2) determined by environmental effects acting on both systolic BP and methylation levels.

AB - We conducted an epigenome-wide association study meta-analysis on blood pressure (BP) in 4820 individuals of European and African ancestry aged 14 to 69. Genome-wide DNA methylation data from peripheral leukocytes were obtained using the Infinium Human Methylation 450k BeadChip. The epigenome-wide association study meta-analysis identified 39 BP-related CpG sites with P<1×10-5. In silico replication in the CHARGE consortium of 17 010 individuals validated 16 of these CpG sites. Out of the 16 CpG sites, 13 showed novel association with BP. Conversely, out of the 126 CpG sites identified as being associated (P<1×10-7) with BP in the CHARGE consortium, 21 were replicated in the current study. Methylation levels of all the 34 CpG sites that were cross-validated by the current study and the CHARGE consortium were heritable and 6 showed association with gene expression. Furthermore, 9 CpG sites also showed association with BP with P<0.05 and consistent direction of the effect in the meta-analysis of the Finnish Twin Cohort (199 twin pairs and 4 singletons; 61% monozygous) and the Netherlands Twin Register (266 twin pairs and 62 singletons; 84% monozygous). Bivariate quantitative genetic modeling of the twin data showed that a majority of the phenotypic correlations between methylation levels of these CpG sites and BP could be explained by shared unique environmental rather than genetic factors, with 100% of the correlations of systolic BP with cg19693031 (TXNIP) and cg00716257 (JDP2) determined by environmental effects acting on both systolic BP and methylation levels.

KW - blood pressure

KW - DNA methylation

KW - epigenome

KW - hypertension

KW - Twin study

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DO - 10.1161/HYPERTENSIONAHA.120.14973

M3 - Article

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SN - 0194-911X

VL - 76

SP - 195

EP - 205

JO - Hypertension

JF - Hypertension

IS - 1

ER -

Identification, Heritability, and Relation With Gene Expression of Novel DNA Methylation Loci for Blood Pressure

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Cohort Studies

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