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

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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 languageEnglish
Pages (from-to)195-205
Number of pages11
JournalHypertension
Volume76
Issue number1
Early online date10 Jun 2020
DOIs
Publication statusPublished - Jul 2020

Funding

FundersFunder number
National Heart, Lung, and Blood InstituteR03AG060619, R01AG016592, HL104125
National Heart, Lung, and Blood Institute
Paavo Nurmen Säätiö
Sigrid Juséliuksen Säätiö
Diabetes Fonds2013.81.1673
Diabetes Fonds
BBMRI-NLRP3, 917.14.374
Seventh Framework Programme
Seventh Framework Programme313010
Seventh Framework Programme
Suomen Akatemia263278, 312073, 265240, 308248, 297908
Suomen Akatemia
Netherlands Heart Foundation CVON2018-27
NBIC/BioAssist/RK2008.024
National Consortium for Healthy Ageing
Nierstichting126925, 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 Council637640
European Research Council
National Institute on AgingP20GM109036
National Institute on Aging
National Heart, Lung, and Blood Institute
Juho Vainion Säätiö
National Institute of General Medical SciencesHL125577, HL69999
National Institute of General Medical Sciences
Suomen Kulttuurirahasto
National Institutes of Health
European Commission261433
European Commission
ENGAGE602768
Emil Aaltosen Säätiö
Samfundet Folkhälsan, Liv och Hälsa
NWO-VIDI016.178.056, 024.003.001
National Institute for Public Health and the Environment
Turun Yliopistollinen KeskussairaalaX51001
Turun Yliopistollinen Keskussairaala
DORIAN278603
Oncode Institute715772
ZonMw
Rijksinstituut voor Volksgezondheid en Milieu
Amsterdam Public Health Research Institute
National Institute of Mental Health1RC2 MH089951, R01 DK092127-04, DA018673, U24 MH068457-06, R01D0042157-01A1, MH081802
National Institute of Mental Health
Suomen Akatemia118065
Suomen Akatemia
Ministerie van Volksgezondheid, Welzijn en SportS/132005
Ministerie van Volksgezondheid, Welzijn en Sport
Centre for Medical Systems Biology
American Heart AssociationGRNT20480211
American Heart Association
European Commission
BBMRI184.033.111, 184.021.007, NWO-56-464-14192
Signe ja Ane Gyllenbergin Säätiö
Avera Institute for Human Genetics2018/EW/00408559
European Science FoundationEU/ QLRT-2001-01254
European Science Foundation
Engineering Research Centers230374, 284167
Engineering Research Centers
Mississippi State Department of HealthHHSN268201800015I/HHSN26800001
SURFsara
Estonian Government0180142s08
Tartu Ülikool
Jackson State UniversityHHSN268201800013I
Jackson State University
Seventh Framework Programme
National Institute on Minority Health and Health DisparitiesU54GM115428
National Institute on Minority Health and Health Disparities
NWO-Groot480-15-001/674
Tampere University Hospital Supporting FoundationHL64157, HL105689
Horizon 2020848146, 322098, 755320, 742927
Horizon 2020
SydäntutkimussäätiöR01HL68630, R01HL125246, R01HL136205, 2K24 HL077506, R21 HL106333-01A1, R01AG026255
Sydäntutkimussäätiö
Biobanking and Biomolecular Resources Research Infrastructure
Finska Läkaresällskapet
University of Mississippi Medical CenterHHSN268201800012I, HHSN268201800011I, HHSN268201800010I
NCHA NGI050-060-810
Koninklijke Nederlandse Akademie van WetenschappenPAH/6635
Koninklijke Nederlandse Akademie van Wetenschappen
Tougaloo CollegeHHSN268201800014I
European Research Council
ZonMw016-115-035, 904-61-090, 904-61-193,480-04-004, 400-05-717, 985-10-002
ZonMw
Tampereen Tuberkuloosisäätiö
Yrjö Jahnssonin Säätiö
FP7-HEALTH-F4-2007-201301413

    Keywords

    • blood pressure
    • DNA methylation
    • epigenome
    • hypertension
    • Twin study

    Cohort Studies

    • Netherlands Twin Register (NTR)

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