DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation

Melissa A. Richard; Tianxiao Huan; Symen Ligthart; Rahul Gondalia; Min A. Jhun; Jennifer A. Brody; Marguerite R. Irvin; Riccardo Marioni; Jincheng Shen; Pei-Chien Tsai; May E. Montasser; Yucheng Jia; Catriona Syme; Elias L. Salfati; Eric Boerwinkle; Weihua Guan; Thomas H. Mosley; Jan Bressler; Alanna C. Morrison; Chunyu Liu; Michael M. Mendelson; Andre G. Uitterlinden; Joyce B. van Meurs; Oscar H. Franco; Guosheng Zhang; Yun Li; James D. Stewart; Joshua C. Bis; Bruce M. Psaty; Yii-Der Ida Chen; Sharon L. R. Kardia; Wei Zhao; Stephen T. Turner; Devin Absher; Stella Aslibekyan; John M. Starr; Allan F. Mcrae; Lifang Hou; Allan C. Just; Joel D. Schwartz; Pantel S. Vokonas; Cristina Menni; Tim D. Spector; Alan Shuldiner; Coleen M. Damcott; Jerome I. Rotter; BIOS Consortium; Marleen van Greevenbroek; Coen Stehouwer; Carla van der Kallen; Casper Schalkwijk; Myriam Fornage

doi:10.1016/j.ajhg.2017.09.028

DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation

Melissa A. Richard^*, Tianxiao Huan, Symen Ligthart, Rahul Gondalia, Min A. Jhun, Jennifer A. Brody, Marguerite R. Irvin, Riccardo Marioni, Jincheng Shen, Pei-Chien Tsai, May E. Montasser, Yucheng Jia, Catriona Syme, Elias L. Salfati, Eric Boerwinkle, Weihua Guan, Thomas H. Mosley, Jan Bressler, Alanna C. Morrison, Chunyu LiuMichael M. Mendelson, Andre G. Uitterlinden, Joyce B. van Meurs, Oscar H. Franco, Guosheng Zhang, Yun Li, James D. Stewart, Joshua C. Bis, Bruce M. Psaty, Yii-Der Ida Chen, Sharon L. R. Kardia, Wei Zhao, Stephen T. Turner, Devin Absher, Stella Aslibekyan, John M. Starr, Allan F. Mcrae, Lifang Hou, Allan C. Just, Joel D. Schwartz, Pantel S. Vokonas, Cristina Menni, Tim D. Spector, Alan Shuldiner, Coleen M. Damcott, Jerome I. Rotter, BIOS Consortium, Marleen van Greevenbroek, Coen Stehouwer, Carla van der Kallen, Casper Schalkwijk, Myriam Fornage^*

^*Corresponding author for this work

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

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Abstract

Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p <1.0 x 10(-7); replication: N = 7,182, p <1.6 x 10(-3)). The replicated methylation sites are heritable (h(2) > 30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.

Original language	English
Pages (from-to)	888-902
Number of pages	15
Journal	American Journal of Human Genetics
Volume	101
Issue number	6
DOIs	https://doi.org/10.1016/j.ajhg.2017.09.028
Publication status	Published - 7 Dec 2017

Keywords

GENOME-WIDE ASSOCIATION
METAANALYSIS
COMMON
HEART
HYPERTENSION
EXPRESSION
VARIANTS
RISK
INDIVIDUALS
POPULATIONS

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Richard, M. A., Huan, T., Ligthart, S., Gondalia, R., Jhun, M. A., Brody, J. A., Irvin, M. R., Marioni, R., Shen, J., Tsai, P.-C., Montasser, M. E., Jia, Y., Syme, C., Salfati, E. L., Boerwinkle, E., Guan, W., Mosley, T. H., Bressler, J., Morrison, A. C., ... Fornage, M. (2017). DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation. American Journal of Human Genetics, 101(6), 888-902. https://doi.org/10.1016/j.ajhg.2017.09.028

@article{469ed51ab0bb433c8c17a621ac6ae618,

title = "DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation",

abstract = "Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p <1.0 x 10(-7); replication: N = 7,182, p <1.6 x 10(-3)). The replicated methylation sites are heritable (h(2) > 30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.",

keywords = "GENOME-WIDE ASSOCIATION, METAANALYSIS, COMMON, HEART, HYPERTENSION, EXPRESSION, VARIANTS, RISK, INDIVIDUALS, POPULATIONS",

author = "Richard, {Melissa A.} and Tianxiao Huan and Symen Ligthart and Rahul Gondalia and Jhun, {Min A.} and Brody, {Jennifer A.} and Irvin, {Marguerite R.} and Riccardo Marioni and Jincheng Shen and Pei-Chien Tsai and Montasser, {May E.} and Yucheng Jia and Catriona Syme and Salfati, {Elias L.} and Eric Boerwinkle and Weihua Guan and Mosley, {Thomas H.} and Jan Bressler and Morrison, {Alanna C.} and Chunyu Liu and Mendelson, {Michael M.} and Uitterlinden, {Andre G.} and {van Meurs}, {Joyce B.} and Franco, {Oscar H.} and Guosheng Zhang and Yun Li and Stewart, {James D.} and Bis, {Joshua C.} and Psaty, {Bruce M.} and Chen, {Yii-Der Ida} and Kardia, {Sharon L. R.} and Wei Zhao and Turner, {Stephen T.} and Devin Absher and Stella Aslibekyan and Starr, {John M.} and Mcrae, {Allan F.} and Lifang Hou and Just, {Allan C.} and Schwartz, {Joel D.} and Vokonas, {Pantel S.} and Cristina Menni and Spector, {Tim D.} and Alan Shuldiner and Damcott, {Coleen M.} and Rotter, {Jerome I.} and {BIOS Consortium} and {van Greevenbroek}, Marleen and Coen Stehouwer and {van der Kallen}, Carla and Casper Schalkwijk and Myriam Fornage",

year = "2017",

month = dec,

day = "7",

doi = "10.1016/j.ajhg.2017.09.028",

language = "English",

volume = "101",

pages = "888--902",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "6",

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Richard, MA, Huan, T, Ligthart, S, Gondalia, R, Jhun, MA, Brody, JA, Irvin, MR, Marioni, R, Shen, J, Tsai, P-C, Montasser, ME, Jia, Y, Syme, C, Salfati, EL, Boerwinkle, E, Guan, W, Mosley, TH, Bressler, J, Morrison, AC, Liu, C, Mendelson, MM, Uitterlinden, AG, van Meurs, JB, Franco, OH, Zhang, G, Li, Y, Stewart, JD, Bis, JC, Psaty, BM, Chen, Y-DI, Kardia, SLR, Zhao, W, Turner, ST, Absher, D, Aslibekyan, S, Starr, JM, Mcrae, AF, Hou, L, Just, AC, Schwartz, JD, Vokonas, PS, Menni, C, Spector, TD, Shuldiner, A, Damcott, CM, Rotter, JI, BIOS Consortium, van Greevenbroek, M , Stehouwer, C , van der Kallen, C , Schalkwijk, C & Fornage, M 2017, 'DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation', American Journal of Human Genetics, vol. 101, no. 6, pp. 888-902. https://doi.org/10.1016/j.ajhg.2017.09.028

TY - JOUR

T1 - DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation

AU - Richard, Melissa A.

AU - Huan, Tianxiao

AU - Ligthart, Symen

AU - Gondalia, Rahul

AU - Jhun, Min A.

AU - Brody, Jennifer A.

AU - Irvin, Marguerite R.

AU - Marioni, Riccardo

AU - Shen, Jincheng

AU - Tsai, Pei-Chien

AU - Montasser, May E.

AU - Jia, Yucheng

AU - Syme, Catriona

AU - Salfati, Elias L.

AU - Boerwinkle, Eric

AU - Guan, Weihua

AU - Mosley, Thomas H.

AU - Bressler, Jan

AU - Morrison, Alanna C.

AU - Liu, Chunyu

AU - Mendelson, Michael M.

AU - Uitterlinden, Andre G.

AU - van Meurs, Joyce B.

AU - Franco, Oscar H.

AU - Zhang, Guosheng

AU - Li, Yun

AU - Stewart, James D.

AU - Bis, Joshua C.

AU - Psaty, Bruce M.

AU - Chen, Yii-Der Ida

AU - Kardia, Sharon L. R.

AU - Zhao, Wei

AU - Turner, Stephen T.

AU - Absher, Devin

AU - Aslibekyan, Stella

AU - Starr, John M.

AU - Mcrae, Allan F.

AU - Hou, Lifang

AU - Just, Allan C.

AU - Schwartz, Joel D.

AU - Vokonas, Pantel S.

AU - Menni, Cristina

AU - Spector, Tim D.

AU - Shuldiner, Alan

AU - Damcott, Coleen M.

AU - Rotter, Jerome I.

AU - BIOS Consortium

AU - van Greevenbroek, Marleen

AU - Stehouwer, Coen

AU - van der Kallen, Carla

AU - Schalkwijk, Casper

AU - Fornage, Myriam

PY - 2017/12/7

Y1 - 2017/12/7

N2 - Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p <1.0 x 10(-7); replication: N = 7,182, p <1.6 x 10(-3)). The replicated methylation sites are heritable (h(2) > 30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.

AB - Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p <1.0 x 10(-7); replication: N = 7,182, p <1.6 x 10(-3)). The replicated methylation sites are heritable (h(2) > 30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.

KW - GENOME-WIDE ASSOCIATION

KW - METAANALYSIS

KW - COMMON

KW - HEART

KW - HYPERTENSION

KW - EXPRESSION

KW - VARIANTS

KW - RISK

KW - INDIVIDUALS

KW - POPULATIONS

U2 - 10.1016/j.ajhg.2017.09.028

DO - 10.1016/j.ajhg.2017.09.028

M3 - Article

C2 - 29198723

SN - 0002-9297

VL - 101

SP - 888

EP - 902

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 6

ER -