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 × 10-7; replication: N = 7,182, p < 1.6 × 10-3). The replicated methylation sites are heritable (h2 > 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 | |
| Publication status | Published - 7 Dec 2017 |
| Externally published | Yes |
Cite this
}
DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation. / BIOS Consortium.
In: American journal of human genetics, Vol. 101, No. 6, 07.12.2017, p. 888-902.Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation
AU - BIOS Consortium
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, André 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 - Palmas, Walter
AU - Liu, Yongmei
AU - Paus, Tomáš
AU - Horvath, Steve
N1 - Copyright © 2017 American Society of Human Genetics. All rights reserved.
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 × 10-7; replication: N = 7,182, p < 1.6 × 10-3). The replicated methylation sites are heritable (h2 > 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 × 10-7; replication: N = 7,182, p < 1.6 × 10-3). The replicated methylation sites are heritable (h2 > 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 - Aged
KW - Blood Pressure/genetics
KW - CpG Islands/genetics
KW - Cross-Sectional Studies
KW - DNA Methylation/genetics
KW - Epigenesis, Genetic/genetics
KW - Genetic Variation/genetics
KW - Genome-Wide Association Study
KW - Humans
KW - Mendelian Randomization Analysis
KW - Middle Aged
KW - Nerve Tissue Proteins/genetics
KW - Quantitative Trait Loci/genetics
KW - Tetraspanins/genetics
U2 - 10.1016/j.ajhg.2017.09.028
DO - 10.1016/j.ajhg.2017.09.028
M3 - Article
VL - 101
SP - 888
EP - 902
JO - American journal of human genetics
JF - American journal of human genetics
SN - 0002-9297
IS - 6
ER -