Epigenetic patterns in blood associated with lipid traits predict incident coronary heart disease events and are enriched for results from genome-wide association studies

Asa K. Hedman; Michael M Mendelson; Riccardo Marioni; Stefan Gustafsson; Roby Joehanes; Marguerite R Irvin; Degui Zhi; Johanna K.  Sandling; Chengcan Yao; Chunyu Liu; Liming Liang; Tianxiao  Huan; Allan F. Mcrae; Serkalem Demissie; Sonia Shah; John Starr; L. Adrienne Cupples; Panos Deloukas; Timothy D. Spector; Johan Sundström; Ronald M. Krauss; Donna K Arnett; Ian Deary; Lars Lind; Daniel Levy; Erik Ingelsson

doi:10.1161/CIRCGENETICS.116.001487

Epigenetic patterns in blood associated with lipid traits predict incident coronary heart disease events and are enriched for results from genome-wide association studies

Asa K. Hedman, Michael M Mendelson, Riccardo Marioni, Stefan Gustafsson, Roby Joehanes, Marguerite R Irvin, Degui Zhi, Johanna K. Sandling, Chengcan Yao, Chunyu Liu, Liming Liang, Tianxiao Huan, Allan F. Mcrae, Serkalem Demissie, Sonia Shah, John Starr, L. Adrienne Cupples, Panos Deloukas, Timothy D. Spector, Johan SundströmRonald M. Krauss, Donna K Arnett, Ian Deary, Lars Lind, Daniel Levy, Erik Ingelsson

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

Abstract

Background Genome-wide association studies (GWAS) have identified loci influencing circulating lipid concentrations in humans; further information on novel contributing genes, pathways and biology may be gained through studies of epigenetic modifications. Methods and Results To identify epigenetic changes associated with lipid concentrations, we assayed genome-wide DNA methylation at cytosine-guanine dinucleotides (CpGs) in whole blood from 2,306 individuals from two population-based cohorts, with replication of findings in 2,025 additional individuals. We identified 193 CpGs associated with lipid levels in the discovery stage (P <1.08E-07) and replicated 33 (at Bonferroni-corrected P<0.05), including 25 novel CpGs not previously associated with lipids. Genes at lipid-associated CpGs were enriched in lipid and amino acid metabolism processes. A differentially methylated locus associated with TG and HDL-C (cg27243685; P= 8.1E-26 and 9.3E-19) was associated with cis-expression of a reverse-cholesterol transporter (ABCG1; P=7.2E-28), and incident cardiovascular disease events (HR per SD increment = 1.38, 95% CI, 1.15-1.66, P=0.0007). We found significant cis methylation quantitative trait loci (cis-meQTLs) at 64% of the 193 CpGs with an enrichment of signals from GWAS of lipid levels (PTC =0.004, PHDL-C=0.008 and PTG=0.00003) and coronary heart disease (P=0.0007). For example, genome-wide significant variants associated with LDL-C and coronary heart disease at APOB were cis-meQTLs for a LDL-C-related differentially methylated locus. Conclusions We report novel associations of DNA methylation with lipid levels, describe epigenetic mechanisms related to previous GWAS discoveries and provide evidence implicating epigenetic regulation of reverse cholesterol transport in blood in relation to occurrence of cardiovascular disease events. Keywords: lipids, cardiovascular diseases, epigenetics, gene expression/regulation, genome-wide analysis

Original language	English
Article number	e001487
Journal	Circulation: Cardiovascular Genetics
Volume	10
Issue number	1
Early online date	17 Feb 2017
DOIs	https://doi.org/10.1161/CIRCGENETICS.116.001487
Publication status	Published - 2017

Keywords / Materials (for Non-textual outputs)

lipids
genome - wide analysis
gene expression/regulation
cardiovascular diseases
epigenetics

Access to Document

10.1161/CIRCGENETICS.116.001487Licence: Creative Commons: Attribution (CC-BY)

HedmanEtalCCG2017EpigeneticPatternsINBloodFinal published version, 2.22 MBLicence: Creative Commons: Attribution (CC-BY)

RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.
Deary, I., Gale, C., Holmes, M., Logie, P., Maclullich, A., Porteous, D., Seckl, J., Starr, J., Wardlaw, J. & Okely, J.
1/09/13 → 31/08/19
Project: Research

Cite this

Hedman, A. K., Mendelson, M. M., Marioni, R., Gustafsson, S., Joehanes, R., Irvin, M. R., Zhi, D., Sandling, J. K., Yao, C., Liu, C., Liang, L., Huan, T., Mcrae, A. F., Demissie, S., Shah, S., Starr, J., Adrienne Cupples, L., Deloukas, P., Spector, T. D., ... Ingelsson, E. (2017). Epigenetic patterns in blood associated with lipid traits predict incident coronary heart disease events and are enriched for results from genome-wide association studies. Circulation: Cardiovascular Genetics, 10(1), Article e001487. https://doi.org/10.1161/CIRCGENETICS.116.001487

@article{394d7057630040f5a79872d70a3663a8,

title = "Epigenetic patterns in blood associated with lipid traits predict incident coronary heart disease events and are enriched for results from genome-wide association studies",

abstract = "Background Genome-wide association studies (GWAS) have identified loci influencing circulating lipid concentrations in humans; further information on novel contributing genes, pathways and biology may be gained through studies of epigenetic modifications. Methods and Results To identify epigenetic changes associated with lipid concentrations, we assayed genome-wide DNA methylation at cytosine-guanine dinucleotides (CpGs) in whole blood from 2,306 individuals from two population-based cohorts, with replication of findings in 2,025 additional individuals. We identified 193 CpGs associated with lipid levels in the discovery stage (P <1.08E-07) and replicated 33 (at Bonferroni-corrected P<0.05), including 25 novel CpGs not previously associated with lipids. Genes at lipid-associated CpGs were enriched in lipid and amino acid metabolism processes. A differentially methylated locus associated with TG and HDL-C (cg27243685; P= 8.1E-26 and 9.3E-19) was associated with cis-expression of a reverse-cholesterol transporter (ABCG1; P=7.2E-28), and incident cardiovascular disease events (HR per SD increment = 1.38, 95% CI, 1.15-1.66, P=0.0007). We found significant cis methylation quantitative trait loci (cis-meQTLs) at 64% of the 193 CpGs with an enrichment of signals from GWAS of lipid levels (PTC =0.004, PHDL-C=0.008 and PTG=0.00003) and coronary heart disease (P=0.0007). For example, genome-wide significant variants associated with LDL-C and coronary heart disease at APOB were cis-meQTLs for a LDL-C-related differentially methylated locus. Conclusions We report novel associations of DNA methylation with lipid levels, describe epigenetic mechanisms related to previous GWAS discoveries and provide evidence implicating epigenetic regulation of reverse cholesterol transport in blood in relation to occurrence of cardiovascular disease events. Keywords: lipids, cardiovascular diseases, epigenetics, gene expression/regulation, genome-wide analysis ",

keywords = "lipids, genome - wide analysis, gene expression/regulation, cardiovascular diseases, epigenetics",

author = "Hedman, {Asa K.} and Mendelson, {Michael M} and Riccardo Marioni and Stefan Gustafsson and Roby Joehanes and Irvin, {Marguerite R} and Degui Zhi and Sandling, {Johanna K.} and Chengcan Yao and Chunyu Liu and Liming Liang and Tianxiao Huan and Mcrae, {Allan F.} and Serkalem Demissie and Sonia Shah and John Starr and {Adrienne Cupples}, L. and Panos Deloukas and Spector, {Timothy D.} and Johan Sundstr{\"o}m and Krauss, {Ronald M.} and Arnett, {Donna K} and Ian Deary and Lars Lind and Daniel Levy and Erik Ingelsson",

year = "2017",

doi = "10.1161/CIRCGENETICS.116.001487",

language = "English",

volume = "10",

journal = "Circulation: Cardiovascular Genetics",

issn = "1942-325X",

publisher = "Lippincott Williams & Wilkins",

number = "1",

}

Hedman, AK, Mendelson, MM, Marioni, R, Gustafsson, S, Joehanes, R, Irvin, MR, Zhi, D, Sandling, JK, Yao, C, Liu, C, Liang, L, Huan, T, Mcrae, AF, Demissie, S, Shah, S, Starr, J, Adrienne Cupples, L, Deloukas, P, Spector, TD, Sundström, J, Krauss, RM, Arnett, DK, Deary, I, Lind, L, Levy, D & Ingelsson, E 2017, 'Epigenetic patterns in blood associated with lipid traits predict incident coronary heart disease events and are enriched for results from genome-wide association studies', Circulation: Cardiovascular Genetics, vol. 10, no. 1, e001487. https://doi.org/10.1161/CIRCGENETICS.116.001487

Epigenetic patterns in blood associated with lipid traits predict incident coronary heart disease events and are enriched for results from genome-wide association studies. / Hedman, Asa K.; Mendelson, Michael M; Marioni, Riccardo et al.
In: Circulation: Cardiovascular Genetics, Vol. 10, No. 1, e001487, 2017.

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

TY - JOUR

T1 - Epigenetic patterns in blood associated with lipid traits predict incident coronary heart disease events and are enriched for results from genome-wide association studies

AU - Hedman, Asa K.

AU - Mendelson, Michael M

AU - Marioni, Riccardo

AU - Gustafsson, Stefan

AU - Joehanes, Roby

AU - Irvin, Marguerite R

AU - Zhi, Degui

AU - Sandling, Johanna K.

AU - Yao, Chengcan

AU - Liu, Chunyu

AU - Liang, Liming

AU - Huan, Tianxiao

AU - Mcrae, Allan F.

AU - Demissie, Serkalem

AU - Shah, Sonia

AU - Starr, John

AU - Adrienne Cupples, L.

AU - Deloukas, Panos

AU - Spector, Timothy D.

AU - Sundström, Johan

AU - Krauss, Ronald M.

AU - Arnett, Donna K

AU - Deary, Ian

AU - Lind, Lars

AU - Levy, Daniel

AU - Ingelsson, Erik

PY - 2017

Y1 - 2017

N2 - Background Genome-wide association studies (GWAS) have identified loci influencing circulating lipid concentrations in humans; further information on novel contributing genes, pathways and biology may be gained through studies of epigenetic modifications. Methods and Results To identify epigenetic changes associated with lipid concentrations, we assayed genome-wide DNA methylation at cytosine-guanine dinucleotides (CpGs) in whole blood from 2,306 individuals from two population-based cohorts, with replication of findings in 2,025 additional individuals. We identified 193 CpGs associated with lipid levels in the discovery stage (P <1.08E-07) and replicated 33 (at Bonferroni-corrected P<0.05), including 25 novel CpGs not previously associated with lipids. Genes at lipid-associated CpGs were enriched in lipid and amino acid metabolism processes. A differentially methylated locus associated with TG and HDL-C (cg27243685; P= 8.1E-26 and 9.3E-19) was associated with cis-expression of a reverse-cholesterol transporter (ABCG1; P=7.2E-28), and incident cardiovascular disease events (HR per SD increment = 1.38, 95% CI, 1.15-1.66, P=0.0007). We found significant cis methylation quantitative trait loci (cis-meQTLs) at 64% of the 193 CpGs with an enrichment of signals from GWAS of lipid levels (PTC =0.004, PHDL-C=0.008 and PTG=0.00003) and coronary heart disease (P=0.0007). For example, genome-wide significant variants associated with LDL-C and coronary heart disease at APOB were cis-meQTLs for a LDL-C-related differentially methylated locus. Conclusions We report novel associations of DNA methylation with lipid levels, describe epigenetic mechanisms related to previous GWAS discoveries and provide evidence implicating epigenetic regulation of reverse cholesterol transport in blood in relation to occurrence of cardiovascular disease events. Keywords: lipids, cardiovascular diseases, epigenetics, gene expression/regulation, genome-wide analysis

AB - Background Genome-wide association studies (GWAS) have identified loci influencing circulating lipid concentrations in humans; further information on novel contributing genes, pathways and biology may be gained through studies of epigenetic modifications. Methods and Results To identify epigenetic changes associated with lipid concentrations, we assayed genome-wide DNA methylation at cytosine-guanine dinucleotides (CpGs) in whole blood from 2,306 individuals from two population-based cohorts, with replication of findings in 2,025 additional individuals. We identified 193 CpGs associated with lipid levels in the discovery stage (P <1.08E-07) and replicated 33 (at Bonferroni-corrected P<0.05), including 25 novel CpGs not previously associated with lipids. Genes at lipid-associated CpGs were enriched in lipid and amino acid metabolism processes. A differentially methylated locus associated with TG and HDL-C (cg27243685; P= 8.1E-26 and 9.3E-19) was associated with cis-expression of a reverse-cholesterol transporter (ABCG1; P=7.2E-28), and incident cardiovascular disease events (HR per SD increment = 1.38, 95% CI, 1.15-1.66, P=0.0007). We found significant cis methylation quantitative trait loci (cis-meQTLs) at 64% of the 193 CpGs with an enrichment of signals from GWAS of lipid levels (PTC =0.004, PHDL-C=0.008 and PTG=0.00003) and coronary heart disease (P=0.0007). For example, genome-wide significant variants associated with LDL-C and coronary heart disease at APOB were cis-meQTLs for a LDL-C-related differentially methylated locus. Conclusions We report novel associations of DNA methylation with lipid levels, describe epigenetic mechanisms related to previous GWAS discoveries and provide evidence implicating epigenetic regulation of reverse cholesterol transport in blood in relation to occurrence of cardiovascular disease events. Keywords: lipids, cardiovascular diseases, epigenetics, gene expression/regulation, genome-wide analysis

KW - lipids

KW - genome - wide analysis

KW - gene expression/regulation

KW - cardiovascular diseases

KW - epigenetics

U2 - 10.1161/CIRCGENETICS.116.001487

DO - 10.1161/CIRCGENETICS.116.001487

M3 - Article

SN - 1942-325X

VL - 10

JO - Circulation: Cardiovascular Genetics

JF - Circulation: Cardiovascular Genetics

IS - 1

M1 - e001487

ER -

Epigenetic patterns in blood associated with lipid traits predict incident coronary heart disease events and are enriched for results from genome-wide association studies

Abstract

Keywords / Materials (for Non-textual outputs)

Access to Document

Fingerprint

Projects

RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.

Cite this