Heritable DNA methylation in CD4+ Cells among complex families displays genetic and non-genetic effects

Kenneth Day; Lindsay L. Waite; Arnald Alonso; Marguerite R. Irvin; Degui Zhi; Krista S. Thibeault; Stella Aslibekyan; Bertha Hidalgo; Ingrid B. Borecki; Jose M. Ordovas; Donna K. Arnett; Hemant K. Tiwari; Devin M. Absher

doi:10.1371/journal.pone.0165488

Heritable DNA methylation in CD4+ Cells among complex families displays genetic and non-genetic effects

Kenneth Day, Lindsay L. Waite, Arnald Alonso, Marguerite R. Irvin, Degui Zhi, Krista S. Thibeault, Stella Aslibekyan, Bertha Hidalgo, Ingrid B. Borecki, Jose M. Ordovas, Donna K. Arnett, Hemant K. Tiwari, Devin M. Absher

College of Public Health

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

16 Scopus citations

Abstract

DNA methylation at CpG sites is both heritable and influenced by environment, but the relative contributions of each to DNA methylation levels are unclear. We conducted a heritability analysis of CpG methylation in human CD4+ cells across 975 individuals from 163 families in the Genetics of Lipid-lowering Drugs and Diet Network (GOLDN). Based on a broad-sense heritability (H2 ) value threshold of 0.4, we identified 20,575 highly heritable CpGs among the 174,445 most variable autosomal CpGs (SD > 0.02). Tests for associations of heritable CpGs with genotype at 2,145,360 SNPs using 717 of 975 individuals showed that 74% were cis-meQTLs (< 1 Mb away from the CpG), 6% of CpGs exhibited trans-meQTL associations (>1 Mb away from the CpG or located on a different chromosome), and 20% of CpGs showed no strong significant associations with genotype (based on a p-value threshold of 1e-7). Genes proximal to the genotype independent heritable CpGs were enriched for functional terms related to regulation of T cell activation. These CpGs were also among those that distinguished T cells from other blood cell lineages. Compared to genes proximal to meQTL-associated heritable CpGs, genotype independent heritable CpGs were moderately enriched in the same genomic regions that escape erasure during primordial germ cell development and could carry potential for generational transmission.

Original language	English
Article number	e0165488
Journal	PLoS ONE
Volume	11
Issue number	10
DOIs	https://doi.org/10.1371/journal.pone.0165488
State	Published - Oct 2016

Bibliographical note

Publisher Copyright:
© 2016 Day et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology
General Agricultural and Biological Sciences
General

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Day, K., Waite, L. L., Alonso, A., Irvin, M. R., Zhi, D., Thibeault, K. S., Aslibekyan, S., Hidalgo, B., Borecki, I. B., Ordovas, J. M., Arnett, D. K., Tiwari, H. K., & Absher, D. M. (2016). Heritable DNA methylation in CD4+ Cells among complex families displays genetic and non-genetic effects. PLoS ONE, 11(10), Article e0165488. https://doi.org/10.1371/journal.pone.0165488

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title = "Heritable DNA methylation in CD4+ Cells among complex families displays genetic and non-genetic effects",

abstract = "DNA methylation at CpG sites is both heritable and influenced by environment, but the relative contributions of each to DNA methylation levels are unclear. We conducted a heritability analysis of CpG methylation in human CD4+ cells across 975 individuals from 163 families in the Genetics of Lipid-lowering Drugs and Diet Network (GOLDN). Based on a broad-sense heritability (H2 ) value threshold of 0.4, we identified 20,575 highly heritable CpGs among the 174,445 most variable autosomal CpGs (SD > 0.02). Tests for associations of heritable CpGs with genotype at 2,145,360 SNPs using 717 of 975 individuals showed that 74% were cis-meQTLs (< 1 Mb away from the CpG), 6% of CpGs exhibited trans-meQTL associations (>1 Mb away from the CpG or located on a different chromosome), and 20% of CpGs showed no strong significant associations with genotype (based on a p-value threshold of 1e-7). Genes proximal to the genotype independent heritable CpGs were enriched for functional terms related to regulation of T cell activation. These CpGs were also among those that distinguished T cells from other blood cell lineages. Compared to genes proximal to meQTL-associated heritable CpGs, genotype independent heritable CpGs were moderately enriched in the same genomic regions that escape erasure during primordial germ cell development and could carry potential for generational transmission.",

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AU - Irvin, Marguerite R.

AU - Zhi, Degui

AU - Thibeault, Krista S.

AU - Aslibekyan, Stella

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AU - Borecki, Ingrid B.

AU - Ordovas, Jose M.

AU - Arnett, Donna K.

AU - Tiwari, Hemant K.

AU - Absher, Devin M.

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N2 - DNA methylation at CpG sites is both heritable and influenced by environment, but the relative contributions of each to DNA methylation levels are unclear. We conducted a heritability analysis of CpG methylation in human CD4+ cells across 975 individuals from 163 families in the Genetics of Lipid-lowering Drugs and Diet Network (GOLDN). Based on a broad-sense heritability (H2 ) value threshold of 0.4, we identified 20,575 highly heritable CpGs among the 174,445 most variable autosomal CpGs (SD > 0.02). Tests for associations of heritable CpGs with genotype at 2,145,360 SNPs using 717 of 975 individuals showed that 74% were cis-meQTLs (< 1 Mb away from the CpG), 6% of CpGs exhibited trans-meQTL associations (>1 Mb away from the CpG or located on a different chromosome), and 20% of CpGs showed no strong significant associations with genotype (based on a p-value threshold of 1e-7). Genes proximal to the genotype independent heritable CpGs were enriched for functional terms related to regulation of T cell activation. These CpGs were also among those that distinguished T cells from other blood cell lineages. Compared to genes proximal to meQTL-associated heritable CpGs, genotype independent heritable CpGs were moderately enriched in the same genomic regions that escape erasure during primordial germ cell development and could carry potential for generational transmission.

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Heritable DNA methylation in CD4+ Cells among complex families displays genetic and non-genetic effects

Abstract

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ASJC Scopus subject areas

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