Heritable DNA Methylation in CD4+ Cells among Complex Families Displays Genetic and Non-Genetic Effects

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-lo...

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Bibliographic Details
Published in:PloS one 2016-10, Vol.11 (10), p.e0165488-e0165488
Main Authors: Day, Kenneth, Waite, Lindsay L, Alonso, Arnald, Irvin, Marguerite R, Zhi, Degui, Thibeault, Krista S, Aslibekyan, Stella, Hidalgo, Bertha, Borecki, Ingrid B, Ordovas, Jose M, Arnett, Donna K, Tiwari, Hemant K, Absher, Devin M
Format: Article
Language:English
Subjects:
Biology and life sciences
Blood cells
CD4 antigen
CD4-Positive T-Lymphocytes - metabolism
Cell activation
CpG islands
CpG Islands - genetics
Deoxyribonucleic acid
DNA
DNA Methylation
Female
Genes
Genetic effects
Genetics
Genomics
Genotypes
Heritability
Humans
Lymphocytes
Lymphocytes T
Male
Medicine and Health Sciences
Molecular Sequence Annotation
Nutrition research
Pedigree
Physical Sciences
Polymorphism, Single Nucleotide
Quantitative Trait Loci - genetics
Single-nucleotide polymorphism
Studies
Twins
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0165488