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

Authors: DAY, KENNETH - Hudsonalpha Institute For Biotechnology; WAITE, LINDSAY - University Of Alabama; ALONSO, ARNALD - Hudsonalpha Institute For Biotechnology; IRVIN, MARGURITE - University Of Alabama; ZHI, DEGUI - University Of Alabama; THIBEAULT, KRISTA - Hudsonalpha Institute For Biotechnology; ASLIBEKYAN, STELLA - University Of Alabama; HIDALGO, BERTHA - University Of Alabama; BORECKI, INGRID - Washington University; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; ARNETT, DONNA - University Of Alabama; TIWARI, HEMANT - University Of Alabama; ABSHER, DEVIN - Hudsonalpha Institute For Biotechnology

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/12/2016
Publication Date: 10/28/2016
Citation: Day, K., Waite, L.L., Alonso, A., Irvin, M.R., Zhi, D., Thibeault, K.S., Aslibekyan, S., Hidalgo, B., Borecki, I., 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. doi: 10.1371/journal.pone.0165488.

Interpretive Summary: At sites of DNA that have a specific sequence of nucleotides (CpG sites,) DNA methylation is both heritable and influenced by environment. However, the relative contributions of each attribute to DNA methylation levels are unclear. For this purpose we investigated the heritability of CpG methylation in a type of blood cell known as CD4+ cells across 975 individuals from 163 families in the Genetics of Lipid-lowering Drugs and Diet Network (GOLDN.) We identified 20,575 highly heritable CpGs among the 174,445 CpGs examined. Moreover, we tested the association of the heritable CpGs with genetic variation at 2,145,360 polymorphisms. Our findings showed that heritability of the CpGs was, in most cases (74%,) related to genetic variation in genomic regions close to the CpG whereas in 6% of the cases the heritability was associated with genetic variants far from the CpG. Finally, 20% of CpGs showed no strong significant associations with genotype. These CpGs were also among those that distinguished T cells from other blood cell lineages. This study is the largest cohort of families for which heritable DNA methylation has been determined in a sorted cell type and demonstrates that some heritable methylation across families cannot be explained by genotype.

Technical 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 approximately 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.