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

• Published in: PloS one 2016-10, Vol.11 (10), p.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: B cells; Display fixtures; DNA; Genes; Genetic aspects; Genetic research; Methylation; T cells
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0165488

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.sup.+ cells across 975 individuals from 163 families in the Genetics of Lipid-lowering Drugs and Diet Network (GOLDN). Based on a broad-sense heritability (H.sup.2) 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 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.