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.
authors: HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, United States of America.
authors: Kenneth
authors: K
authors: Day
authors: HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, United States of America.|University of Alabama at Birmingham, School of Public Health, Department of Biostatistics, Birmingham, Alabama, United States of America.
authors: Lindsay L
authors: LL
authors: Waite
authors: HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, United States of America.
authors: Arnald
authors: A
authors: Alonso
authors: University of Alabama at Birmingham, School of Public Health, Department of Epidemiology, Birmingham, Alabama, United States of America.
authors: Marguerite R
authors: MR
authors: Irvin
authors: University of Alabama at Birmingham, School of Public Health, Department of Biostatistics, Birmingham, Alabama, United States of America.
authors: Degui
authors: D
authors: Zhi
authors: HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, United States of America.
authors: Krista S
authors: KS
authors: Thibeault
authors: University of Alabama at Birmingham, School of Public Health, Department of Epidemiology, Birmingham, Alabama, United States of America.
authors: Stella
authors: S
authors: Aslibekyan
authors: University of Alabama at Birmingham, School of Public Health, Department of Biostatistics, Birmingham, Alabama, United States of America.
authors: Bertha
authors: B
authors: Hidalgo
authors: Washington University, Division of Statistical Genomics, St. Louis, Missouri, United States of America.
authors: Ingrid B
authors: IB
authors: Borecki
authors: Tufts University, Jean Mayer USDA Human Nutrition Research Center on Aging, Boston, Massachusetts, United States of America.|IMDEA-Food, Madrid, Spain.
authors: Jose M
authors: JM
authors: Ordovas
authors: University of Alabama at Birmingham, School of Public Health, Department of Epidemiology, Birmingham, Alabama, United States of America.
authors: Donna K
authors: DK
authors: Arnett
authors: University of Alabama at Birmingham, School of Public Health, Department of Biostatistics, Birmingham, Alabama, United States of America.
authors: Hemant K
authors: HK
authors: Tiwari
authors: HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, United States of America.
authors: Devin M
authors: DM
authors: Absher
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D006801:Humans; D008297:Male; D058977:Molecular Sequence Annotation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics