Theory Article Volume 13, Issue 12 pp 15699—15749

Shifting epigenetic contexts influence regulatory variation and disease risk

Epigenetic context and heritable disease associations. (A) Adjusted p-values for hypergeometric tests showing enrichment/depletion (positive/negative) for GWAS variants nearby regions increasing (blue) or decreasing (red) accessibility across adult tissues for a number of age-associated diseases (see Supplementary Table 4). (B) Cross-set disease associations, and additional per-SNP metrics, for variants nearby developmental and age-altered region sets along with unaltered DNase sites and variants not nearby accessible regions. See Supplementary Table 4 and Methods. (C) Model for the effects of epigenetic context on disease association and sequence evolution. (Top): Example enhancer elements more accessible in fetal, adult, and old-adult tissues (left-right) which have been modified by mutations. (Left): Deleterious mutations disrupting regulation in development stand to have the biggest impact on fitness, while having a moderate effect on tissue homeostasis. (Middle): Mutations disrupting regulation in young-adult tissues have a moderate impact on fitness, but a larger effect on tissue homeostasis (particularly over adulthood). (Right): Mutations disrupting regulation in old-adult tissues have weak impacts on fitness, and a weak effect on tissue homeostasis (which has already deteriorated with age). (Bottom): Illustrating patterns of accessibility, disease association, sequence constraint and variant allele age for these sets of regions changing accessibility over time.

Figure 3. Epigenetic context and heritable disease associations. (A) Adjusted p-values for hypergeometric tests showing enrichment/depletion (positive/negative) for GWAS variants nearby regions increasing (blue) or decreasing (red) accessibility across adult tissues for a number of age-associated diseases (see Supplementary Table 4). (B) Cross-set disease associations, and additional per-SNP metrics, for variants nearby developmental and age-altered region sets along with unaltered DNase sites and variants not nearby accessible regions. See Supplementary Table 4 and Methods. (C) Model for the effects of epigenetic context on disease association and sequence evolution. (Top): Example enhancer elements more accessible in fetal, adult, and old-adult tissues (left-right) which have been modified by mutations. (Left): Deleterious mutations disrupting regulation in development stand to have the biggest impact on fitness, while having a moderate effect on tissue homeostasis. (Middle): Mutations disrupting regulation in young-adult tissues have a moderate impact on fitness, but a larger effect on tissue homeostasis (particularly over adulthood). (Right): Mutations disrupting regulation in old-adult tissues have weak impacts on fitness, and a weak effect on tissue homeostasis (which has already deteriorated with age). (Bottom): Illustrating patterns of accessibility, disease association, sequence constraint and variant allele age for these sets of regions changing accessibility over time.