614 - Epigenetic Age Acceleration in Adolescents after Individual and Neighborhood Adverse Exposures

Publication Number: 4601.614

Barbara Chaiyachati, Children's Hospital of Philadelphia, Philadelphia, PA, United States; Jamie Catalano, Children's Hospital of Philadelphia, Philadelphia, PA, United States; Jennifer Xu, Childrens Hospital of Philadelphia, Philadelphia, NC, United States; Tyler M. Moore, University of Pennsylvania, Philadelphia, PA, United States; Ran Barzilay, Childrens Hospital of Philadelphia, Philadelphia, PA, United States; Joseph Glessner, Childrens Hospital of Philadelphia, Philadelphia, PA, United States; Frank D. Mentch, Childrens Hospital of Philadelphia, Philadelphia, PA, United States; Raquel E.. Gur, Childrens Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, United States; Hakon Hakonarson, The Children's Hospital of Philadelphia, UPENN, Philadelphia, PA, United States

Background: DNA methylation (DNAm) signatures can be associated with chronologic age and years until mortality. Acceleration of DNAm signatures, or epigenetic age acceleration (EAA), has been variably demonstrated after adverse life exposures, including in adolescence.

Objective: Assess association between individual and neighborhood adversities with EAA in an adolescent cohort.

Design/Methods: The Center for Applied Genomics is a biorepository from which the Philadelphia Neurodevelopmental Cohort was recruited as a quasi-epidemiologic representation of greater Philadelphia. This study was approved by CHOP and Penn IRBs. Methylation was completed by Illumina HumanMethylation450 BeadChip (450K). After quality control in Enmix, minfi (cell type adjustment) and ComBat (batch effects), five DNAm clocks were calculated by ClockFoundation or in R. Adversity exposures included self-report of PTSD criterion A exposures (count: 0,1,2, >3) and neighborhood environment at block-group-level (positive values reflect risks, e.g., unemployment and vacant lots). Sex-stratified multivariable linear regression was completed for clock age-residuals (Horvath skin-blood), age acceleration by ClockFoundation (Horvath pan-tissue, Pheno, Grim), pace of aging (DunedinPace) on exposures accounting for cell estimates and age difference (in years) between biosample collection and clinical assessment. FDR correction accounted for multiple testing.

Results: The analysis cohort included 613 samples (271 females; 342 males) with median biosample age 14 years (range 7-21). Cohort exposures included 52% report of at least one trauma experience. Reports of trauma were associated with epigenetic age acceleration in only one clock (Grim, males: beta=0.301, p=0.028). Neighborhood risk was associated with accelerated aging across all clocks: Horvath S&B (females: beta=0.308, p=0.008; males beta=0.411, p< 0.001), Grim (females: beta= 0.748, p< 0.001; males beta= 0.649, p< 0.001), Horvath pan tissue (females only, beta= 0.465, p=0.008), Pheno (females only, beta= 1.252, p=0.002), and pace of aging DunedinPACE (females, beta= 0.022, p=0.002; males beta=0.014, p=0.012). There was no statistical interaction between individual and neighborhood exposures influence on EAA.

Conclusion(s): In these results, adverse exposures at the neighborhood level were more often associated with EAA by DNA methylation than exposures at the individual level. The mixed results may reflect important nuance in exposure influence on biologic aging, suggesting further consideration of chronic stressors on broad epigenetic signatures.

Table 1. Participant demographics and adverse exposures by sex
AgeDiff reflects quantification of difference in age between biosample collection and PNC assessment. Race and ethnicity collected within study procedures. Trauma experiences were self-reported DSM PTSD criterion A experiences with maximum of 8. Neighbhorhood risk comprised of census block factors including factors such as unemployment and vacant lots; normed to zero with higher values reflecting higher risk.

Figure 1. Relationship between adversities and epigenetic aging by sex
Linear regression lines illustrating the unadjusted relationships between (a) trauma exposure and (b) neighborhood risk with epigenetic aging across five DNA methylation clocks (Horvath pan-tissue, Horvath S&B, Pheno, Grim, and DunedinPACE). Shaded regions indicate 95% confidence intervals, and panels are stratified by sex. DunedinPace output recentered to zero for comparison.

Table 2. Associations of trauma and neighborhood adversity with epigenetic age acceleration.
Beta coefficients, 95% confidence intervals, and FDR-adjusted p-values from sex-stratified linear regressions of five DNA methylation clocks (Horvath pan-tissue, Horvath skin & blood, Pheno, Grim, DunedinPACE) on trauma (self-reported, DSM criterion A; ordinally binned) and neighborhood risk (block-group-level indicators; higher values = higher risk). Models adjusted for estimated cell counts (CD4, CD8, Bcell, NK, Mono, granulocytes) and ageDiff. Global FDR correction applied across clocks for each cohort.