Multi-Ancestry Genome-wide Association Study Accounting for Gene-Psychosocial Factor Interactions Identifies Novel Loci for Blood Pressure Traits.

Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p value <5e-8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (PLCL2), synaptic function and neurotransmission (LIN7A, PFIA2), as well as genes previously implicated in neuropsychiatric or stress-related disorders (FSTL5, CHODL). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations.

Novel age-associated DNA methylation changes and epigenetic age acceleration in middle-aged African Americans and whites.

BACKGROUND: African Americans (AAs) experience premature chronic health outcomes and longevity disparities consistent with an accelerated aging phenotype. DNA methylation (DNAm) levels at specific CpG positions are hallmarks of aging evidenced by the presence of age-associated differentially methylated CpG positions (aDMPs) that are the basis for the epigenetic clock for measuring biological age acceleration. Since DNAm has not been widely studied among non-European populations, we examined the association between DNAm and chronological age in AAs and whites, and the association between race, poverty, sex, and epigenetic age acceleration. RESULTS: We measured genome-wide DNA methylation (866,836 CpGs) using the Illumina MethylationEPIC BeadChip in blood DNA extracted from 487 middle-aged AA (N = 244) and white (N = 243), men (N = 248), and women (N = 239). The mean (sd) age was 48.4 (8.8) in AA and 49.0 (8.7) in whites (p = 0.48). We identified 4930 significantly associated aDMPs in AAs and 469 in whites. Of these, 75.6% and 53.1% were novel, largely driven by the increased number of measured CpGs in the EPIC array, in AA and whites, respectively. AAs had more age-associated DNAm changes than whites in genes implicated in age-related diseases and cellular pathways involved in growth and development. We assessed three epigenetic age acceleration measures (universal, intrinsic, and extrinsic). AAs had a significantly slower extrinsic aging compared to whites. Furthermore, compared to AA women, both AA and white men had faster aging in the universal age acceleration measure (+ 2.04 and + 1.24 years, respectively, p < 0.05). CONCLUSIONS: AAs have more wide-spread methylation changes than whites. Race and sex interact to underlie biological age acceleration suggesting altered DNA methylation patterns may be important in age-associated health disparities.

Association between epigenetic age acceleration and depressive symptoms in a prospective cohort study of urban-dwelling adults.

OBJECTIVE: This study tests associations of DNA methylation-based (DNAm) measures of epigenetic age acceleration (EAA) with cross-sectional and longitudinal depressive symptoms in an urban sample of middle-aged adults. METHODS: White and African-American adult participants in the Healthy Aging in Neighborhoods of Diversity across the Life Span study for whom DNA samples were analyzed (baseline age: 30-65 years) we included. We estimated three DNAm based EAA measures: (1) universal epigenetic age acceleration (AgeAccel); (2) intrinsic epigenetic age acceleration (IEAA); and (3) extrinsic epigenetic age acceleration (EEAA). Depressive symptoms were assessed using the 20-item Center for Epidemiological Studies-Depression scale total and sub-domain scores at baseline (2004-2009) and follow-up visits (2009-2013). Linear mixed-effects regression models were conducted, adjusting potentially confounding covariates, selection bias and multiple testing (N = 329 participants, ∼52% men, k = 1.9 observations/participant, mean follow-up time∼4.7 years). RESULTS: None of the epigenetic age acceleration measures were associated with total depressive symptom scores at baseline or over time. IEAA - a measure of cellular epigenetic age acceleration irrespective of white blood cell composition - was cross-sectionally associated with decrement in "positive affect" in the total population (γ011± SE = -0.090 ±â€¯0.030, P = 0.003, Cohen's D: -0.16) and among Whites (γ011 ±â€¯SE = -0.135 ± 0.048, P = 0.005, Cohen's D: -0.23), after correction for multiple testing. Baseline "positive affect" was similarly associated with AgeAccel. LIMITATIONS: Limitations included small sample size, weak-moderate effects and measurement error. CONCLUSIONS: IEAA and AgeAccel, two measures of EAA using Horvath algorithm, were linked to a reduced "positive affect", overall and among Whites. Future studies are needed to replicate our findings and test bi-directional relationships.