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Identifying genetic variants that are associated with variation in DNA methylation, an analysis commonly referred to as methylation quantitative trait locus (meQTL) mapping, is an important first step towards understanding the genetic architecture underlying epigenetic variation. Most existing meQTL mapping studies have focused on individuals of European ancestry and are underrepresented in other populations, with a particular absence of large studies in populations with African ancestry. We fill this critical knowledge gap by performing a large-scale cis-meQTL mapping study in 961 African Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. We identify a total of 4,565,687 cis-acting meQTLs in 320,965 meCpGs. We find that 45% of meCpGs harbor multiple independent meQTLs, suggesting potential polygenic genetic architecture underlying methylation variation. A large percentage of the cis-meQTLs also colocalize with cis-expression QTLs (eQTLs) in the same population. Importantly, the identified cis-meQTLs explain a substantial proportion (median = 24.6%) of methylation variation. In addition, the cis-meQTL associated CpG sites mediate a substantial proportion (median = 24.9%) of SNP effects underlying gene expression. Overall, our results represent an important step toward revealing the co-regulation of methylation and gene expression, facilitating the functional interpretation of epigenetic and gene regulation underlying common diseases in African Americans. Here, the authors performed a large-scale in-depth cis-meQTL mapping study in 961 African Americans from the GENOA study, investigating the co-regulation of methylation and gene expression in African Americans.

With the emergence of new health information technologies, health information can be shared across networks, with or without patients' awareness and/or their consent. It is often argued that there can be an ethical obligation to participate in biomedical research, motivated by altruism, particularly when risks are low. In this study, we explore whether altruism contributes to the belief that there is an ethical obligation to share information about one's health as well as how other health care experiences, perceptions, and concerns might be related to belief in such an obligation. We conducted an online survey using the National Opinion Research Center's (NORC) probability-based, nationally representative sample of U.S. adults. Our final analytic sample included complete responses from 2069 participants. We used multivariable logistic regression to examine how altruism, together with other knowledge, attitudes, and experiences contribute to the belief in an ethical obligation to allow health information to be used for research. We find in multivariable regression that general altruism is associated with a higher likelihood of belief in an ethical obligation to allow one's health information to be used for research (OR = 1.22, SE = 0.14, p = 0.078). Trust in the health system and in care providers are both associated with a significantly higher likelihood of believing there is an ethical obligation to allow health information to be used (OR = 1.48, SE = 0.76, p<0.001; OR = 1.58, SE = 0.26, p<0.01, respectively). Belief that there is an ethical obligation to allow one's health information to be used for research is shaped by altruism and by one's experience with, and perceptions of, health care and by general concerns about the use of personal information. Altruism cannot be assumed and researchers must recognize the ways encounters with the health care system influence (un)willingness to share one's health information.

Background Since older adults spend significant time in their neighborhood environment, environmental factors such as neighborhood socioeconomic disadvantage, high racial segregation, low healthy food availability, low access to recreation, and minimal social engagement may have adverse effects on cognitive function and increase susceptibility to dementia. DNA methylation, which is associated with neighborhood characteristics as well as cognitive function and white matter hyperintensity (WMH), may act as a mediator between neighborhood characteristics and neurocognitive outcomes. Methods In this study, we examined whether DNA methylation in peripheral blood leukocytes mediates the relationship between neighborhood characteristics and cognitive function ( N  = 542) or WMH ( N  = 466) in older African American (AA) participants without preliminary evidence of dementia from the Genetic Epidemiology Network of Arteriopathy (GENOA). Results For a 1-mile buffer around a participant’s residence, each additional fast food destination or unfavorable food store with alcohol per square mile was nominally associated with a 0.05 (95%CI: 0.01, 0.09) and a 0.04 (0.00, 0.08) second improvement in visual conceptual tracking score, respectively. Also, each additional alcohol drinking place per square mile was nominally associated with a 0.62 (0.05, 1.19) word increase in delayed recall score, indicating better memory function (all p  < 0.05). Neighborhood characteristics were not associated with WMH. We did not find evidence that DNA methylation mediates the observed associations between neighborhood characteristics and cognitive function. Conclusions The presence of fast food destinations and unfavorable food stores with alcohol was associated cognitive measures, possibly due to greater social interaction provided in these venues. However, replication of these findings is necessary. Further examination of the potential pathways between the neighborhood environment and cognitive function/WMH may allow the development of potential behavioral, infrastructural, and pharmaceutical interventions to facilitate aging in place and healthy brain aging in older adults, especially in marginal populations that are most at risk.

Cigarette smoking is an environmental risk factor for many chronic diseases, and disease risk can often be managed by smoking control. Smoking can induce cellular and molecular changes, including epigenetic modification, but the short- and long-term epigenetic modifications caused by cigarette smoking at the gene level have not been well understood. Recent studies have identified smoking-related DNA methylation (DNAm) sites in Caucasians. To determine whether the same DNAm sites associate with smoking in African Americans, and to identify novel smoking-related DNAm sites, we conducted a methylome-wide association study of cigarette smoking using a discovery sample of 972 African Americans, and a replication sample of 239 African Americans with two array-based methods. Among 15 DNAm sites significantly associated with smoking after correction for multiple testing in our discovery sample, 5 DNAm sites are replicated in an independent cohort, and 14 sites in the replication sample have effects in the same direction as in the discovery sample. The top two smoking-related DNAm sites in F2RL3 (factor II receptor-like 3) and GPR15 (G-protein-coupled receptor 15) observed in African Americans are consistent with previous findings in Caucasians. The associations between the replicated DNAm sites and smoking remain significant after adjusting for genetic background. Despite the distinct genetic background between African Americans and Caucasians, the DNAm from the two ethnic groups shares common associations with cigarette smoking, which suggests a common molecular mechanism of epigenetic modification influenced by environmental exposure.

Gene expression may be an important biological mediator in associations between social factors and health. However, previous studies were limited by small sample sizes and use of differing cell types with heterogeneous expression patterns. We use a large population-based cohort with gene expression measured solely in monocytes to investigate associations between seven social factors and expression of genes previously found to be sensitive to social factors. We employ three methodological approaches: 1) omnibus test for the entire gene set (Global ANCOVA), 2) assessment of each association individually (linear regression), and 3) machine learning method that performs variable selection with correlated predictors (elastic net). In global analyses, significant associations with the a priori defined socially sensitive gene set were detected for major or lifetime discrimination and chronic burden (p = 0.019 and p = 0.047, respectively). Marginally significant associations were detected for loneliness and adult socioeconomic status (p = 0.066, p = 0.093, respectively). No associations were significant in linear regression analyses after accounting for multiple testing. However, a small percentage of gene expressions (up to 11%) were associated with at least one social factor using elastic net. The Global ANCOVA and elastic net findings suggest that a small percentage of genes may be \"socially sensitive,\" (i.e. demonstrate differential expression by social factor), yet single gene approaches such as linear regression may be ill powered to capture this relationship. Future research should further investigate the biological mechanisms through which social factors act to influence gene expression and how systemic changes in gene expression affect overall health.

Background Epigenetic age acceleration, a measure of biological aging based on DNA methylation, is associated with cardiovascular mortality. However, little is known about its relationship with hypertensive target organ damage to the heart, kidneys, brain, and peripheral arteries. Methods We investigated associations between intrinsic (IEAA) or extrinsic (EEAA) epigenetic age acceleration, blood pressure, and six types of organ damage in a primarily hypertensive cohort of 1390 African Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. DNA methylation from peripheral blood leukocytes was collected at baseline (1996–2000), and measures of target organ damage were assessed in a follow-up visit (2000–2004). Linear regression with generalized estimating equations was used to test for associations between epigenetic age acceleration and target organ damage, as well as effect modification of epigenetic age by blood pressure or sex. Sequential Oligogenic Linkage Analysis Routines (SOLAR) was used to test for evidence of shared genetic and/or environmental effects between epigenetic age acceleration and organ damage pairs that were significantly associated. Results After adjustment for sex, chronological age, and time between methylation and organ damage measures, higher IEAA was associated with higher urine albumin to creatinine ratio (UACR, p  = 0.004), relative wall thickness (RWT, p  = 0.022), and left ventricular mass index (LVMI, p  = 0.007), and with lower ankle-brachial index (ABI, p  = 0.014). EEAA was associated with higher LVMI ( p  = 0.005). Target organ damage associations for all but IEAA with LVMI remained significant after further adjustment for blood pressure and antihypertensive use ( p  < 0.05). Further adjustment for diabetes attenuated the IEAA associations with UACR and RWT, and adjustment for smoking attenuated the IEAA association with ABI. No effect modification by age or sex was observed. Conclusions Measures of epigenetic age acceleration may help to better characterize the functional mechanisms underlying organ damage from cellular aging and/or hypertension. These measures may act as subclinical biomarkers for damage to the kidney, heart, and peripheral vasculature; however more research is needed to determine whether these relationships remain independent of lifestyle factors and comorbidities.

Background Genome‐wide association studies (GWAS) have made little progress in identifying variants linked to depression. We hypothesized that examining depressive symptoms and considering gene–environment interaction (GxE) might improve efficiency for gene discovery. We therefore conducted a GWAS and genome‐wide by environment interaction study (GWEIS) of depressive symptoms. Methods Using data from the SHARe cohort of the Women's Health Initiative, comprising African Americans (n = 7,179) and Hispanics/Latinas (n = 3,138), we examined genetic main effects and GxE with stressful life events and social support. We also conducted a heritability analysis using genome‐wide complex trait analysis (GCTA). Replication was attempted in four independent cohorts. Results No SNPs achieved genome‐wide significance for main effects in either discovery sample. The top signals in African Americans were rs73531535 (located 20 kb from GPR139, P = 5.75 × 10−8) and rs75407252 (intronic to CACNA2D3, P = 6.99 × 10−7). In Hispanics/Latinas, the top signals were rs2532087 (located 27 kb from CD38, P = 2.44 × 10−7) and rs4542757 (intronic to DCC, P = 7.31 × 10−7). In the GEWIS with stressful life events, one interaction signal was genome‐wide significant in African Americans (rs4652467; P = 4.10 × 10−10; located 14 kb from CEP350). This interaction was not observed in a smaller replication cohort. Although heritability estimates for depressive symptoms and stressful life events were each less than 10%, they were strongly genetically correlated (rG = 0.95), suggesting that common variation underlying self‐reported depressive symptoms and stressful life event exposure, though modest on their own, were highly overlapping in this sample. Conclusions Our results underscore the need for larger samples, more GEWIS, and greater investigation into genetic and environmental determinants of depressive symptoms in minorities.

Epidemiological studies of DNA methylation (DNAm) profiles may hold substantial promise for identifying mechanisms through which genetic and environmental factors jointly contribute to disease risk. Different cell types are likely to have different DNAm patterns. We investigate the DNAm differences between two types of biospecimens available in many genetic epidemiology studies. We compared DNAm patterns in two different DNA samples from each of 34 participants in the Genetic Epidemiology Network of Arteriopathy study (20 Caucasians and 14 African-Americans). One was extracted from peripheral blood cells (PBC) and the other from transformed B-lymphocytes (TBL). The genome-wide DNAm profiles were compared at over 27,000 genome-wide methylation sites. We found that 26 out of the 34 participants had correlation coefficients higher than 0.9 between methylation profiles of PBC and TBL. Although a high correlation was observed in the DNAm profile between PBC and TBL, we also observed variation across samples from different DNA resources and donors. Using principal component analysis of the DNAm profiles, the two sources of the DNA samples could be accurately predicted. We also identified 3,723 autosomal DNAm sites that had significantly different methylation statuses in PBC compared to TBL (Bonferroni corrected p value <0.05). Both PBC and TBL provide a rich resource for understanding the DNAm profiles in humans participating in epidemiologic studies. While the majority of DNAm findings in PBC and TBL may be consistent, caution must be used when interpreting results because of the possibility of cell type-specific methylation modification.

Although considerable evidence exists on the association between negative health outcomes and daily experiences of discrimination, less is known about such experiences in the health care system at the national level. It is critically necessary to measure and address discrimination in the health care system to mitigate harm to patients and as part of the larger ongoing project of responding to health inequities. To (1) identify the national prevalence of patient-reported experiences of discrimination in the health care system, the frequency with which they occur, and the main types of discrimination experienced and (2) examine differences in the prevalence of discrimination across demographic groups. This cross-sectional national survey fielded online in May 2019 used a general population sample from the National Opinion Research Center's AmeriSpeak Panel. Surveys were sent to 3253 US adults aged 21 years or older, including oversamples of African American respondents, Hispanic respondents, and respondents with annual household incomes below 200% of the federal poverty level. Analyses drew on 3 survey items measuring patient-reported experiences of discrimination, the primary types of discrimination experienced, the frequency with which they occurred, and the demographic and health-related characteristics of the respondents. Weighted bivariable and multivariable logistic regressions were conducted to assess associations between experiences of discrimination and several demographic and health-related characteristics. Of 2137 US adult respondents who completed the survey (66.3% response rate; unweighted 51.0% female; mean [SD] age, 49.6 [16.3] years), 458 (21.4%) reported that they had experienced discrimination in the health care system. After applying weights to generate population-level estimates, most of those who had experienced discrimination (330 [72.0%]) reported experiencing it more than once. Of 458 reporting experiences of discrimination, racial/ethnic discrimination was the most common type (79 [17.3%]), followed by discrimination based on educational or income level (59 [12.9%]), weight (53 [11.6%]), sex (52 [11.4%]), and age (44 [9.6%]). In multivariable analysis, the odds of experiencing discrimination were higher for respondents who identified as female (odds ratio [OR], 1.88; 95% CI, 1.50-2.36) and lower for older respondents (OR, 0.98; 95% CI, 0.98-0.99), respondents earning at least $50 000 in annual household income (OR, 0.76; 95% CI, 0.60-0.95), and those reporting good (OR, 0.59; 95% CI, 0.46-0.75) or excellent (OR, 0.41; 95% CI, 0.31-0.56) health compared with poor or fair health. The results of this study suggest that experiences of discrimination in the health care system appear more common than previously recognized and deserve considerable attention. These findings contribute to understanding of the scale at which interpersonal discrimination occurs in the US health care system and provide crucial evidence for next steps in assessing the risks and consequences of such discrimination. The findings also point to a need for further analysis of how interpersonal discrimination interacts with structural inequities and social determinants of health to build effective responses.

OBJECTIVE The metabolic syndrome (MetS) is defined as concomitant disorders of lipid and glucose metabolism, central obesity, and high blood pressure, with an increased risk of type 2 diabetes and cardiovascular disease. This study tests whether common genetic variants with pleiotropic effects account for some of the correlated architecture among five metabolic phenotypes that define MetS. RESEARCH DESIGN AND METHODS Seven studies of the STAMPEED consortium, comprising 22,161 participants of European ancestry, underwent genome-wide association analyses of metabolic traits using a panel of ∼2.5 million imputed single nucleotide polymorphisms (SNPs). Phenotypes were defined by the National Cholesterol Education Program (NCEP) criteria for MetS in pairwise combinations. Individuals exceeding the NCEP thresholds for both traits of a pair were considered affected. RESULTS Twenty-nine common variants were associated with MetS or a pair of traits. Variants in the genes LPL, CETP, APOA5 (and its cluster), GCKR (and its cluster), LIPC, TRIB1, LOC100128354/MTNR1B, ABCB11, and LOC100129150 were further tested for their association with individual qualitative and quantitative traits. None of the 16 top SNPs (one per gene) associated simultaneously with more than two individual traits. Of them 11 variants showed nominal associations with MetS per se. The effects of 16 top SNPs on the quantitative traits were relatively small, together explaining from ∼9% of the variance in triglycerides, 5.8% of high-density lipoprotein cholesterol, 3.6% of fasting glucose, and 1.4% of systolic blood pressure. CONCLUSIONS Qualitative and quantitative pleiotropic tests on pairs of traits indicate that a small portion of the covariation in these traits can be explained by the reported common genetic variants.