Admixture mapping of cognitive function in diverse Hispanic and Latino adults: Results from the Hispanic Community Health Study/Study of Latinos.

INTRODUCTION: We conducted admixture mapping and fine-mapping analyses to identify ancestry-of-origin loci influencing cognitive abilities. METHODS: We estimated the association of local ancestry intervals across the genome with five neurocognitive measures in 7140 diverse Hispanic and Latino adults (mean age 55 years). We prioritized genetic variants in associated loci and tested them for replication in four independent cohorts. RESULTS: We identified nine local ancestry-associated regions for the five neurocognitive measures. There was strong biological support for the observed associations to cognitive function at all loci and there was statistical evidence of independent replication at 4q12, 9p22.1, and 13q12.13. DISCUSSION: Our study identified multiple novel loci harboring genes implicated in cognitive functioning and dementia, and uncovered ancestry-relevant genetic variants. It adds to our understanding of the genetic architecture of cognitive function in Hispanic and Latino adults and demonstrates the power of admixture mapping to discover unique haplotypes influencing cognitive function, complementing genome-wide association studies. HIGHLIGHTS: We identified nine ancestry-of-origin chromosomal regions associated with five neurocognitive traits. In each associated region, we identified single nucleotide polymorphisms (SNPs) that explained, at least in part, the admixture signal and were tested for replication in independent samples of Black, non-Hispanic White, and Hispanic/Latino adults with the same or similar neurocognitive tests. Statistical evidence of independent replication of the prioritized SNPs was observed for three of the nine associations, at chr4q12, chr9p22.1, and chr13q12.13. At all loci, there was strong biological support for the observed associations to cognitive function and dementia, prioritizing genes such as KIT, implicated in autophagic clearance of neurotoxic proteins and on mast cell and microglial-mediated inflammation; SLC24A2, implicated in synaptic plasticity associated with learning and memory; and MTMR6, implicated in phosphoinositide lipids metabolism.

DNA Methylation-Derived Immune Cell Proportions and Cancer Risk, Including Lung Cancer, in Black Participants.

Prior cohort studies assessing cancer risk based on immune cell subtype profiles have predominantly focused on White populations. This limitation obscures vital insights into how cancer risk varies across race. Immune cell subtype proportions were estimated using deconvolution based on leukocyte DNA methylation markers from blood samples collected at baseline on participants without cancer in the Atherosclerosis Risk in Communities (ARIC) Study. Over a mean of 17.5 years of follow-up, 668 incident cancers were diagnosed in 2,467 Black participants. Cox proportional hazards regression was used to examine immune cell subtype proportions and overall cancer incidence and site-specific incidence (lung, breast, and prostate cancers). Higher T regulatory cell proportions were associated with statistically significantly higher lung cancer risk (hazard ratio = 1.22, 95% confidence interval = 1.06-1.41 per percent increase). Increased memory B cell proportions were associated with significantly higher risk of prostate cancer (1.17, 1.04-1.33) and all cancers (1.13, 1.05-1.22). Increased CD8+ naïve cell proportions were associated with significantly lower risk of all cancers in participants ≥55 years (0.91, 0.83-0.98). Other immune cell subtypes did not display statistically significant associations with cancer risk. These results in Black participants align closely with prior findings in largely White populations. Findings from this study could help identify those at high cancer risk and outline risk stratifying to target patients for cancer screening, prevention, and other interventions. Further studies should assess these relationships in other cancer types, better elucidate the interplay of B cells in cancer risk, and identify biomarkers for personalized risk stratification.

Metabolomic profiles in Jamaican children with and without autism spectrum disorder.

Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with a wide range of behavioral and cognitive impairments. While genetic and environmental factors are known to contribute to its etiology, the underlying metabolic perturbations associated with ASD which can potentially connect genetic and environmental factors, remain poorly understood. Therefore, we conducted a metabolomic case-control study and performed a comprehensive analysis to identify significant alterations in metabolite profiles between children with ASD and typically developing (TD) controls. Objective: To elucidate potential metabolomic signatures associated with ASD in children and identify specific metabolites that may serve as biomarkers for the disorder. Methods: We conducted metabolomic profiling on plasma samples from participants in the second phase of Epidemiological Research on Autism in Jamaica (ERAJ-2), which was a 1:1 age (±6 months)-and sex-matched cohort of 200 children with ASD and 200 TD controls (2-8 years old). Using high-throughput liquid chromatography-mass spectrometry techniques, we performed a targeted metabolite analysis, encompassing amino acids, lipids, carbohydrates, and other key metabolic compounds. After quality control and imputation of missing values, we performed univariable and multivariable analysis using normalized metabolites while adjusting for covariates, age, sex, socioeconomic status, and child's parish of birth. Results: Our findings revealed unique metabolic patterns in children with ASD for four metabolites compared to TD controls. Notably, three of these metabolites were fatty acids, including myristoleic acid, eicosatetraenoic acid, and octadecenoic acid. Additionally, the amino acid sarcosine exhibited a significant association with ASD. Conclusions: These findings highlight the role of metabolites in the etiology of ASD and suggest opportunities for the development of targeted interventions.

Factors associated with blood mercury concentrations and their interactions with three glutathione S-transferase genes (GSTT1, GSTM1, and GSTP1): an exposure assessment study of typically developing Jamaican children.

BACKGROUND: Jamaican soil is abundant in heavy metals including mercury (Hg). Due to availability and ease of access, fish is a traditional dietary component in Jamaica and a significant source of Hg exposure. Mercury is a xenobiotic and known neuro-toxicant that affects children's neurodevelopment. Human glutathione S-transferase (GST) genes, including GSTT1, GSTM1, and GSTP1, affect Hg conjugation and elimination mechanisms. METHODS: In this exposure assessment study we used data from 375 typically developing (TD) 2-8-year-old Jamaican children to explore the association between environmental Hg exposure, GST genes, and their interaction effects on blood Hg concentrations (BHgCs). We used multivariable general linear models (GLMs). RESULTS: We identified the child's age, consumption of saltwater fish, canned fish (sardine, mackerel), string beans, grain, and starches (pasta, macaroni, noodles) as the environmental factors significantly associated with BHgCs (all P < 0.05). A significant interaction between consumption of canned fish (sardine, mackerel) and GSTP1 in relation to BHgC using either a co-dominant or recessive genetic model (overall interaction P = 0.01 and P < 0.01, respectively) indicated that consumption of canned fish (sardine, mackerel) was significantly associated with higher mean BHgC only among children with the GSTP1 Ile105Val, Ile/Ile [Ratio of mean Hg (95% CI) = 1.59 (1.09, 2.32), P = 0.02] and Ile/Val [Ratio of mean Hg (95% CI) = 1.46 (1.12, 1.91), P = 0.01] genotypes. CONCLUSIONS: Since this is the first study from Jamaica to report these findings, replication in other populations is recommended.

Identification of circulating proteins associated with general cognitive function among middle-aged and older adults.

Identifying circulating proteins associated with cognitive function may point to biomarkers and molecular process of cognitive impairment. Few studies have investigated the association between circulating proteins and cognitive function. We identify 246 protein measures quantified by the SomaScan assay as associated with cognitive function (p < 4.9E-5, n up to 7289). Of these, 45 were replicated using SomaScan data, and three were replicated using Olink data at Bonferroni-corrected significance. Enrichment analysis linked the proteins associated with general cognitive function to cell signaling pathways and synapse architecture. Mendelian randomization analysis implicated higher levels of NECTIN2, a protein mediating viral entry into neuronal cells, with higher Alzheimer's disease (AD) risk (p = 2.5E-26). Levels of 14 other protein measures were implicated as consequences of AD susceptibility (p < 2.0E-4). Proteins implicated as causes or consequences of AD susceptibility may provide new insight into the potential relationship between immunity and AD susceptibility as well as potential therapeutic targets.

Epigenome-wide association study using peripheral blood leukocytes identifies genomic regions associated with periodontal disease and edentulism in the Atherosclerosis Risk in Communities study.

AIM: To investigate individual susceptibility to periodontitis by conducting an epigenome-wide association study using peripheral blood. MATERIALS AND METHODS: We included 1077 African American and 457 European American participants of the Atherosclerosis Risk in Communities (ARIC) study who had completed a dental examination or reported being edentulous at Visit 4 and had available data on DNA methylation from Visit 2 or 3. DNA methylation levels were compared by periodontal disease severity and edentulism through discovery analyses and subsequent testing of individual CpGs. RESULTS: Our discovery analysis replicated findings from a previous study reporting a region in gene ZFP57 (6p22.1) that was significantly hypomethylated in severe periodontal disease compared with no/mild periodontal disease in European American participants. Higher methylation levels in a separate region in an unknown gene (located in Chr10: 743,992-744,958) was associated with significantly higher odds of edentulism compared with no/mild periodontal disease in African American participants. In subsequent CpG testing, four CpGs in a region previously associated with periodontitis located within HOXA4 were significantly hypermethylated in severe periodontal disease compared with no/mild periodontal disease in African American participants (odds ratio per 1 SD increase in methylation level: cg11015251: 1.28 (1.02, 1.61); cg14359292: 1.24 (1.01, 1.54); cg07317062: 1.30 (1.05, 1.61); cg08657492: 1.25 (1.01, 1.55)). CONCLUSIONS: Our study highlights epigenetic variations in ZPF57 and HOXA4 that are significantly and reproducibly associated with periodontitis. Future studies should evaluate gene regulatory mechanisms in the candidate regions of these loci.

Proteomic Analysis Identifies Circulating Proteins Associated With Plasma Amyloid-ß and Incident Dementia.

Background: Plasma amyloid-ß (Aß) (Aß42, Aß40, and Aß42/Aß40), biomarkers of the Alzheimer's form of dementia, are under consideration for clinical use. The associations of these peptides with circulating proteins may identify novel plasma biomarkers of dementia and inform peripheral factors influencing the levels of these peptides. Methods: We analyzed the association of these 3 plasma Aß measures with 4638 circulating proteins among a subset of the participants of the Atherosclerosis Risk in Communities (ARIC) study (midlife: n = 1955; late life: n = 2082), related the Aß-associated proteins with incident dementia in the overall ARIC cohort (midlife: n = 11,069, late life: n = 4110) with external replication in the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study (n = 4973), estimated the proportion of Aß variance explained, and conducted enrichment analyses to characterize the proteins associated with the plasma Aß peptides. Results: At midlife, of the 296 Aß-associated proteins, 8 were associated with incident dementia from midlife and late life in the ARIC study, and NPPB, IBSP, and THBS2 were replicated in the AGES-Reykjavik Study. At late life, of the 34 Aß-associated proteins, none were associated with incident dementia at midlife, and kidney function explained 10%, 12%, and 0.2% of the variance of Aß42, Aß40, and Aß42/Aß40, respectively. Aß42-associated proteins at midlife were found to be enriched in the liver, and those at late life were found to be enriched in the spleen. Conclusions: This study identifies circulating proteins associated with plasma Aß levels and incident dementia and informs peripheral factors associated with plasma Aß levels.

Multivariate genetic analysis of personality and cognitive traits reveals abundant pleiotropy.

Personality and cognitive function are heritable mental traits whose genetic foundations may be distributed across interconnected brain functions. Previous studies have typically treated these complex mental traits as distinct constructs. We applied the 'pleiotropy-informed' multivariate omnibus statistical test to genome-wide association studies of 35 measures of neuroticism and cognitive function from the UK Biobank (n = 336,993). We identified 431 significantly associated genetic loci with evidence of abundant shared genetic associations, across personality and cognitive function domains. Functional characterization implicated genes with significant tissue-specific expression in all tested brain tissues and brain-specific gene sets. We conditioned independent genome-wide association studies of the Big 5 personality traits and cognitive function on our multivariate findings, boosting genetic discovery in other personality traits and improving polygenic prediction. These findings advance our understanding of the polygenic architecture of these complex mental traits, indicating a prominence of pleiotropic genetic effects across higher order domains of mental function such as personality and cognitive function.

Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function: A Meta-analysis of Community-Based Cohorts.

BACKGROUND AND OBJECTIVES: Previous studies suggest that lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer disease (AD) and AD-related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults. METHODS: We included dementia-free participants from 9 diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear DNA. Brain MRI markers included total brain, hippocampal, and white matter hyperintensity volumes. General cognitive function was derived from distinct cognitive domains. We performed cohort-specific association analyses of mtDNA CN with AD/ADRD endophenotypes assessed within ±5 years (i.e., cross-sectional analyses) or 5-20 years after blood draw (i.e., prospective analyses) adjusting for potential confounders. We further explored associations stratified by sex and age (<60 vs ≥60 years). Fixed-effects or sample size-weighted meta-analyses were performed to combine results. Finally, we performed mendelian randomization (MR) analyses to assess causality. RESULTS: We included up to 19,152 participants (mean age 59 years, 57% women). Higher mtDNA CN was cross-sectionally associated with better general cognitive function (ß = 0.04; 95% CI 0.02-0.06) independent of age, sex, batch effects, race/ethnicity, time between blood draw and cognitive evaluation, cohort-specific variables, and education. Additional adjustment for blood cell counts or cardiometabolic traits led to slightly attenuated results. We observed similar significant associations with cognition in prospective analyses, although of reduced magnitude. We found no significant associations between mtDNA CN and brain MRI measures in meta-analyses. MR analyses did not reveal a causal relation between mtDNA CN in blood and cognition. DISCUSSION: Higher mtDNA CN in blood is associated with better current and future general cognitive function in large and diverse communities across the United States. Although MR analyses did not support a causal role, additional research is needed to assess causality. Circulating mtDNA CN could serve nevertheless as a biomarker of current and future cognitive function in the community.

DNA methylation analysis is used to identify novel genetic loci associated with circulating fibrinogen levels in blood.

BACKGROUND: Fibrinogen plays an essential role in blood coagulation and inflammation. Circulating fibrinogen levels may be determined based on interindividual differences in DNA methylation at cytosine-phosphate-guanine (CpG) sites and vice versa. OBJECTIVES: To perform an EWAS to examine an association between blood DNA methylation levels and circulating fibrinogen levels to better understand its biological and pathophysiological actions. METHODS: We performed an epigenome-wide association study of circulating fibrinogen levels in 18 037 White, Black, American Indian, and Hispanic participants, representing 14 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. Circulating leukocyte DNA methylation was measured using the Illumina 450K array in 12 904 participants and using the EPIC array in 5133 participants. In each study, an epigenome-wide association study of fibrinogen was performed using linear mixed models adjusted for potential confounders. Study-specific results were combined using array-specific meta-analysis, followed by cross-replication of epigenome-wide significant associations. We compared models with and without CRP adjustment to examine the role of inflammation. RESULTS: We identified 208 and 87 significant CpG sites associated with fibrinogen levels from the 450K (p < 1.03 × 10-7) and EPIC arrays (p < 5.78 × 10-8), respectively. There were 78 associations from the 450K array that replicated in the EPIC array and 26 vice versa. After accounting for overlapping sites, there were 83 replicated CpG sites located in 61 loci, of which only 4 have been previously reported for fibrinogen. The examples of genes located near these CpG sites were SOCS3 and AIM2, which are involved in inflammatory pathways. The associations of all 83 replicated CpG sites were attenuated after CRP adjustment, although many remained significant. CONCLUSION: We identified 83 CpG sites associated with circulating fibrinogen levels. These associations are partially driven by inflammatory pathways shared by both fibrinogen and CRP.

Plasma metabolites associated with cognitive function across race/ethnicities affirming the importance of healthy nutrition.

INTRODUCTION: We studied the replication and generalization of previously identified metabolites potentially associated with global cognitive function in multiple race/ethnicities and assessed the contribution of diet to these associations. METHODS: We tested metabolite-cognitive function associations in U.S.A. Hispanic/Latino adults (n = 2222) from the Community Health Study/ Study of Latinos (HCHS/SOL) and in European (n = 1365) and African (n = 478) Americans from the Atherosclerosis Risk In Communities (ARIC) Study. We applied Mendelian Randomization (MR) analyses to assess causal associations between the metabolites and cognitive function and between Mediterranean diet and cognitive function. RESULTS: Six metabolites were consistently associated with lower global cognitive function across all studies. Of these, four were sugar-related (e.g., ribitol). MR analyses provided weak evidence for a potential causal effect of ribitol on cognitive function and bi-directional effects of cognitive performance on diet. DISCUSSION: Several diet-related metabolites were associated with global cognitive function across studies with different race/ethnicities. HIGHLIGHTS: Metabolites associated with cognitive function in Puerto Rican adults were recently identified. We demonstrate the generalizability of these associations across diverse race/ethnicities. Most identified metabolites are related to sugars. Mendelian Randomization (MR) provides weak evidence for a causal effect of ribitol on cognitive function. Beta-cryptoxanthin and other metabolites highlight the importance of a healthy diet.

Additive or Interactive Associations of Food Allergies with Glutathione S-Transferase Genes in Relation to ASD and ASD Severity in Jamaican Children.

To investigate additive and interactive associations of food allergies with three glutathione S-transferase (GST) genes in relation to ASD and ASD severity in Jamaican children. Using data from 344 1:1 age- and sex-matched ASD cases and typically developing controls, we assessed additive and interactive associations of food allergies with polymorphisms in GST genes (GSTM1, GSTP1 and GSTT1) in relation to ASD by applying conditional logistic regression models, and in relation to ASD severity in ASD cases as measured by the Autism Diagnostic Observation Schedule-2nd Edition (ADOS-2) total and domains specific comparison scores (CSs) by fitting general linear models. Although food allergies and GST genes were not associated with ASD, ASD cases allergic to non-dairy food had higher mean ADOS-2 Restricted and Repetitive Behaviors (RRB) CS (8.8 vs. 8.0, P = 0.04). In addition, allergy to dairy was associated with higher mean RRB CS only among ASD cases with GSTT1 DD genotype (9.9 vs. 7.8, P < 0.01, interaction P = 0.01), and GSTP1 Val/Val genotype under a recessive genetic model (9.8 vs. 7.8, P = 0.02, interaction P = 0.06). Our findings are consistent with the role for GST genes in ASD and food allergies, though require replication in other populations.

Interactions between Environmental Factors and Glutathione S-Transferase (GST) Genes with Respect to Detectable Blood Aluminum Concentrations in Jamaican Children.

Aluminum (Al) is a metallic toxicant at high concentrations following natural or unnatural exposures. Dietary intake is considered as the main source of aluminum exposure in children. We used data from 366 typically developing (TD) children (ages 2−8 years) who participated as controls in an age- and sex-matched case−control study in Jamaica. We investigated additive and interactive associations among environmental factors and children's genotypes for glutathione S-transferase (GST) genes (GSTT1, GSTM1, GSTP1), in relation to having a detectable blood aluminum concentration (BAlC) of >5.0 µg/L, using multivariable logistic regression models. Findings from interactive models revealed that the odds of having a detectable BAlC was significantly higher among children who ate string beans (p ≤ 0.01), whereas about 40% lower odds of having a detectable BAlC was observed in children with higher parental education level, (p = 0.02). A significant interaction between consumption of saltwater fish and GSTP1 in relation to having a detectable BAlC using either co-dominant or dominant genetic models (overall interaction p = 0.02 for both models) indicated that consumption of saltwater fish was associated with higher odds of having a detectable BAlC only among children with the GSTP1 Ile105Val Ile/Ile genotype using either co-dominant or dominant models [OR (95% CI) = 2.73 (1.07, 6.96), p = 0.04; and OR (95% CI) = 2.74 (1.08, 6.99), p = 0.03]. Since this is the first study from Jamaica that reports such findings, replication in other populations is warranted.

Clonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease.

Age-related changes to the genome-wide DNA methylation (DNAm) pattern observed in blood are well-documented. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the age-related acquisition and expansion of leukemogenic mutations in hematopoietic stem cells (HSCs), is associated with blood cancer and coronary artery disease (CAD). Epigenetic regulators DNMT3A and TET2 are the two most frequently mutated CHIP genes. Here, we present results from an epigenome-wide association study for CHIP in 582 Cardiovascular Health Study (CHS) participants, with replication in 2655 Atherosclerosis Risk in Communities (ARIC) Study participants. We show that DNMT3A and TET2 CHIP have distinct and directionally opposing genome-wide DNAm association patterns consistent with their regulatory roles, albeit both promoting self-renewal of HSCs. Mendelian randomization analyses indicate that a subset of DNAm alterations associated with these two leading CHIP genes may promote the risk for CAD.

Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning.

Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.

Detoxification Role of Metabolic Glutathione S-Transferase (GST) Genes in Blood Lead Concentrations of Jamaican Children with and without Autism Spectrum Disorder.

Glutathione S-transferases (GST) are involved in the detoxification of exogenous chemicals including lead (Pb). Using data from 344 pairs of autism spectrum disorder (ASD) cases and age- and sex-matched typically developing (TD) controls (2−8 years old) from Jamaica, we investigated the interaction between three GST genes and ASD status as determinants of blood Pb concentrations (BPbCs). We found that ASD cases had lower geometric mean BPbCs than TD children (1.74 vs. 2.27 µg/dL, p < 0.01). Using a co-dominant genetic model, ASD cases with the Ile/Val genotype for the GSTP1 Ile105Val polymorphism had lower GM BPbCs than TD controls, after adjusting for a known interaction between GSTP1 and GSTT1, child's parish, socioeconomic status, consumption of lettuce, fried plantains, and canned fish (Ile/Val: 1.78 vs. 2.13 µg/dL, p = 0.03). Similarly, among carriers of the I/I or I/D (I*) genotype for GSTT1 and GSTM1, ASD cases had lower adjusted GM BPbCs than TD controls (GSTT1 I*: 1.61 vs. 1.91 µg/dL, p = 0.01; GSTM1 I*: 1.71 vs. 2.04 µg/dL, p = 0.01). Our findings suggest that genetic polymorphisms in GST genes may influence detoxification of Pb by the enzymes they encode in Jamaican children with and without ASD.

Integrative analysis of clinical and epigenetic biomarkers of mortality.

DNA methylation (DNAm) has been reported to be associated with many diseases and with mortality. We hypothesized that the integration of DNAm with clinical risk factors would improve mortality prediction. We performed an epigenome-wide association study of whole blood DNAm in relation to mortality in 15 cohorts (n = 15,013). During a mean follow-up of 10 years, there were 4314 deaths from all causes including 1235 cardiovascular disease (CVD) deaths and 868 cancer deaths. Ancestry-stratified meta-analysis of all-cause mortality identified 163 CpGs in European ancestry (EA) and 17 in African ancestry (AA) participants at p < 1 × 10-7 , of which 41 (EA) and 16 (AA) were also associated with CVD death, and 15 (EA) and 9 (AA) with cancer death. We built DNAm-based prediction models for all-cause mortality that predicted mortality risk after adjusting for clinical risk factors. The mortality prediction model trained by integrating DNAm with clinical risk factors showed an improvement in prediction of cancer death with 5% increase in the C-index in a replication cohort, compared with the model including clinical risk factors alone. Mendelian randomization identified 15 putatively causal CpGs in relation to longevity, CVD, or cancer risk. For example, cg06885782 (in KCNQ4) was positively associated with risk for prostate cancer (Beta = 1.2, PMR  = 4.1 × 10-4 ) and negatively associated with longevity (Beta = -1.9, PMR  = 0.02). Pathway analysis revealed that genes associated with mortality-related CpGs are enriched for immune- and cancer-related pathways. We identified replicable DNAm signatures of mortality and demonstrated the potential utility of CpGs as informative biomarkers for prediction of mortality risk.

Midlife determinants of healthy cardiovascular aging: The Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND AND AIMS: Risk factor cutoffs are derived from associations with clinical cardiovascular disease (CVD), but how these risk factors associate with preserved cardiovascular health into old age is not well studied. We investigated midlife determinants of healthy versus nonhealthy cardiovascular aging in the Atherosclerosis Risk in Communities (ARIC) study. METHODS: ARIC participants were categorized by cardiovascular status in older age (mean age 75.8 ± 5.3 years, range 66-90): healthy, subclinical disease (assessed by biomarkers and left ventricular function), clinical CVD (coronary heart disease, stroke, or heart failure), or prior death. We examined associations of midlife (mean age 52.1 ± 5.1 years) systolic and diastolic blood pressure (SBP, DBP), low-density lipoprotein cholesterol (LDL-C), triglycerides, hemoglobin A1c (HbA1c), and body mass index (BMI) with cardiovascular status in older age using multinomial logistic regression analyses. RESULTS: Compared with healthy status, odds for subclinical disease (odds ratio [OR] 1.30, 95% confidence interval [CI] 1.09-1.55) and clinical CVD (OR 1.87, 95% CI 1.53-2.29) at older age increased starting with midlife SBP 120-129 mmHg, whereas odds for death increased starting with SBP 110-119 mmHg (OR 1.29, 95% CI 1.10-1.52); findings were similar for DBP. Odds for subclinical disease increased for HbA1c ≥ 6.5% and BMI starting at 30-<35 kg/m2; odds for clinical CVD or death increased starting at HbA1c 5.5-5.9%, LDL-C >160 mg/dL, and BMI 30-<35 kg/m2. CONCLUSIONS: More-stringent levels of modifiable risk factors in midlife beyond current clinical practice and guidelines were associated with preserved cardiovascular health in older age.

Gaseous air pollutants and DNA methylation in a methylome-wide association study of an ethnically and environmentally diverse population of U.S. adults.

Epigenetic mechanisms may underlie air pollution-health outcome associations. We estimated gaseous air pollutant-DNA methylation (DNAm) associations using twelve subpopulations within Women's Health Initiative (WHI) and Atherosclerosis Risk in Communities (ARIC) cohorts (n = 8397; mean age 61.3 years; 83% female; 46% African-American, 46% European-American, 8% Hispanic/Latino). We used geocoded participant address-specific mean ambient carbon monoxide (CO), nitrogen oxides (NO2; NOx), ozone (O3), and sulfur dioxide (SO2) concentrations estimated over the 2-, 7-, 28-, and 365-day periods before collection of blood samples used to generate Illumina 450 k array leukocyte DNAm measurements. We estimated methylome-wide, subpopulation- and race/ethnicity-stratified pollutant-DNAm associations in multi-level, linear mixed-effects models adjusted for sociodemographic, behavioral, meteorological, and technical covariates. We combined stratum-specific estimates in inverse variance-weighted meta-analyses and characterized significant associations (false discovery rate; FDR<0.05) at Cytosine-phosphate-Guanine (CpG) sites without among-strata heterogeneity (PCochran's Q > 0.05). We attempted replication in the Cooperative Health Research in Region of Augsburg (KORA) study and Normative Aging Study (NAS). We observed a -0.3 (95% CI: -0.4, -0.2) unit decrease in percent DNAm per interquartile range (IQR, 7.3 ppb) increase in 28-day mean NO2 concentration at cg01885635 (chromosome 3; regulatory region 290 bp upstream from ZNF621; FDR = 0.03). At intragenic sites cg21849932 (chromosome 20; LIME1; intron 3) and cg05353869 (chromosome 11; KLHL35; exon 2), we observed a -0.3 (95% CI: -0.4, -0.2) unit decrease (FDR = 0.04) and a 1.2 (95% CI: 0.7, 1.7) unit increase (FDR = 0.04), respectively, in percent DNAm per IQR (17.6 ppb) increase in 7-day mean ozone concentration. Results were not fully replicated in KORA and NAS. We identified three CpG sites potentially susceptible to gaseous air pollution-induced DNAm changes near genes relevant for cardiovascular and lung disease. Further harmonized investigations with a range of gaseous pollutants and averaging durations are needed to determine the effect of gaseous air pollutants on DNA methylation and ultimately gene expression.

Genetic Risk, Midlife Life's Simple 7, and Incident Dementia in the Atherosclerosis Risk in Communities Study.

BACKGROUND: and ObjectivesHigher scores in Life's Simple 7 (LS7), a metric for cardiovascular and brain health, have been associated with lower risk of dementia. It is uncertain whether this association holds among those with high genetic risk of dementia. Our objective is to evaluate the extent that LS7 may offset dementia risk across the range of genetic risk.Methods PARTICIPANTS: in the Atherosclerosis Risk in Communities (ARIC) Study were followed from 1987-89 to 2019. We derived midlife LS7 scores and generated genetic risk scores (GRS) using genome-wide summary statistics of Alzheimer's Disease, which have been used to study the genetic risk for dementia. Incident dementia was ascertained based on the criteria of the National Institute on Aging-Alzheimer's Association workgroups and Diagnostic and Statistical Manual of Mental Disorders. The associations of the GRS and LS7 with incident dementia were evaluated using Cox regression. RESULTS: This study included 8,823 European Americans (EA) and 2,738 African Americans (AA) (mean age at baseline: 54). We observed 1,603 cases of dementia among EA and 631 among AA (median follow-up: 26.2 years). Higher GRS were associated with higher risk of dementia (EA, hazard ratio [HR] per standard deviation [SD] 1.44, 95% confidence interval [CI]: 1.37, 1.51; AA, HR 1.26, 95% CI: 1.16, 1.36). Among EA, higher LS7 scores were consistently associated with lower risk of dementia across quintiles of GRS, including the highest quintile (HR per point 0.91, 95% CI: 0.87, 0.96). Among AA, the associations between LS7 and incident dementia within stratum of GRS had the same direction as among EA, though wide confidence intervals and smaller sample sizes limited reliable inferences. CONCLUSIONS: Across strata of GRS, higher midlife LS7 scores were associated with lower risk of dementia. Larger sample sizes from diverse populations are needed to obtain more reliable estimates of the effects of modifiable health factors on dementia risk within genetic risk stratum in each ancestry group.