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1.
Artigo em Inglês | MEDLINE | ID: mdl-31630168

RESUMO

Methylation levels measured at defined sites across the genome have recently been shown to be correlated with an individual's chronological age. Age acceleration, or the difference between age estimated from DNA methylation status and chronological age, has been proposed as a novel biomarker of aging. In this study, the cross-sectional association between two different measures of age acceleration and cognitive function was investigated using whole blood samples from 2,157 African-American participants 47-70 years of age in the population-based Atherosclerosis Risk in Communities (ARIC) Study. Cognition was evaluated using three domain-specific tests. A significant inverse association between a one-year increase in age acceleration calculated using a blood-based age predictor and scores on the Word Fluency Test was found using a general linear model adjusted for chronological age, gender, and years of education (ß = -0.140 words; p = 0.001) and after adding other potential confounding variables (ß = -0.104 words, p = 0.023). The results were replicated in 1,670 European participants in the Generation Scotland: Scottish Family Health Study (fully adjusted model: ß = -0.199 words; p = 0.034). A significant association was also identified in a trans-ethnic meta-analysis across cohorts that included an additional 708 European American ARIC study participants (fully adjusted model: ß = -0.110 words, p = 0.003). There were no associations found using an estimate of age acceleration derived from multiple tissues. These findings provide evidence that age acceleration is a correlate of performance on a test of verbal fluency in middle-aged adults.

2.
BMC Cancer ; 19(1): 964, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31623592

RESUMO

BACKGROUND: CpG Island Methylator Phenotype (CIMP) is an epigenetic phenotype in CRC characterized by hypermethylation of CpG islands in promoter regions of tumor suppressor genes, leading to their transcriptional silencing and loss of function. While the prevalence of CRC differs across geographical regions, no studies have compared prevalence of CIMP-High phenotype across regions. The purpose of this project was to compare the prevalence of CIMP across geographical regions after adjusting for variations in methodologies to measure CIMP in a meta-analysis. METHODS: We searched PubMed, Medline, and Embase for articles focusing on CIMP published from 2000 to 2018. Two reviewers independently identified 111 articles to be included in final meta-analysis. We classified methods used to quantify CIMP into 4 categories: a) Classical (MINT marker) Panel group b) Weisenberg-Ogino (W-O) group c) Human Methylation Arrays group and d) Miscellaneous group. We compared the prevalence of CIMP across geographical regions after correcting for methodological variations using meta-regression techniques. RESULTS: The pooled prevalence of CIMP-High across all studies was 22% (95% confidence interval:21-24%; I2 = 94.75%). Pooled prevalence of CIMP-H across Asia, Australia, Europe, North America and South America was 22, 21, 21, 27 and 25%, respectively. Meta-regression analysis identified no significant differences in the prevalence of CIMP-H across geographical regions after correction for methodological variations. In exploratory analysis, we observed variations in CIMP-H prevalence across countries. CONCLUSION: Although no differences were found for CIMP-H prevalence across countries, further studies are needed to compare the influence of demographic, lifestyle and environmental factors in relation to the prevalence of CIMP across geographical regions.

3.
J Autism Dev Disord ; 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31538260

RESUMO

Mode of delivery, preterm birth, and low birth weight (LBW) are hypothesized to be associated with autism spectrum disorder (ASD) in the offspring. Using data from 343 ASD cases (2-8 years) and their age- and sex-matched typically developing controls in Jamaica we investigated these hypotheses. Our statistical analyses revealed that the parish of residence could modify the association between cesarean delivery and ASD, with a difference found in this relationship in Kingston parish [matched odds ratio (MOR) (95% confidence interval (CI)) 2.30 (1.17-4.53)] and other parishes [MOR (95% CI) 0.87 (0.48-1.59)]. Although the associations of LBW and preterm birth with ASD were not significant, we observed a significant interaction between LBW and the household socioeconomic status. These findings require replication.

4.
Circulation ; 140(8): 645-657, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31424985

RESUMO

BACKGROUND: DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts. METHODS: Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts. RESULTS: Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts. CONCLUSION: Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31261817

RESUMO

Environmental exposure to lead (Pb), mercury (Hg), arsenic (As), cadmium (Cd), manganese (Mn), and aluminum (Al) has been associated with neurodevelopmental disorders including autism spectrum disorder (ASD). We conducted a pilot study during May 2015-May 2107 to estimate blood concentrations of six metals (Pb, Hg, As, Cd, Mn, and Al) and identify their associated factors for children with ASD or suspected of having ASD in Romania. Sixty children, age 2-8 years, were administered versions of ADOS or ADI-R translated from English to Romanian. After assessment, 2-3 mL of blood was obtained and analyzed for the concentrations of the six metals. The mean age of children was 51.9 months and about 90% were male. More than half (65%) of the children were born in Bucharest. Over 90% of concentrations of As and Cd were below limits of detection. Geometric mean concentrations of Pb, Mn, Al, and Hg were 1.14 µg/dL, 10.84 µg/L, 14.44 µg/L, and 0.35 µg/L, respectively. Multivariable linear regression analysis revealed that children who were female, had less educated parents, exhibited pica, and ate cold breakfast (e.g., cereal), watermelon, and lamb had significantly higher concentrations of Pb compared to their respective referent categories (all p < 0.05 except for eating lamb, which was marginally significant, p = 0.053). Although this is the first study that provides data on concentrations of the six metals for Romanian children with ASD, the findings from this study could be useful for designing future epidemiologic studies for investigating the role of these six metals in ASD in Romanian children.

6.
Environ Int ; 132: 104723, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31208937

RESUMO

BACKGROUND: DNA methylation (DNAm) may contribute to processes that underlie associations between air pollution and poor health. Therefore, our objective was to evaluate associations between DNAm and ambient concentrations of particulate matter (PM) ≤2.5, ≤10, and 2.5-10 µm in diameter (PM2.5; PM10; PM2.5-10). METHODS: We conducted a methylome-wide association study among twelve cohort- and race/ethnicity-stratified subpopulations from the Women's Health Initiative and the Atherosclerosis Risk in Communities study (n = 8397; mean age: 61.5 years; 83% female; 45% African American; 9% Hispanic/Latino American). We averaged geocoded address-specific estimates of daily and monthly mean PM concentrations over 2, 7, 28, and 365 days and 1 and 12 months before exams at which we measured leukocyte DNAm in whole blood. We estimated subpopulation-specific, DNAm-PM associations at approximately 485,000 Cytosine-phosphate-Guanine (CpG) sites in multi-level, linear, mixed-effects models. We combined subpopulation- and site-specific estimates in fixed-effects, inverse variance-weighted meta-analyses, then for associations that exceeded methylome-wide significance and were not heterogeneous across subpopulations (P < 1.0 × 10-7; PCochran's Q > 0.10), we characterized associations using publicly accessible genomic databases and attempted replication in the Cooperative Health Research in the Region of Augsburg (KORA) study. RESULTS: Analyses identified significant DNAm-PM associations at three CpG sites. Twenty-eight-day mean PM10 was positively associated with DNAm at cg19004594 (chromosome 20; MATN4; P = 3.33 × 10-8). One-month mean PM10 and PM2.5-10 were positively associated with DNAm at cg24102420 (chromosome 10; ARPP21; P = 5.84 × 10-8) and inversely associated with DNAm at cg12124767 (chromosome 7; CFTR; P = 9.86 × 10-8). The PM-sensitive CpG sites mapped to neurological, pulmonary, endocrine, and cardiovascular disease-related genes, but DNAm at those sites was not associated with gene expression in blood cells and did not replicate in KORA. CONCLUSIONS: Ambient PM concentrations were associated with DNAm at genomic regions potentially related to poor health among racially, ethnically and environmentally diverse populations of U.S. women and men. Further investigation is warranted to uncover mechanisms through which PM-induced epigenomic changes may cause disease.

7.
Nat Commun ; 10(1): 2581, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31197173

RESUMO

Despite existing reports on differential DNA methylation in type 2 diabetes (T2D) and obesity, our understanding of its functional relevance remains limited. Here we show the effect of differential methylation in the early phases of T2D pathology by a blood-based epigenome-wide association study of 4808 non-diabetic Europeans in the discovery phase and 11,750 individuals in the replication. We identify CpGs in LETM1, RBM20, IRS2, MAN2A2 and the 1q25.3 region associated with fasting insulin, and in FCRL6, SLAMF1, APOBEC3H and the 15q26.1 region with fasting glucose. In silico cross-omics analyses highlight the role of differential methylation in the crosstalk between the adaptive immune system and glucose homeostasis. The differential methylation explains at least 16.9% of the association between obesity and insulin. Our study sheds light on the biological interactions between genetic variants driving differential methylation and gene expression in the early pathogenesis of T2D.


Assuntos
Metilação de DNA/fisiologia , Diabetes Mellitus Tipo 2/genética , Glucose/metabolismo , Insulina/metabolismo , Obesidade/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Simulação por Computador , Ilhas de CpG/genética , Diabetes Mellitus Tipo 2/metabolismo , Epigênese Genética/fisiologia , Epigenômica/métodos , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Homeostase/genética , Humanos , Masculino , Redes e Vias Metabólicas/genética , Pessoa de Meia-Idade , Obesidade/metabolismo , Polimorfismo de Nucleotídeo Único/fisiologia , Adulto Jovem
8.
Biom J ; 61(4): 934-954, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31058353

RESUMO

A weighted quantile sum (WQS) regression has been used to assess the associations between environmental exposures and health outcomes. However, the currently available WQS approach, which is based on additive effects, does not allow exploring for potential interactions of exposures with other covariates in relation to a health outcome. In addition, the current WQS cannot account for clustering, thus it may not be valid for analysis of clustered data. We propose a generalized WQS approach that can assess interactions by estimating stratum-specific weights of exposures in a mixture, while accounting for potential clustering effect of matched pairs of cases and controls as well as censored exposure data due to being below the limits of detection. The performance of the proposed method in identifying interactions is evaluated through simulations based on various scenarios of correlation structures among the exposures and with an outcome. We also assess how well the proposed method performs in the presence of the varying levels of censoring in exposures. Our findings from the simulation study show that the proposed method outperforms the traditional WQS, as indicated by higher power of detecting interactions. We also find no strong evidence that the proposed method falsely identifies interactions when there are no true interactive effects. We demonstrate application of the proposed method to real data from the Epidemiological Research on Autism Spectrum Disorder (ASD) in Jamaica (ERAJ) by examining interactions between exposure to manganese and glutathione S-transferase family gene, GSTP1 in relation to ASD.

9.
Transl Oncol ; 11(5): 1188-1201, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30071442

RESUMO

BACKGROUND: CpG island methylator phenotype (CIMP) tumors, comprising 20% of colorectal cancers, are associated with female sex, age, right-sided location, and BRAF mutations. However, other factors potentially associated with CIMP have not been robustly examined. This meta-analysis provides a comprehensive assessment of the clinical, pathologic, and molecular characteristics that define CIMP tumors. METHODS: We conducted a comprehensive search of the literature from January 1999 through April 2018 and identified 122 articles, on which comprehensive data abstraction was performed on the clinical, pathologic, molecular, and mutational characteristics of CIMP subgroups, classified based on the extent of DNA methylation of tumor suppressor genes assessed using a variety of laboratory methods. Associations of CIMP with outcome parameters were estimated using pooled odds ratio or standardized mean differences using random-effects model. RESULTS: We confirmed prior associations including female sex, older age, right-sided tumor location, poor differentiation, and microsatellite instability. In addition to the recognized association with BRAF mutations, CIMP was also associated with PIK3CA mutations and lack of mutations in KRAS and TP53. Evidence of an activated immune response was seen with high rates of tumor-infiltrating lymphocytes (but not peritumoral lymphocytes), Crohn-like infiltrates, and infiltration with Fusobacterium nucleatum bacteria. Additionally, CIMP tumors were associated with advance T-stage and presence of perineural and lymphovascular invasion. CONCLUSION: The meta-analysis highlights key features distinguishing CIMP in colorectal cancer, including molecular characteristics of an active immune response. Improved understanding of this unique molecular subtype of colorectal cancer may provide insights into prevention and treatment.

10.
JAMA Psychiatry ; 75(9): 949-959, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-29998287

RESUMO

Importance: Depressive disorders arise from a combination of genetic and environmental risk factors. Epigenetic disruption provides a plausible mechanism through which gene-environment interactions lead to depression. Large-scale, epigenome-wide studies on depression are missing, hampering the identification of potentially modifiable biomarkers. Objective: To identify epigenetic mechanisms underlying depression in middle-aged and elderly persons, using DNA methylation in blood. Design, Setting, and Participants: To date, the first cross-ethnic meta-analysis of epigenome-wide association studies (EWAS) within the framework of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium was conducted. The discovery EWAS included 7948 individuals of European origin from 9 population-based cohorts. Participants who were assessed for both depressive symptoms and whole-blood DNA methylation were included in the study. Results of EWAS were pooled using sample-size weighted meta-analysis. Replication of the top epigenetic sites was performed in 3308 individuals of African American and European origin from 2 population-based cohorts. Main Outcomes and Measures: Whole-blood DNA methylation levels were assayed with Illumina-Infinium Human Methylation 450K BeadChip and depressive symptoms were assessed by questionnaire. Results: The discovery cohorts consisted of 7948 individuals (4104 [51.6%] women) with a mean (SD) age of 65.4 (5.8) years. The replication cohort consisted of 3308 individuals (2456 [74.2%] women) with a mean (SD) age of 60.3 (6.4) years. The EWAS identified methylation of 3 CpG sites to be significantly associated with increased depressive symptoms: cg04987734 (P = 1.57 × 10-08; n = 11 256; CDC42BPB gene), cg12325605 (P = 5.24 × 10-09; n = 11 256; ARHGEF3 gene), and an intergenic CpG site cg14023999 (P = 5.99 × 10-08; n = 11 256; chromosome = 15q26.1). The predicted expression of the CDC42BPB gene in the brain (basal ganglia) (effect, 0.14; P = 2.7 × 10-03) and of ARHGEF3 in fibroblasts (effect, -0.48; P = 9.8 × 10-04) was associated with major depression. Conclusions and Relevance: This study identifies 3 methylated sites associated with depressive symptoms. All 3 findings point toward axon guidance as the common disrupted pathway in depression. The findings provide new insights into the molecular mechanisms underlying the complex pathophysiology of depression. Further research is warranted to determine the utility of these findings as biomarkers of depression and evaluate any potential role in the pathophysiology of depression and their downstream clinical effects.

11.
J Gen Intern Med ; 33(10): 1721-1728, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30030736

RESUMO

BACKGROUND: Previous studies suggest that heart failure (HF) is an independent risk factor for cognitive decline. A better understanding of the relationship between HF, cognitive status, and cognitive decline in a community-based sample may help clinicians understand disease risk. OBJECTIVE: To examine whether persons with HF have a higher prevalence of cognitive impairment and whether persons developing HF have more rapid cognitive decline. DESIGN: This observational cohort study of American adults in the Atherosclerosis Risk in Communities (ARIC) study has two components: cross-sectional analysis examining the association between prevalent HF and cognition using multinomial logistic regression, and change over time analysis detailing the association between incident HF and change in cognition over 15 years. PARTICIPANTS: Among visit 5 (2011-2013) participants (median age 75 years), 6495 had neurocognitive information available for cross-sectional analysis. Change over time analysis examined the 5414 participants who had cognitive scores and no prevalent HF at visit 4 (1996-1998). MEASUREMENTS: The primary outcome was cognitive status, classified as normal, mild cognitive impairment [MCI], and dementia on the basis of standardized cognitive tests (delayed word recall, word fluency, and digit symbol substitution). Cognitive change was examined over a 15-year period. Control variables included socio-demographic, vascular, and smoking/drinking measures. RESULTS: At visit 5, participants with HF had a higher prevalence of dementia (adjusted relative risk ratio [RRR] = 1.60 [95% CI 1.13, 2.25]) and MCI (RRR = 1.36 [1.12, 1.64]) than those without HF. A decline in cognition between visits 4 and 5 was - 0.07 standard deviation units [- 0.13, - 0.01] greater among persons who developed HF compared to those who did not. Results did not differ by ejection fraction. CONCLUSION: HF is associated with neurocognitive dysfunction and decline independent of other co-morbid conditions. Further study is needed to determine the underlying pathophysiology.

12.
Circ Genom Precis Med ; 11(3): e001937, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29555670

RESUMO

BACKGROUND: DNA methylation-based patterns of biological aging, known as epigenetic age acceleration, are predictive of all-cause mortality, but little is known about their association with cardiovascular disease (CVD). METHODS: We estimated 2 versions of epigenetic age acceleration (Horvath and Hannum) using whole-blood samples from 2543 blacks. Linear and Cox proportional hazards regression, respectively, were used to assess the association of age acceleration with carotid intima-media thickness (cross-sectionally) and incident cardiovascular events, including CVD mortality, myocardial infarction, fatal coronary heart disease, peripheral arterial disease, and heart failure, during a median 21-year follow-up. All models were adjusted for chronological age and traditional CVD risk factors. RESULTS: In comparison to chronological age, the 2 measures of epigenetic age acceleration were weaker, but independent, potential risk markers for subclinical atherosclerosis and most incident cardiovascular outcomes, including fatal coronary heart disease, peripheral arterial disease, and heart failure. For example, each 5-year increment of epigenetic age acceleration was associated with an average of 0.01 mm greater carotid intima-media thickness (each P≤0.01), and the hazard ratios (95% confidence intervals) of fatal coronary heart disease per 5-year increment in Horvath and Hannum age acceleration were 1.17 (1.02-1.33) and 1.22 (1.04-1.44), respectively. CONCLUSIONS: In this sample of blacks, increased epigenetic age acceleration in whole blood was a potential risk marker for incident fatal coronary heart disease, peripheral arterial disease, and heart failure independently of chronological age and traditional CVD risk factors. DNA methylation-based measures of biological aging may help to identify new pathophysiological mechanisms contributing to the development of CVD.

13.
J Autism Dev Disord ; 48(8): 2766-2778, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29549549

RESUMO

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with poorly understood etiology. Many maternal exposures during pregnancy and breastfeeding potentially interfere with neurodevelopment. Using data from two age- and sex-matched case-control studies in Jamaica (n = 298 pairs), results of conditional logistic regression analyses suggest that maternal exposures to fever or infection (matched odds ratio (MOR) = 3.12, 95% CI 1.74-5.60), physical trauma (MOR 2.02, 95% CI 1.01-4.05), and oil-based paints (MOR 1.99, 95% CI 1.14-3.46) may be associated with ASD. Additionally, maternal exposure to oil-based paints may modify the relationship between maternal exposure to pesticides and ASD, which deepens our understanding of the association between pesticides and ASD.

14.
Mol Psychiatry ; 23(11): 2133-2144, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29311653

RESUMO

Cognitive functions are important correlates of health outcomes across the life-course. Individual differences in cognitive functions are partly heritable. Epigenetic modifications, such as DNA methylation, are susceptible to both genetic and environmental factors and may provide insights into individual differences in cognitive functions. Epigenome-wide meta-analyses for blood-based DNA methylation levels at ~420,000 CpG sites were performed for seven measures of cognitive functioning using data from 11 cohorts. CpGs that passed a Bonferroni correction, adjusting for the number of CpGs and cognitive tests, were assessed for: longitudinal change; being under genetic control (methylation QTLs); and associations with brain health (structural MRI), brain methylation and Alzheimer's disease pathology. Across the seven measures of cognitive functioning (meta-analysis n range: 2557-6809), there were epigenome-wide significant (P < 1.7 × 10-8) associations for global cognitive function (cg21450381, P = 1.6 × 10-8), and phonemic verbal fluency (cg12507869, P = 2.5 × 10-9). The CpGs are located in an intergenic region on chromosome 12 and the INPP5A gene on chromosome 10, respectively. Both probes have moderate correlations (~0.4) with brain methylation in Brodmann area 20 (ventral temporal cortex). Neither probe showed evidence of longitudinal change in late-life or associations with white matter brain MRI measures in one cohort with these data. A methylation QTL analysis suggested that rs113565688 was a cis methylation QTL for cg12507869 (P = 5 × 10-5 and 4 × 10-13 in two lookup cohorts). We demonstrate a link between blood-based DNA methylation and measures of phonemic verbal fluency and global cognitive ability. Further research is warranted to understand the mechanisms linking genomic regulatory changes with cognitive function to health and disease.

15.
Alzheimer Dis Assoc Disord ; 32(2): 131-136, 2018 Apr-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29116943

RESUMO

Previous reports suggest race/ethnic and sex heterogeneity in the association between the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor gamma (PPARG) gene and cognitive decline. Tests of verbal memory, processing speed, and verbal fluency and a composite global Z-score were used to assess cognitive performance longitudinally in a large (n=11,620) biracial cohort of older adults in the Atherosclerosis Risk in Communities Neurocognitive Study from midlife to older age. Linear mixed models were used to estimate associations between the Ala12 allele and cognitive performance over 20 years of follow-up. Heterogeneity was present for rate of cognitive decline as measured by the global Z-score by race, sex, and Ala12 allele status (P=0.01 for 4-way interaction term: race×sex×time×Ala12 carrier status). Stratified analysis showed a significantly increased rate of global cognitive decline over the 20-year follow-up for carriers of the Ala12 allele compared with noncarriers among black male individuals (-0.92 SD decline vs. -0.57 SD; P=0.02) but not among black female, white male, or white female individuals. Decline in global cognitive function among black male Ala12 carriers was primarily driven by decline in verbal memory. Our data underscore the context-dependent association between the Pro12Ala polymorphism and cognitive decline, specifically race/ethnic background and sex.

16.
Am J Hum Genet ; 101(6): 888-902, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29198723

RESUMO

Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0 × 10-7; replication: N = 7,182, p < 1.6 × 10-3). The replicated methylation sites are heritable (h2 > 30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.


Assuntos
Pressão Sanguínea/genética , Metilação de DNA/genética , Proteínas do Tecido Nervoso/genética , Tetraspaninas/genética , Idoso , Ilhas de CpG/genética , Estudos Transversais , Epigênese Genética/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Locos de Características Quantitativas/genética
17.
PLoS One ; 12(7): e0180046, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28704393

RESUMO

OBJECTIVE: We performed single-variant and gene-based association analyses of plasma amyloid-ß (aß) concentrations using whole exome sequence from 1,414 African and European Americans. Our goal was to identify genes that influence plasma aß42 concentrations and aß42:aß40 ratios in late middle age (mean = 59 years), old age (mean = 77 years), or change over time (mean = 18 years). METHODS: Plasma aß measures were linearly regressed onto age, gender, APOE ε4 carrier status, and time elapsed between visits (fold-changes only) separately by race. Following inverse normal transformation of the residuals, seqMeta was used to conduct race-specific single-variant and gene-based association tests while adjusting for population structure. Linear regression models were fit on autosomal variants with minor allele frequencies (MAF)≥1%. T5 burden and Sequence Kernel Association (SKAT) gene-based tests assessed functional variants with MAF≤5%. Cross-race fixed effects meta-analyses were Bonferroni-corrected for the number of variants or genes tested. RESULTS: Seven genes were associated with aß in late middle age or change over time; no associations were identified in old age. Single variants in KLKB1 (rs3733402; p = 4.33x10-10) and F12 (rs1801020; p = 3.89x10-8) were significantly associated with midlife aß42 levels through cross-race meta-analysis; the KLKB1 variant replicated internally using 1,014 additional participants with exome chip. ITPRIP, PLIN2, and TSPAN18 were associated with the midlife aß42:aß40 ratio via the T5 test; TSPAN18 was significant via the cross-race meta-analysis, whereas ITPRIP and PLIN2 were European American-specific. NCOA1 and NT5C3B were associated with the midlife aß42:aß40 ratio and the fold-change in aß42, respectively, via SKAT in African Americans. No associations replicated externally (N = 725). CONCLUSION: We discovered age-dependent genetic effects, established associations between vascular-related genes (KLKB1, F12, PLIN2) and midlife plasma aß levels, and identified a plausible Alzheimer's Disease candidate gene (ITPRIP) influencing cell death. Plasma aß concentrations may have dynamic biological determinants across the lifespan; plasma aß study designs or analyses must consider age.


Assuntos
Afro-Americanos/genética , Peptídeos beta-Amiloides/sangue , Grupo com Ancestrais do Continente Europeu/genética , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA/métodos , Idoso , Exoma , Feminino , Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Estados Unidos/etnologia
18.
Autism ; 21(5): 564-572, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28367671

RESUMO

The administration requirements of the Autism Diagnostic Observation Schedule and the Autism Diagnostic Interview-Revised, widely used in high-income countries, make them less feasible for diagnosis of autism spectrum disorder in low- and middle-income countries. The flexible administration requirements of the Childhood Autism Rating Scale have resulted in its use in both high-income countries and low- and middle-income countries. This study examines the agreement between assessments using the Childhood Autism Rating Scale with those using the Autism Diagnostic Observation Schedule or Autism Diagnostic Observation Schedule, Second Edition and Autism Diagnostic Interview-Revised in Jamaica. Children aged 2-8 years (n = 149) diagnosed with autism by an experienced clinician using the Childhood Autism Rating Scale were re-evaluated using the Autism Diagnostic Observation Schedule and Autism Diagnostic Interview-Revised. The proportion diagnosed with autism spectrum disorder using the Autism Diagnostic Observation Schedule, Autism Diagnostic Observation Schedule, Second Edition, and Autism Diagnostic Interview-Revised was determined and mean domain scores compared using analysis of variance (ANOVA). The mean age was 64.4 (standard deviation = 21.6) months; the male:female ratio was 6:1. The diagnostic agreement of the Childhood Autism Rating Scale with the Autism Diagnostic Observation Schedule and Autism Diagnostic Observation Schedule, Second Edition was 100.0% and 98.0%, respectively. Agreement with the Autism Diagnostic Interview-Revised was 94.6%. Domain scores were highest for children with more severe symptoms (p < 0.01). Despite a high level of agreement of the Childhood Autism Rating Scale with the Autism Diagnostic Observation Schedule, Autism Diagnostic Observation Schedule, Second Edition, and Autism Diagnostic Interview-Revised, the Childhood Autism Rating Scale should be evaluated further with a broader range of autism spectrum disorder symptomatology, and by clinicians with varying experience before recommendation for use in low- and middle-income countries.


Assuntos
Transtorno do Espectro Autista/diagnóstico , Países em Desenvolvimento , Pobreza , Análise de Variância , Criança , Pré-Escolar , Feminino , Humanos , Jamaica , Masculino
19.
Clin Epigenetics ; 9: 21, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28289478

RESUMO

BACKGROUND: Cerebral white matter hyperintensities (WMH) on magnetic resonance imaging (MRI) are part of the spectrum of brain vascular injury accompanying aging and are associated with a substantial risk of stroke and dementia. We investigated the association of cerebral WMH burden on MRI with a DNA methylation-based biomarker of aging, termed DNA methylation age acceleration, which represents the deviation of the DNA methylation-predicted age from the chronologic age. RESULTS: In this cross-sectional observational study of 713 African-American participants of the Atherosclerosis Risk in Communities study, aged 51-73 years, estimates of predicted age were obtained based on two algorithms (Hannum et al. and Horvath) from DNA methylation measured using the Illumina HM450 array on genomic DNA extracted from blood. Age acceleration, calculated as the residual values from the regression of each of the predicted age measures onto the chronologic age, was significantly associated with WMH burden after accounting for chronologic age and sex, body mass index, systolic blood pressure, hypertension, diabetes, current smoking, and blood cell composition, and results were similar for either Hannum et al.- or Horvath-derived estimates (P = 0.016 and 0.026). An age acceleration increase by 1 year was associated with an increase of WMH burden by ~1 grade. To shed light on possible biological mechanisms underlying this association, we conducted a genome-wide association study of age acceleration and identified four loci harboring genes implicated in hemostasis, cell proliferation, protein degradation, and histone methylation. However, none of these loci were associated with WMH burden. CONCLUSIONS: In this population-based study of middle-aged to older African-American adults, we report an association between accelerated epigenetic aging and increased WMH burden, independent of known risk factors, including chronologic age. Additional studies are needed to clarify whether DNA methylation age reflects biological mechanisms implicated in the aging of the cerebral white matter.


Assuntos
Afro-Americanos/genética , Envelhecimento/genética , Aterosclerose/epidemiologia , Metilação de DNA , Substância Branca/diagnóstico por imagem , Idoso , Envelhecimento/etnologia , Algoritmos , Aterosclerose/genética , Índice de Massa Corporal , Estudos Transversais , Epigênese Genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade
20.
PLoS Med ; 14(1): e1002215, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28095459

RESUMO

BACKGROUND: The link between DNA methylation, obesity, and adiposity-related diseases in the general population remains uncertain. METHODS AND FINDINGS: We conducted an association study of body mass index (BMI) and differential methylation for over 400,000 CpGs assayed by microarray in whole-blood-derived DNA from 3,743 participants in the Framingham Heart Study and the Lothian Birth Cohorts, with independent replication in three external cohorts of 4,055 participants. We examined variations in whole blood gene expression and conducted Mendelian randomization analyses to investigate the functional and clinical relevance of the findings. We identified novel and previously reported BMI-related differential methylation at 83 CpGs that replicated across cohorts; BMI-related differential methylation was associated with concurrent changes in the expression of genes in lipid metabolism pathways. Genetic instrumental variable analysis of alterations in methylation at one of the 83 replicated CpGs, cg11024682 (intronic to sterol regulatory element binding transcription factor 1 [SREBF1]), demonstrated links to BMI, adiposity-related traits, and coronary artery disease. Independent genetic instruments for expression of SREBF1 supported the findings linking methylation to adiposity and cardiometabolic disease. Methylation at a substantial proportion (16 of 83) of the identified loci was found to be secondary to differences in BMI. However, the cross-sectional nature of the data limits definitive causal determination. CONCLUSIONS: We present robust associations of BMI with differential DNA methylation at numerous loci in blood cells. BMI-related DNA methylation and gene expression provide mechanistic insights into the relationship between DNA methylation, obesity, and adiposity-related diseases.


Assuntos
Índice de Massa Corporal , Doença da Artéria Coronariana/genética , Metilação de DNA , Regulação da Expressão Gênica , Leucócitos/metabolismo , Metabolismo dos Lipídeos , Idoso , Doença da Artéria Coronariana/etiologia , Epigênese Genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Metabolismo dos Lipídeos/genética , Masculino , Análise da Randomização Mendeliana , Obesidade/complicações , Análise de Sequência com Séries de Oligonucleotídeos
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