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1.
Eur J Hum Genet ; 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31558840

RESUMO

Insights into individual differences in gene expression and its heritability (h2) can help in understanding pathways from DNA to phenotype. We estimated the heritability of gene expression of 52,844 genes measured in whole blood in the largest twin RNA-Seq sample to date (1497 individuals including 459 monozygotic twin pairs and 150 dizygotic twin pairs) from classical twin modeling and identity-by-state-based approaches. We estimated for each gene h2total, composed of cis-heritability (h2cis, the variance explained by single nucleotide polymorphisms in the cis-window of the gene), and trans-heritability (h2res, the residual variance explained by all other genome-wide variants). Mean h2total was 0.26, which was significantly higher than heritability estimates earlier found in a microarray-based study using largely overlapping (>60%) RNA samples (mean h2 = 0.14, p = 6.15 × 10-258). Mean h2cis was 0.06 and strongly correlated with beta of the top cis expression quantitative loci (eQTL, ρ = 0.76, p < 10-308) and with estimates from earlier RNA-Seq-based studies. Mean h2res was 0.20 and correlated with the beta of the corresponding trans-eQTL (ρ = 0.04, p < 1.89 × 10-3) and was significantly higher for genes involved in cytokine-cytokine interactions (p = 4.22 × 10-15), many other immune system pathways, and genes identified in genome-wide association studies for various traits including behavioral disorders and cancer. This study provides a thorough characterization of cis- and trans-h2 estimates of gene expression, which is of value for interpretation of GWAS and gene expression studies.

2.
Mol Psychiatry ; 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501512

RESUMO

Recurrent and chronic major depressive disorder (MDD) accounts for a substantial part of the disease burden because this course is most prevalent and typically requires long-term treatment. We associated blood DNA methylation profiles from 581 MDD patients at baseline with MDD status 6 years later. A resampling approach showed a highly significant association between methylation profiles in blood at baseline and future disease status (P = 2.0 × 10-16). Top MWAS results were enriched specific pathways, overlapped with genes found in GWAS of MDD disease status, autoimmune disease and inflammation, and co-localized with eQTLS and (genic enhancers of) of transcription sites in brain and blood. Many of these findings remained significant after correction for multiple testing. The major themes emerging were cellular responses to stress and signaling mechanisms linked to immune cell migration and inflammation. This suggests that an immune signature of treatment-resistant depression is already present at baseline. We also created a methylation risk score (MRS) to predict MDD status 6 years later. The AUC of our MRS was 0.724 and higher than risk scores created using a set of five putative MDD biomarkers, genome-wide SNP data, and 27 clinical, demographic and lifestyle variables. Although further studies are needed to examine the generalizability to different patient populations, these results suggest that methylation profiles in blood may present a promising avenue to support clinical decision making by providing empirical information about the likelihood MDD is chronic or will recur in the future.

3.
BMC Genomics ; 20(1): 704, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31506065

RESUMO

BACKGROUND: It is well-known that methylation changes occur as humans age, however, understanding how age-related changes in DNA methylation vary by sex is lacking. In this study, we characterize the effect of age on DNA methylation in a sex-specific manner and determine if these effects vary by genomic context. We used the Illumina HumanMethylation 450 K array and DNA derived from whole blood for 400 adult participants (189 males and 211 females) from Bangladesh to identify age-associated CpG sites and regions and characterize the location of these age-associated sites with respect to CpG islands (vs. shore, shelf, or open sea) and gene regions (vs. intergenic). We conducted a genome-wide search for age-associated CpG sites (among 423,604 sites) using a reference-free approach to adjust for cell type composition (the R package RefFreeEWAS) and performed an independent replication analysis of age-associated CpGs. RESULTS: The number of age-associated CpGs (p < 5 x 10- 8) were 986 among men and 3479 among women of which 2027(63.8%) and 572 (64.1%) replicated (using Bonferroni adjusted p < 1.2 × 10- 5). For both sexes, age-associated CpG sites were more likely to be hyper-methylated with increasing age (compared to hypo-methylated) and were enriched in CpG islands and promoter regions compared with other locations and all CpGs on the array. Although we observed strong correlation between chronological age and previously-developed epigenetic age models (r ≈ 0.8), among our top (based on lowest p-value) age-associated CpG sites only 12 for males and 44 for females are included in these prediction models, and the median chronological age compared to predicted age was 44 vs. 51.7 in males and 45 vs. 52.1 in females. CONCLUSIONS: Our results describe genome-wide features of age-related changes in DNA methylation. The observed associations between age and methylation were generally consistent for both sexes, although the associations tended to be stronger among women. Our population may have unique age-related methylation changes that are not captured in the established methylation-based age prediction model we used, which was developed to be non-tissue-specific.

4.
Transl Psychiatry ; 9(1): 193, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31431611

RESUMO

The pathophysiology of major depressive disorder (MDD) is highly heterogeneous. Previous evidence at the DNA level as well as on the serum protein level suggests that the role of inflammation in MDD pathology is stronger in patients with hyperphagia during an active episode. Which inflammatory pathways differ in MDD patients with hyperphagia inflammatory pathways in terms of gene expression is unknown. We analyzed whole-blood gene expression profiles of 881 current MDD cases and 331 controls from the Netherlands Study of Depression and Anxiety (NESDA). The MDD patients were stratified according to patients with hyperphagia (characterized by increased appetite and/or weight, N = 246) or hypophagia (characterized by decreased appetite and/or weight, N = 342). Using results of differential gene expression analysis between controls and the MDD subgroups, enrichment of curated inflammatory pathways was estimated. The majority of the pathways were significantly (FDR < 0.1) enriched in the expression profiles of MDD cases with hyperphagia, including top pathways related to factors responsible for the onset of inflammatory response ('caspase', 'GATA3', 'NFAT', and 'inflammasomes' pathways). Only two pathways ('adaptive immune system' and 'IL-8- and CXCR2-mediated signaling') were enriched in the MDD with hypophagia subgroup, these were also enriched in the total current MDD group and the group with hyperphagia. This confirms the importance of inflammation in MDD pathology of patients with hyperphagia, and suggests that distinguishing more uniform MDD phenotypes can help in finding their pathophysiological basis.

5.
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
6.
BMC Biol ; 17(1): 50, 2019 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-31234833

RESUMO

BACKGROUND: Identification of imprinted genes, demonstrating a consistent preference towards the paternal or maternal allelic expression, is important for the understanding of gene expression regulation during embryonic development and of the molecular basis of developmental disorders with a parent-of-origin effect. Combining allelic analysis of RNA-Seq data with phased genotypes in family trios provides a powerful method to detect parent-of-origin biases in gene expression. RESULTS: We report findings in 296 family trios from two large studies: 165 lymphoblastoid cell lines from the 1000 Genomes Project and 131 blood samples from the Genome of the Netherlands (GoNL) participants. Based on parental haplotypes, we identified > 2.8 million transcribed heterozygous SNVs phased for parental origin and developed a robust statistical framework for measuring allelic expression. We identified a total of 45 imprinted genes and one imprinted unannotated transcript, including multiple imprinted transcripts showing incomplete parental expression bias that was located adjacent to strongly imprinted genes. For example, PXDC1, a gene which lies adjacent to the paternally expressed gene FAM50B, shows a 2:1 paternal expression bias. Other imprinted genes had promoter regions that coincide with sites of parentally biased DNA methylation identified in the blood from uniparental disomy (UPD) samples, thus providing independent validation of our results. Using the stranded nature of the RNA-Seq data in lymphoblastoid cell lines, we identified multiple loci with overlapping sense/antisense transcripts, of which one is expressed paternally and the other maternally. Using a sliding window approach, we searched for imprinted expression across the entire genome, identifying a novel imprinted putative lncRNA in 13q21.2. Overall, we identified 7 transcripts showing parental bias in gene expression which were not reported in 4 other recent RNA-Seq studies of imprinting. CONCLUSIONS: Our methods and data provide a robust and high-resolution map of imprinted gene expression in the human genome.


Assuntos
Alelos , Expressão Gênica/genética , Impressão Genômica/genética , Haplótipos/genética , Análise Química do Sangue , Linhagem Celular , Humanos , Análise de Sequência de RNA
7.
Nat Genet ; 51(3): 445-451, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30643256

RESUMO

We introduce two novel methods for multivariate genome-wide-association meta-analysis (GWAMA) of related traits that correct for sample overlap. A broad range of simulation scenarios supports the added value of our multivariate methods relative to univariate GWAMA. We applied the novel methods to life satisfaction, positive affect, neuroticism, and depressive symptoms, collectively referred to as the well-being spectrum (Nobs = 2,370,390), and found 304 significant independent signals. Our multivariate approaches resulted in a 26% increase in the number of independent signals relative to the four univariate GWAMAs and in an ~57% increase in the predictive power of polygenic risk scores. Supporting transcriptome- and methylome-wide analyses (TWAS and MWAS, respectively) uncovered an additional 17 and 75 independent loci, respectively. Bioinformatic analyses, based on gene expression in brain tissues and cells, showed that genes differentially expressed in the subiculum and GABAergic interneurons are enriched in their effect on the well-being spectrum.


Assuntos
Genoma Humano/genética , Encéfalo/fisiologia , Biologia Computacional/métodos , Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Interneurônios/fisiologia , Herança Multifatorial/genética , Análise Multivariada , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Transcriptoma/genética
8.
Eur J Hum Genet ; 27(3): 455-465, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30552425

RESUMO

X-inactivation is a well-established dosage compensation mechanism ensuring that X-chromosomal genes are expressed at comparable levels in males and females. Skewed X-inactivation is often explained by negative selection of one of the alleles. We demonstrate that imbalanced expression of the paternal and maternal X-chromosomes is common in the general population and that the random nature of the X-inactivation mechanism can be sufficient to explain the imbalance. To this end, we analyzed blood-derived RNA and whole-genome sequencing data from 79 female children and their parents from the Genome of the Netherlands project. We calculated the median ratio of the paternal over total counts at all X-chromosomal heterozygous single-nucleotide variants with coverage ≥10. We identified two individuals where the same X-chromosome was inactivated in all cells. Imbalanced expression of the two X-chromosomes (ratios ≤0.35 or ≥0.65) was observed in nearly 50% of the population. The empirically observed skewing is explained by a theoretical model where X-inactivation takes place in an embryonic stage in which eight cells give rise to the hematopoietic compartment. Genes escaping X-inactivation are expressed from both alleles and therefore demonstrate less skewing than inactivated genes. Using this characteristic, we identified three novel escapee genes (SSR4, REPS2, and SEPT6), but did not find support for many previously reported escapee genes in blood. Our collective data suggest that skewed X-inactivation is common in the general population. This may contribute to manifestation of symptoms in carriers of recessive X-linked disorders. We recommend that X-inactivation results should not be used lightly in the interpretation of X-linked variants.


Assuntos
População/genética , Inativação do Cromossomo X , Proteínas de Ligação ao Cálcio/genética , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Glicoproteínas de Membrana/genética , Países Baixos , Polimorfismo de Nucleotídeo Único , Receptores Citoplasmáticos e Nucleares/genética , Receptores de Peptídeos/genética , Septinas/genética
9.
Health Equity ; 2(1): 152-160, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30283862

RESUMO

Objectives: Heart disease is the leading cause of death in American Indians (AIs). For AI patients with severe coronary artery disease requiring coronary artery bypass graft (CABG) surgery, little data exist. The purpose of this study was to evaluate short-term outcomes of Northern Plains AI undergoing CABG and identify variations in patient presentation. Methods: All patients undergoing isolated CABG between June 2012 and June 2017 were studied. Seventy-four AI and 1236 non-American Indian (non-AI) patients were identified. Risk factors, preoperative characteristics, cardiac status, procedural information, and outcomes were collected. Univariate analysis comparing short-term clinical outcomes between AI and non-AI populations was performed. Multivariable logistic regression models were constructed and outcome differences assessed. Unadjusted Kaplan-Meier survival estimates were produced using 5-year survival data. Results: AI patients presented with increased risk factors, including higher rates of diabetes mellitus (AI 63.5% vs. non-AI 38.7% p=< 0.001) and smoking/tobacco use (AI 60.8% vs. non-AI 20.0% p=> 0.001). Seventy-nine percent of AI patients resided on or near federal reservations and presented from rural locations. Internal mammary artery (IMA) graft use in both groups was high (AI 95.9% vs. non-AI 94.9% p=0.904), and multiarterial grafting with left internal mammary artery and radial artery use was common in both groups (AI 67.6% vs. non-AI 69.6% p=0.814). No significant differences in unadjusted 30-day mortality or short-term outcomes were detected. Adjusted Kaplan-Meier survival curves were similar between race groups up through 5 years after CABG (p-value=0.38). Conclusion: AIs presented with significantly more risk factors for cardiovascular disease compared with the general population, with especially high rates of insulin-dependent diabetes and active tobacco use. Despite this, outcomes were similar between groups. In propensity-matched groups, AIs were at decreased risk for prolonged length of stay and combined morbidity/mortality. In contrast to previous reports, AI racial identity did not adversely affect survival up to 5 years after CABG.

10.
Epigenetics Chromatin ; 11(1): 54, 2018 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-30253792

RESUMO

BACKGROUND: DNA methylation arrays are widely used in epigenome-wide association studies and methylation quantitative trait locus (mQTL) studies. Here, we performed the first genome-wide analysis of monozygotic (MZ) twin correlations and mQTLs on data obtained with the Illumina MethylationEPIC BeadChip (EPIC array) and compared the performance of the EPIC array to the Illumina HumanMethylation450 BeadChip (HM450 array) for buccal-derived DNA. RESULTS: Good-quality EPIC data were obtained for 102 buccal-derived DNA samples from 49 MZ twin pairs (mean age = 7.5 years, range = 1-10). Differences between MZ twins in the cellular content of buccal swabs were a major driver for differences in their DNA methylation profiles, highlighting the importance to adjust for cellular composition in DNA methylation studies of buccal-derived DNA. After adjusting for cellular composition, the genome-wide mean correlation (r) between MZ twins was 0.21 for the EPIC array, and cis mQTL analysis in 84 twins identified 1,296,323 significant associations (FDR 5%), encompassing 33,749 methylation sites and 616,029 genetic variants. MZ twin correlations were slightly larger (p < 2.2 × 10-16) for novel EPIC probes (N = 383,066, mean r = 0.22) compared to probes that are also present on HM450 (N = 406,822, mean r = 0.20). In line with this observation, a larger percentage of novel EPIC probes was associated with genetic variants (novel EPIC probes with significant mQTL 4.7%, HM450 probes with mQTL 3.9%, p < 2.2 × 10-16). Methylation sites with a large MZ correlation and sites associated with mQTLs were most strongly enriched in epithelial cell DNase I hypersensitive sites (DHSs), enhancers, and histone mark H3K4me3. CONCLUSIONS: We conclude that the contribution of familial factors to individual differences in DNA methylation and the effect of mQTLs are larger for novel EPIC probes, especially those within regulatory elements connected to active regions specific to the investigated tissue.

11.
Nat Commun ; 9(1): 3738, 2018 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-30218040

RESUMO

X-chromosome inactivation (XCI), i.e., the inactivation of one of the female X chromosomes, restores equal expression of X-chromosomal genes between females and males. However, ~10% of genes show variable degrees of escape from XCI between females, although little is known about the causes of variable XCI. Using a discovery data-set of 1867 females and 1398 males and a replication sample of 3351 females, we show that genetic variation at three autosomal loci is associated with female-specific changes in X-chromosome methylation. Through cis-eQTL expression analysis, we map these loci to the genes SMCHD1/METTL4, TRIM6/HBG2, and ZSCAN9. Low-expression alleles of the loci are predominantly associated with mild hypomethylation of CpG islands near genes known to variably escape XCI, implicating the autosomal genes in variable XCI. Together, these results suggest a genetic basis for variable escape from XCI and highlight the potential of a population genomics approach to identify genes involved in XCI.

12.
Nat Commun ; 9(1): 3097, 2018 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-30082726

RESUMO

Identification of causal drivers behind regulatory gene networks is crucial in understanding gene function. Here, we develop a method for the large-scale inference of gene-gene interactions in observational population genomics data that are both directed (using local genetic instruments as causal anchors, akin to Mendelian Randomization) and specific (by controlling for linkage disequilibrium and pleiotropy). Analysis of genotype and whole-blood RNA-sequencing data from 3072 individuals identified 49 genes as drivers of downstream transcriptional changes (Wald P < 7 × 10-10), among which transcription factors were overrepresented (Fisher's P = 3.3 × 10-7). Our analysis suggests new gene functions and targets, including for SENP7 (zinc-finger genes involved in retroviral repression) and BCL2A1 (target genes possibly involved in auditory dysfunction). Our work highlights the utility of population genomics data in deriving directed gene expression networks. A resource of trans-effects for all 6600 genes with a genetic instrument can be explored individually using a web-based browser.

13.
Health Promot Pract ; : 1524839918788581, 2018 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-30117342

RESUMO

This research examines the practice of community coaching within coalitions in the Communities Preventing Childhood Obesity project. A quasi-experimental design was used in seven Midwestern states. Each state selected two rural, low-income communities with functioning health coalitions. Coalitions were randomly assigned to be intervention or comparison communities. After 4 years of the coaching intervention, ripple effect mapping served as one method for examining the coalitions' work that may affect children's weight status. A research team from each state conducted ripple effect mapping with their two coalitions, resulting in 14 ripple maps. Community capitals framework and the social-ecological model were used for coding the items identified within the ripple maps. A quantitative scoring analysis determined if differences existed between the intervention and comparison coalitions in terms of the activities, programs, funding, and partnerships for social-ecological model score (e.g., individual, community, policy levels), community capitals score, and ripples score (e.g., number of branches formed within the maps). All scores were higher in intervention communities; however, the differences were not statistically significant ( p > .05). Assessing community assets, such as availability of a community coach, is necessary in order to decide whether to deploy certain resources when designing health promotion strategies.

14.
Behav Genet ; 48(5): 374-385, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30030655

RESUMO

Measurement of gene expression levels and detection of eQTLs (expression quantitative trait loci) are difficult in tissues with limited sample availability, such as the brain. However, eQTL overlap between tissues might be high, which would allow for inference of eQTL functioning in the brain via eQTLs detected in readily accessible tissues, e.g. whole blood. Applying Stratified Linkage Disequilibrium Score Regression (SLDSR), we quantified the enrichment in polygenic signal of blood and brain eQTLs in genome-wide association studies (GWAS) of 11 complex traits. We looked at eQTLs discovered in 44 tissues by the Genotype-Tissue Expression (GTEx) consortium and two other large representative studies, and found no tissue-specific eQTL effects. Next, we integrated the GTEx eQTLs with regions associated with tissue-specific histone modifiers, and interrogated their effect on rheumatoid arthritis and schizophrenia. We observed substantially enriched effects of eQTLs located inside regions bearing modification H3K4me1 on schizophrenia, but not rheumatoid arthritis, and not tissue-specific. Finally, we extracted eQTLs associated with tissue-specific differentially expressed genes and determined their effects on rheumatoid arthritis and schizophrenia, these analysis revealed limited enrichment of eQTLs associated with gene specifically expressed in specific tissues. Our results pointed to strong enrichment of eQTLs in their effect on complex traits, without evidence for tissue-specific effects. Lack of tissue-specificity can be either due to a lack of statistical power or due to the true absence of tissue-specific effects. We conclude that eQTLs are strongly enriched in GWAS signal and that the enrichment is not specific to the eQTL discovery tissue. Until sample sizes for eQTL discovery grow sufficiently large, working with relatively accessible tissues as proxy for eQTL discovery is sensible and restricting lookups for GWAS hits to a specific tissue for which limited samples are available might not be advisable.

15.
Hum Mutat ; 39(10): 1393-1401, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29980163

RESUMO

Postzygotic mutations are DNA changes acquired from the zygote stage onwards throughout the lifespan. These changes lead to differences in DNA sequence among cells of an individual, potentially contributing to the etiology of complex disorders. Here we compared whole genome DNA sequence data of two monozygotic twin pairs, 40 and 100 years old, to detect somatic mosaicism. DNA samples were sequenced twice on two Illumina platforms (13X and 40X read depth) for increased specificity. Using differences in allelic ratios resulted in sets of 1,720 and 1,739 putative postzygotic mutations in the 40-year-old twin pair and 100-year-old twin pair, respectively, for subsequent enrichment analysis. This set of putative mutations was strongly (p < 4.37e-91) enriched in both twin pairs for regulatory elements. The corresponding genes were significantly enriched for genes that are alternatively spliced, and for genes involved in GTPase activity. This research shows that somatic mosaicism can be detected in monozygotic twin pairs by using allelic ratios calculated from DNA sequence data and that the mutations which are found by this approach are not randomly distributed throughout the genome.

16.
Am J Psychiatry ; 175(8): 774-782, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-29656664

RESUMO

OBJECTIVE: Major depressive disorder is associated with an increased risk of mortality and aging-related diseases. The authors examined whether major depression is associated with higher epigenetic aging in blood as measured by DNA methylation (DNAm) patterns, whether clinical characteristics of major depression have a further impact on these patterns, and whether the findings replicate in brain tissue. METHOD: DNAm age was estimated using all methylation sites in blood of 811 depressed patients and 319 control subjects with no lifetime psychiatric disorders and low depressive symptoms from the Netherlands Study of Depression and Anxiety. The residuals of the DNAm age estimates regressed on chronological age were calculated to indicate epigenetic aging. Major depression diagnosis and clinical characteristics were assessed with questionnaires and psychiatric interviews. Analyses were adjusted for sociodemographic characteristics, lifestyle, and health status. Postmortem brain samples of 74 depressed patients and 64 control subjects were used for replication. Pathway enrichment analysis was conducted using ConsensusPathDB to gain insight into the biological processes underlying epigenetic aging in blood and brain. RESULTS: Significantly higher epigenetic aging was observed in patients with major depression compared with control subjects (Cohen's d=0.18), with a significant dose effect with increasing symptom severity in the overall sample. In the depression group, epigenetic aging was positively and significantly associated with childhood trauma score. The case-control difference was replicated in an independent data set of postmortem brain samples. The top significantly enriched Gene Ontology terms included neuronal processes. CONCLUSIONS: As compared with control subjects, patients with major depression exhibited higher epigenetic aging in blood and brain tissue, suggesting that they are biologically older than their corresponding chronological age. This effect was even more profound in the presence of childhood trauma.

17.
PLoS One ; 13(3): e0194608, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29554151

RESUMO

When some individuals are screen-detected before the beginning of the study, but otherwise would have been diagnosed symptomatically during the study, this results in different case-ascertainment probabilities among screened and unscreened participants, referred to here as lead-time-biased case-ascertainment (LTBCA). In fact, this issue can arise even in risk-factor studies nested within a randomized screening trial; even though the screening intervention is randomly allocated to trial arms, there is no randomization to potential risk-factors and uptake of screening can differ by risk-factor strata. Under the assumptions that neither screening nor the risk factor affects underlying incidence and no other forms of bias operate, we simulate and compare the underlying cumulative incidence and that observed in the study due to LTBCA. The example used will be constructed from the randomized Prostate, Lung, Colorectal, and Ovarian cancer screening trial. The derived mathematical model is applied to simulating two nested studies to evaluate the potential for screening bias in observational lung cancer studies. Because of differential screening under plausible assumptions about preclinical incidence and duration, the simulations presented here show that LTBCA due to chest x-ray screening can significantly increase the estimated risk of lung cancer due to smoking by 1% and 50%. Traditional adjustment methods cannot account for this bias, as the influence screening has on observational study estimates involves events outside of the study observation window (enrollment and follow-up) that change eligibility for potential participants, thus biasing case ascertainment.


Assuntos
Detecção Precoce de Câncer , Programas de Rastreamento/métodos , Modelos Teóricos , Ensaios Clínicos Controlados Aleatórios como Assunto , Idoso , Viés , Estudos de Casos e Controles , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Detecção Precoce de Câncer/métodos , Detecção Precoce de Câncer/estatística & dados numéricos , Feminino , Humanos , Incidência , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiologia , Masculino , Programas de Rastreamento/estatística & dados numéricos , Pessoa de Meia-Idade , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/epidemiologia , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Fatores de Risco , Programa de SEER , Estados Unidos/epidemiologia
18.
Am J Prev Med ; 53(6): 892-897, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29153127

RESUMO

INTRODUCTION: North Dakota's school-reported kindergarten immunization rates were among the lowest in the U.S. during the 2015-2016 school year. Ninety percent of kindergartners were fully immunized in accordance with state requirements, 3% had an exemption, and as many as 7% were noncompliant. School enforcement of immunization requirements has been noted as variable. This study sought to better understand the relationship between school-reported immunization rates and the enforcement of immunization requirements. METHODS: Kindergarten immunization rates were compared between schools annually enforcing immunization requirements to the point of excluding noncompliant children and schools not enforcing. In addition, immunization rates were assessed after an educational intervention that led some school districts to change their enforcement policies during the 2015-2016 school year. Analyses were completed in 2016 and 2017. RESULTS: Kindergarten immunization rates were significantly higher in schools that annually enforced compared with schools that did not enforce (p≤0.001, all vaccines; difference between means: diphtheria-tetanus-attenuated pertussis=7.5% [95% CI=3.9%, 11.1%]; polio=6.2% [95% CI=3.3%, 9.1%]; measles, mumps, and rubella=7% [95% CI=3.5%, 10.5%]; hepatitis B=3.7% [95% CI=1.5%, 5.9%]; and varicella=6.9% [95% CI=3.4%, 10.4%]). School districts that began enforcing saw a significant increase in vaccination rates (diphtheria-tetanus-attenuated pertussis=6% [95% CI=2%, 11%] and measles, mumps, and rubella=7% [95% CI=3%, 11%]). Enforcement in newly enforcing districts led to a large decrease in the number of noncompliant students and did not lead to significant increases in exemption rates. CONCLUSIONS: In North Dakota, lack of school enforcement is strongly associated with lower immunization rates and a large noncompliant population. Addressing noncompliance through school enforcement could significantly increase school-reported immunization rates.


Assuntos
Programas de Imunização , Imunização/estatística & dados numéricos , Instituições Acadêmicas/estatística & dados numéricos , Estudantes/estatística & dados numéricos , Pré-Escolar , Grupos Focais , Humanos , Esquemas de Imunização , North Dakota
19.
J Hum Genet ; 62(11): 979-988, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29066854

RESUMO

Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are important biomarkers for disease development and progression. To gain insight into the genetic causes of variance in NLR and PLR in the general population, we conducted genome-wide association (GWA) analyses and estimated SNP heritability in a sample of 5901 related healthy Dutch individuals. GWA analyses identified a new genome-wide significant locus on the HBS1L-MYB intergenic region for PLR, which replicated in a sample of 2538 British twins. For platelet count, we replicated three known genome-wide significant loci in our cohort (at CCDC71L-PIK3CG, BAK1 and ARHGEF3). For neutrophil count, we replicated the PSMD3 locus. For the identified top SNPs, we found significant cis and trans expression quantitative trait loci effects for several loci involved in hematological and immunological pathways. Linkage Disequilibrium score (LD) regression analyses for PLR and NLR confirmed that both traits are heritable, with a polygenetic SNP heritability for PLR of 14.1%, and for NLR of 2.4%. Genetic correlations were present between ratios and the constituent counts, with the genetic correlation (r=0.45) of PLR with platelet count reaching statistical significance. In conclusion, we established that two important biomarkers have a significant heritable SNP component, and identified the first genome-wide locus for PLR.


Assuntos
Biomarcadores/sangue , Plaquetas , Proteínas de Ligação ao GTP/genética , Estudo de Associação Genômica Ampla , Proteínas de Choque Térmico HSP70/genética , Fatores de Alongamento de Peptídeos/genética , Locos de Características Quantitativas/genética , Classe Ib de Fosfatidilinositol 3-Quinase/genética , Estudos de Coortes , Feminino , Humanos , Desequilíbrio de Ligação/genética , Linfócitos/metabolismo , Masculino , Neutrófilos/metabolismo , Contagem de Plaquetas , Polimorfismo de Nucleotídeo Único/genética , Complexo de Endopeptidases do Proteassoma/genética , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Proteína Killer-Antagonista Homóloga a bcl-2/genética
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