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1.
Int J Epidemiol ; 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31549173

RESUMO

BACKGROUND: DNA methylation changes in peripheral blood have recently been identified in relation to lung cancer risk. Some of these changes have been suggested to mediate part of the effect of smoking on lung cancer. However, limitations with conventional mediation analyses mean that the causal nature of these methylation changes has yet to be fully elucidated. METHODS: We first performed a meta-analysis of four epigenome-wide association studies (EWAS) of lung cancer (918 cases, 918 controls). Next, we conducted a two-sample Mendelian randomization analysis, using genetic instruments for methylation at CpG sites identified in the EWAS meta-analysis, and 29 863 cases and 55 586 controls from the TRICL-ILCCO lung cancer consortium, to appraise the possible causal role of methylation at these sites on lung cancer. RESULTS: Sixteen CpG sites were identified from the EWAS meta-analysis [false discovery rate (FDR) < 0.05], for 14 of which we could identify genetic instruments. Mendelian randomization provided little evidence that DNA methylation in peripheral blood at the 14 CpG sites plays a causal role in lung cancer development (FDR > 0.05), including for cg05575921-AHRR where methylation is strongly associated with both smoke exposure and lung cancer risk. CONCLUSIONS: The results contrast with previous observational and mediation analysis, which have made strong claims regarding the causal role of DNA methylation. Thus, previous suggestions of a mediating role of methylation at sites identified in peripheral blood, such as cg05575921-AHRR, could be unfounded. However, this study does not preclude the possibility that differential DNA methylation at other sites is causally involved in lung cancer development, especially within lung tissue.

2.
Sci Rep ; 9(1): 13452, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31530827

RESUMO

For cancers, such as common solid tumours, variants in the genome give a selective growth advantage to certain cells. It has recently been argued that the mean count of coding single nucleotide variants acting as disease-drivers in common solid tumours is frequently small in size, but significantly variable by cancer type (hypermutation is excluded from this study). In this paper we investigate this proposal through the use of integrative machine-learning-based classifiers we have proposed recently for predicting the disease-driver status of single nucleotide variants (SNVs) in the human cancer genome. We find that predicted driver counts are compatible with this proposal, have similar variabilities by cancer type and, to a certain extent, the drivers are identifiable by these machine learning methods. We further discuss predicted driver counts stratified by stage of disease and driver counts in non-coding regions of the cancer genome, in addition to driver-genes.

3.
Hum Mol Genet ; 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31276585

RESUMO

Immune mediated diseases (IMDs) arise when tolerance is lost and chronic inflammation is targeted towards healthy tissues. Despite their growing prevalence, therapies to treat IMDs are lacking. Cytokines and their receptors orchestrate inflammatory responses by regulating elaborate signaling networks across multiple cell-types; this makes it challenging to pinpoint therapeutically relevant drivers of IMDs. We developed an analytical framework which integrates Mendelian randomization (MR) and multiple-trait colocalization (moloc) analyses to highlight putative cell-specific drivers of IMDs. MR evaluated causal associations between the levels of 10 circulating cytokines and 9 IMDs within human populations. Subsequently, we undertook moloc analyses to assess whether IMD trait, cytokine protein and corresponding gene expression are driven by a shared causal variant. Moreover, we leveraged gene expression data from 3 separate cell-types (monocytes, neutrophils and T cells) to discern whether associations may be attributed to cell-type specific drivers of disease. MR analyses supported a causal role for IL-18 in inflammatory bowel disease (IBD) (P = 1.17 x 10-4) and eczema/dermatitis (P = 2.81 x 10-3), as well as associations between IL-2rα and IL-6R with several other IMDs. Multiple-trait colocalization strengthened evidence of a causal association for these results, as well as providing evidence of a monocyte and neutrophil-driven role for IL-18 in IBD pathogenesis. In contrast, IL-2rα and IL-6R associations were found to be T cell specific. Our analytical pipeline can help to elucidate putative molecular pathways in the pathogeneses of IMDs, which could be applied to other disease contexts.

4.
Hypertension ; 74(2): 375-383, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31230546

RESUMO

Hypertensive disorders of pregnancy (HDP) are associated with low birth weight, shorter gestational age, and increased risk of maternal and offspring cardiovascular diseases later in life. The mechanisms involved are poorly understood, but epigenetic regulation of gene expression may play a part. We performed meta-analyses in the Pregnancy and Childhood Epigenetics Consortium to test the association between either maternal HDP (10 cohorts; n=5242 [cases=476]) or preeclampsia (3 cohorts; n=2219 [cases=135]) and epigenome-wide DNA methylation in cord blood using the Illumina HumanMethylation450 BeadChip. In models adjusted for confounders, and with Bonferroni correction, HDP and preeclampsia were associated with DNA methylation at 43 and 26 CpG sites, respectively. HDP was associated with higher methylation at 27 (63%) of the 43 sites, and across all 43 sites, the mean absolute difference in methylation was between 0.6% and 2.6%. Epigenome-wide associations of HDP with offspring DNA methylation were modestly consistent with the equivalent epigenome-wide associations of preeclampsia with offspring DNA methylation (R2=0.26). In longitudinal analyses conducted in 1 study (n=108 HDP cases; 550 controls), there were similar changes in DNA methylation in offspring of those with and without HDP up to adolescence. Pathway analysis suggested that genes located at/near HDP-associated sites may be involved in developmental, embryogenesis, or neurological pathways. HDP is associated with offspring DNA methylation with potential relevance to development.

5.
Diabetes ; 68(8): 1681-1691, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31088856

RESUMO

Liver dysfunction and type 2 diabetes (T2D) are consistently associated. However, it is currently unknown whether liver dysfunction contributes to, results from, or is merely correlated with T2D due to confounding. We used Mendelian randomization to investigate the presence and direction of any causal relation between liver function and T2D risk including up to 64,094 T2D case and 607,012 control subjects. Several biomarkers were used as proxies of liver function (i.e., alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], and γ-glutamyl transferase [GGT]). Genetic variants strongly associated with each liver function marker were used to investigate the effect of liver function on T2D risk. In addition, genetic variants strongly associated with T2D risk and with fasting insulin were used to investigate the effect of predisposition to T2D and insulin resistance, respectively, on liver function. Genetically predicted higher circulating ALT and AST were related to increased risk of T2D. There was a modest negative association of genetically predicted ALP with T2D risk and no evidence of association between GGT and T2D risk. Genetic predisposition to higher fasting insulin, but not to T2D, was related to increased circulating ALT. Since circulating ALT and AST are markers of nonalcoholic fatty liver disease (NAFLD), these findings provide some support for insulin resistance resulting in NAFLD, which in turn increases T2D risk.

6.
Clin Chim Acta ; 494: 138-142, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30898509

RESUMO

Haptoglobin (Hp) is a major plasma acute-phase glycoprotein, which binds free haemoglobin to neutralize its toxicity. The HP gene exists as two copy number variants (CNV), Hp1 and HP2, which differ in two ways: serum Hp level and functional differences in Hp protein products. Both mechanisms may underlie the HP CNV's influence on susceptibility and/or outcome in several diseases. A single nucleotide polymorphism rs2000999 has also been associated with serum Hp level. In a meta-analysis of three studies from England, France and Japan, with a combined sample size of 1210 participants, we show that rs2000999's effect on circulating Hp level is independent from that of the HP CNV. The combined use of rs2000999 and the HP CNV can be an important genetic epidemiological tool to discriminate between the two potential mechanisms underlying differences between HP1 and HP2 alleles.


Assuntos
Alelos , Haptoglobinas/análise , Adolescente , Adulto , Análise Química do Sangue , Variações do Número de Cópias de DNA/genética , Feminino , França , Genótipo , Humanos , Japão , Masculino , Epidemiologia Molecular , Polimorfismo de Nucleotídeo Único/genética , Reino Unido
7.
Transl Psychiatry ; 9(1): 105, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30820025

RESUMO

Integrative approaches that harness large-scale molecular datasets can help develop mechanistic insight into findings from genome-wide association studies (GWAS). We have performed extensive analyses to uncover transcriptional and epigenetic processes which may play a role in complex trait variation. This was undertaken by applying Bayesian multiple-trait colocalization systematically across the genome to identify genetic variants responsible for influencing intermediate molecular phenotypes as well as complex traits. In this analysis, we leveraged high-dimensional quantitative trait loci data derived from the prefrontal cortex tissue (concerning gene expression, DNA methylation and histone acetylation) and GWAS findings for five complex traits (Neuroticism, Schizophrenia, Educational Attainment, Insomnia and Alzheimer's disease). There was evidence of colocalization for 118 associations, suggesting that the same underlying genetic variant influenced both nearby gene expression as well as complex trait variation. Of these, 73 associations provided evidence that the genetic variant also influenced proximal DNA methylation and/or histone acetylation. These findings support previous evidence at loci where epigenetic mechanisms may putatively mediate effects of genetic variants on traits, such as KLC1 and schizophrenia. We also uncovered evidence implicating novel loci in disease susceptibility, including genes expressed predominantly in the brain tissue, such as MDGA1, KIRREL3 and SLC12A5. An inverse relationship between DNA methylation and gene expression was observed more than can be accounted for by chance, supporting previous findings implicating DNA methylation as a transcriptional repressor. Our study should prove valuable in helping future studies prioritize candidate genes and epigenetic mechanisms for in-depth functional follow-up analyses.

8.
Hum Genomics ; 13(1): 6, 2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30704525

RESUMO

BACKGROUND: Mitochondrial DNA copy number (mtDNA CN) exhibits interindividual and intercellular variation, but few genome-wide association studies (GWAS) of directly assayed mtDNA CN exist. We undertook a GWAS of qPCR-assayed mtDNA CN in the Avon Longitudinal Study of Parents and Children (ALSPAC) and the UK Blood Service (UKBS) cohort. After validating and harmonising data, 5461 ALSPAC mothers (16-43 years at mtDNA CN assay) and 1338 UKBS females (17-69 years) were included in a meta-analysis. Sensitivity analyses restricted to females with white cell-extracted DNA and adjusted for estimated or assayed cell proportions. Associations were also explored in ALSPAC children and UKBS males. RESULTS: A neutrophil-associated locus approached genome-wide significance (rs709591 [MED24], ß (change in SD units of mtDNA CN per allele) [SE] - 0.084 [0.016], p = 1.54e-07) in the main meta-analysis of adult females. This association was concordant in magnitude and direction in UKBS males and ALSPAC neonates. SNPs in and around ABHD8 were associated with mtDNA CN in ALSPAC neonates (rs10424198, ß [SE] 0.262 [0.034], p = 1.40e-14), but not other study groups. In a meta-analysis of unrelated individuals (N = 11,253), we replicated a published association in TFAM (ß [SE] 0.046 [0.017], p = 0.006), with an effect size much smaller than that observed in the replication analysis of a previous in silico GWAS. CONCLUSIONS: In a hypothesis-generating GWAS, we confirm an association between TFAM and mtDNA CN and present putative loci requiring replication in much larger samples. We discuss the limitations of our work, in terms of measurement error and cellular heterogeneity, and highlight the need for larger studies to better understand nuclear genomic control of mtDNA copy number.


Assuntos
Variações do Número de Cópias de DNA , DNA Mitocondrial/genética , Estudo de Associação Genômica Ampla/métodos , Adolescente , Adulto , Criança , Estudos de Coortes , Feminino , Humanos , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
9.
Genome Med ; 11(1): 6, 2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30704512

RESUMO

BACKGROUND: The extent to which changes in gene expression can influence cardiovascular disease risk across different tissue types has not yet been systematically explored. We have developed an analysis pipeline that integrates tissue-specific gene expression, Mendelian randomization and multiple-trait colocalization to develop functional mechanistic insight into the causal pathway from a genetic variant to a complex trait. METHODS: We undertook an expression quantitative trait loci-wide association study to uncover genetic variants associated with both nearby gene expression and cardiovascular traits. Fine-mapping was performed to prioritize possible causal variants for detected associations. Two-sample Mendelian randomization (MR) was then applied using findings from genome-wide association studies (GWAS) to investigate whether changes in gene expression within certain tissue types may influence cardiovascular trait variation. We subsequently used Bayesian multiple-trait colocalization to further interrogate the findings and also gain insight into whether DNA methylation, as well as gene expression, may play a role in disease susceptibility. Finally, we applied our analysis pipeline genome-wide using summary statistics from large-scale GWAS. RESULTS: Eight genetic loci were associated with changes in gene expression and measures of cardiovascular function. Our MR analysis provided evidence of tissue-specific effects at multiple loci, of which the effects at the ADCY3 and FADS1 loci for body mass index and cholesterol, respectively, were particularly insightful. Multiple-trait colocalization uncovered evidence which suggested that changes in DNA methylation at the promoter region upstream of FADS1/TMEM258 may also affect cardiovascular trait variation along with gene expression. Furthermore, colocalization analyses uncovered evidence of tissue specificity between gene expression in liver tissue and cholesterol levels. Applying our pipeline genome-wide using summary statistics from GWAS uncovered 233 association signals at loci which represent promising candidates for further evaluation. CONCLUSIONS: Disease susceptibility can be influenced by differential changes in tissue-specific gene expression and DNA methylation. The approach undertaken in our study can be used to elucidate mechanisms in disease, as well as helping prioritize putative causal genes at associated loci where multiple nearby genes may be co-regulated. Future studies which continue to uncover quantitative trait loci for molecular traits across various tissue and cell types will further improve our capability to understand and prevent disease.


Assuntos
Doenças Cardiovasculares/genética , Predisposição Genética para Doença , Análise da Randomização Mendeliana/métodos , Criança , Metilação de DNA , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Dessaturases/metabolismo , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Fígado/metabolismo , Masculino , Especificidade de Órgãos , Regiões Promotoras Genéticas
10.
PLoS Genet ; 15(2): e1007951, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30707692

RESUMO

Mendelian randomization (MR) has been used to estimate the causal effect of body mass index (BMI) on particular traits thought to be affected by BMI. However, BMI may also be a modifiable, causal risk factor for outcomes where there is no prior reason to suggest that a causal effect exists. We performed a MR phenome-wide association study (MR-pheWAS) to search for the causal effects of BMI in UK Biobank (n = 334 968), using the PHESANT open-source phenome scan tool. A subset of identified associations were followed up with a formal two-stage instrumental variable analysis in UK Biobank, to estimate the causal effect of BMI on these phenotypes. Of the 22 922 tests performed, our MR-pheWAS identified 587 associations below a stringent P value threshold corresponding to a 5% estimated false discovery rate. These included many previously identified causal effects, for instance, an adverse effect of higher BMI on risk of diabetes and hypertension. We also identified several novel effects, including protective effects of higher BMI on a set of psychosocial traits, identified initially in our preliminary MR-pheWAS in circa 115,000 UK Biobank participants and replicated in a different subset of circa 223,000 UK Biobank participants. Our comprehensive MR-pheWAS identified potential causal effects of BMI on a large and diverse set of phenotypes. This included both previously identified causal effects, and novel effects such as a protective effect of higher BMI on feelings of nervousness.


Assuntos
Índice de Massa Corporal , Adiposidade/genética , Adulto , Idoso , Ansiedade/genética , Bancos de Espécimes Biológicos , Estudos de Coortes , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Fatores de Risco , Reino Unido
11.
Nat Genet ; 51(2): 230-236, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30664745

RESUMO

Osteoarthritis is the most common musculoskeletal disease and the leading cause of disability globally. Here, we performed a genome-wide association study for osteoarthritis (77,052 cases and 378,169 controls), analyzing four phenotypes: knee osteoarthritis, hip osteoarthritis, knee and/or hip osteoarthritis, and any osteoarthritis. We discovered 64 signals, 52 of them novel, more than doubling the number of established disease loci. Six signals fine-mapped to a single variant. We identified putative effector genes by integrating expression quantitative trait loci (eQTL) colocalization, fine-mapping, and human rare-disease, animal-model, and osteoarthritis tissue expression data. We found enrichment for genes underlying monogenic forms of bone development diseases, and for the collagen formation and extracellular matrix organization biological pathways. Ten of the likely effector genes, including TGFB1 (transforming growth factor beta 1), FGF18 (fibroblast growth factor 18), CTSK (cathepsin K), and IL11 (interleukin 11), have therapeutics approved or in clinical trials, with mechanisms of action supportive of evaluation for efficacy in osteoarthritis.


Assuntos
Predisposição Genética para Doença/genética , Osteoartrite do Quadril/genética , Adulto , Idoso , Bancos de Espécimes Biológicos , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Reino Unido
13.
Oral Oncol ; 85: 87-94, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30220325

RESUMO

OBJECTIVES: Head and neck squamous cell carcinoma (HNSCC) is often associated with chronic systemic inflammation (SI). In the present study, we assessed if DNA methylation-derived SI (mdSI) indices: Neutrophil-to-Lymphocyte ratio (mdNLR) and Lymphocyte-to-Monocyte ratio (mdLMR) are associated with the presence of HNSCC and overall survival (OS). MATERIALS AND METHODS: We used two peripheral blood DNA methylation datasets: an HNSCC case-control dataset (n = 183) and an HNSCC survival dataset (n = 407) to estimate mdSI indices. We then performed multivariate regressions to test the association between mdSI indices, HNSCC development and OS. RESULTS: Multivariate logistic regression revealed that elevated mdNLR was associated with increased odds of being an HNSCC case (OR = 3.25, 95% CI = 2.14-5.34, P = 4 × 10-7) while the converse was observed for mdLMR (OR = 0.88, 95% CI = 0.81-0.90, P = 2 × 10-3). In the HNSCC survival dataset, HPV16-E6 seropositive HNSCC cases had an elevated mdLMR (P = 9 × 10-5) and a lower mdNLR (P = 0.003) compared to seronegative patients. Multivariate Cox regression in the HNSCC survival dataset revealed that lower mdLMR (HR = 1.96, 95% CI = 1.30-2.95, P = 0.0013) but not lower mdNLR (HR = 0.68, 95% CI = 0.46-1.00, P = 0.0501) was associated with increased risk of death. CONCLUSION: Our results indicate that mdSI estimated by DNA methylation data is associated with the presence of HNSCC and overall survival. The mdSI indices may be used as a valuable research tool to reliably estimate SI in the absence of cell-based estimates. Rigorous validation of our findings in large prospective studies is warranted in the future.

14.
Gigascience ; 7(8)2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30165448

RESUMO

Background: Identifying phenotypic correlations between complex traits and diseases can provide useful etiological insights. Restricted access to much individual-level phenotype data makes it difficult to estimate large-scale phenotypic correlation across the human phenome. Two state-of-the-art methods, metaCCA and LD score regression, provide an alternative approach to estimate phenotypic correlation using only genome-wide association study (GWAS) summary results. Results: Here, we present an integrated R toolkit, PhenoSpD, to use LD score regression to estimate phenotypic correlations using GWAS summary statistics and to utilize the estimated phenotypic correlations to inform correction of multiple testing for complex human traits using the spectral decomposition of matrices (SpD). The simulations suggest that it is possible to identify nonindependence of phenotypes using samples with partial overlap; as overlap decreases, the estimated phenotypic correlations will attenuate toward zero and multiple testing correction will be more stringent than in perfectly overlapping samples. Also, in contrast to LD score regression, metaCCA will provide approximate genetic correlations rather than phenotypic correlation, which limits its application for multiple testing correction. In a case study, PhenoSpD using UK Biobank GWAS results suggested 399.6 independent tests among 487 human traits, which is close to the 352.4 independent tests estimated using true phenotypic correlation. We further applied PhenoSpD to an estimated 5,618 pair-wise phenotypic correlations among 107 metabolites using GWAS summary statistics from Kettunen's publication and PhenoSpD suggested the equivalent of 33.5 independent tests for these metabolites. Conclusions: PhenoSpD extends the use of summary-level results, providing a simple and conservative way to reduce dimensionality for complex human traits using GWAS summary statistics. This is particularly valuable in the age of large-scale biobank and consortia studies, where GWAS results are much more accessible than individual-level data.

15.
Dev Psychopathol ; 30(3): 1145-1156, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30068408

RESUMO

In 785 mother-child (50% male) pairs from a longitudinal epidemiological birth cohort, we investigated associations between inflammation-related epigenetic polygenic risk scores (i-ePGS), environmental exposures, cognitive function, and child and adolescent internalizing and externalizing problems. We examined prenatal and postnatal effects. For externalizing problems, one prenatal effect was found: i-ePGS at birth associated with higher externalizing problems (ages 7-15) indirectly through lower cognitive function (age 7). For internalizing problems, we identified two effects. For a prenatal effect, i-ePGS at birth associated with higher internalizing symptoms via continuity in i-ePGS at age 7. For a postnatal effect, higher postnatal adversity exposure (birth through age 7) associated with higher internalizing problems (ages 7-15) via higher i-ePGS (age 7). Hence, externalizing problems were related mainly to prenatal effects involving lower cognitive function, whereas internalizing problems appeared related to both prenatal and postnatal effects. The present study supports a link between i-ePGS and child and adolescent mental health.


Assuntos
Transtornos do Comportamento Infantil/etiologia , Inflamação/complicações , Saúde Mental , Adolescente , Criança , Feminino , Humanos , Masculino , Gravidez , Estudos Prospectivos , Fatores de Risco
16.
Hum Mol Genet ; 27(16): 2927-2939, 2018 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-29860447

RESUMO

Genomic imprinting is an epigenetic mechanism leading to parent-of-origin silencing of alleles. So far, the precise number of imprinted regions in humans is uncertain. In this study, we leveraged genome-wide DNA methylation in whole blood measured longitudinally at three time points (birth, childhood and adolescence) and genome-wide association studies (GWAS) data in 740 mother-child duos from the Avon Longitudinal Study of parents and children to identify candidate imprinted loci. We reasoned that cis-meQTLs at genomic regions that were imprinted would show strong evidence of parent-of-origin associations with DNA methylation, enabling the detection of imprinted regions. Using this approach, we identified genome-wide significant cis-meQTLs that exhibited parent-of-origin effects (POEs) at 82 loci, 34 novel and 48 regions previously implicated in imprinting (3.7-10

17.
Epigenetics Chromatin ; 11(1): 25, 2018 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-29848354

RESUMO

BACKGROUND: The well-established association of chronological age with changes in DNA methylation is primarily founded on the analysis of large sets of blood samples, while conclusions regarding tissue-specificity are typically based on small number of samples, tissues and CpGs. Here, we systematically investigate the tissue-specific character of age-related DNA methylation changes at the level of the CpG, functional genomic region and nearest gene in a large dataset. RESULTS: We assembled a compendium of public data, encompassing genome-wide DNA methylation data (Illumina 450k array) on 8092 samples from 16 different tissues, including 7 tissues with moderate to high sample numbers (Dataset size range 96-1202, Ntotal = 2858). In the 7 tissues (brain, buccal, liver, kidney, subcutaneous fat, monocytes and T-helper cells), we identified 7850 differentially methylated positions that gained (gain-aDMPs; cut-offs: Pbonf ≤ 0.05, effect size ≥ 2%/10 years) and 4,287 that lost DNA methylation with age (loss-aDMPs), 92% of which had not previously been reported for whole blood. The majority of all aDMPs identified occurred in one tissue only (gain-aDMPs: 85.2%; loss-aDMPs: 97.4%), an effect independent of statistical power. This striking tissue-specificity extended to both the functional genomic regions (defined by chromatin state segmentation) and the nearest gene. However, aDMPs did accumulate in regions with the same functional annotation across tissues, namely polycomb-repressed CpG islands for gain-aDMPs and regions marked by active histone modifications for loss-aDMPs. CONCLUSION: Our analysis shows that age-related DNA methylation changes are highly tissue-specific. These results may guide the development of improved tissue-specific markers of chronological and, perhaps, biological age.


Assuntos
Acetiltransferases/genética , Envelhecimento/genética , Metilação de DNA , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Química Encefálica , Criança , Pré-Escolar , Bases de Dados Genéticas , Epigênese Genética , Feminino , Humanos , Lactente , Recém-Nascido , Rim/química , Fígado/química , Masculino , Pessoa de Meia-Idade , Monócitos/química , Boca/química , Especificidade de Órgãos , Regiões Promotoras Genéticas , Adulto Jovem
18.
Hum Mol Genet ; 27(18): 3293-3304, 2018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-29893838

RESUMO

We have undertaken a systematic Mendelian randomization (MR) study using methylation quantitative trait loci (meQTL) as genetic instruments to assess the relationship between genetic variation, DNA methylation and 139 complex traits. Using two-sample MR, we identified 1148 associations across 61 traits where genetic variants were associated with both proximal DNA methylation (i.e. cis-meQTL) and complex trait variation (P < 1.39 × 10-08). Joint likelihood mapping provided evidence that the genetic variant which influenced DNA methylation levels for 348 of these associations across 47 traits was also responsible for variation in complex traits. These associations showed a high rate of replication in the BIOS QTL and UK Biobank datasets for 14 selected traits, as 101 of the attempted 128 associations survived multiple testing corrections (P < 3.91 × 10-04). Integrating expression quantitative trait loci (eQTL) data suggested that genetic variants responsible for 306 of the 348 refined meQTL associations also influence gene expression, which indicates a coordinated system of effects that are consistent with causality. CpG sites were enriched for histone mark peaks in tissue types relevant to their associated trait and implicated genes were enriched across relevant biological pathways. Though we are unable to distinguish mediation from horizontal pleiotropy in these analyses, our findings should prove valuable in prioritizing candidate loci where DNA methylation may influence traits and help develop mechanistic insight into the aetiology of complex disease.

19.
Elife ; 72018 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-29846171

RESUMO

Results from genome-wide association studies (GWAS) can be used to infer causal relationships between phenotypes, using a strategy known as 2-sample Mendelian randomization (2SMR) and bypassing the need for individual-level data. However, 2SMR methods are evolving rapidly and GWAS results are often insufficiently curated, undermining efficient implementation of the approach. We therefore developed MR-Base (http://www.mrbase.org): a platform that integrates a curated database of complete GWAS results (no restrictions according to statistical significance) with an application programming interface, web app and R packages that automate 2SMR. The software includes several sensitivity analyses for assessing the impact of horizontal pleiotropy and other violations of assumptions. The database currently comprises 11 billion single nucleotide polymorphism-trait associations from 1673 GWAS and is updated on a regular basis. Integrating data with software ensures more rigorous application of hypothesis-driven analyses and allows millions of potential causal relationships to be efficiently evaluated in phenome-wide association studies.

20.
Am J Med Genet B Neuropsychiatr Genet ; 177(5): 489-502, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29687944

RESUMO

Copy number variants (CNVs) are associated with psychiatric conditions in clinical populations. The relationship between rare CNV burden and neuropsychiatric traits in young, general populations is underexplored. A total of 6,807 children from the Avon Longitudinal Study of Parents and Children (ALSPAC) were studied. CNVs were inferred from single nucleotide polymorphism-array data using PennCNV. After excluding children with known candidate CNVs for schizophrenia (SCZ), rare (<1%) CNV burden (total number of genes affected by CNVs, total length of CNVs, and largest CNV carried) was analyzed in relation to: psychotic experiences (PEs) and anxiety/depression in adolescence; autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD), ASD and ADHD traits, and cognitive measures during childhood. Outcomes were also assessed in relation to known SCZ CNVs. The number of genes affected by rare CNVs was associated with a continuous measure of ASD: the standardized mean difference [SMD] per gene affected was increased by 0.018 [95%CI 0.011,0.025], p = 3e-07 for duplications and by 0.021 [95%CI 0.010, 0.032], p = 1e-04 for deletions. In line with our published results on educational attainment in ALSPAC, intelligence quotient (IQ) was associated with CNV burden: the SMD per gene affected was -0.017 [95%CI -0.025, -0.008] p = 1e-04 for duplications and -0.023 [95%CI -0.037, -0.009], p = .002 for deletions. Associations were also observed for measures of coherence, attention, memory, and social cognition. SCZ-associated deletions were associated with IQ (SMD: -0.617 [95%CI -0.936, -0.298], p = 2e-04), but not with PEs or other traits. We found that rare CNV burden and known SCZ candidate CNVs are associated with neuropsychiatric phenotypes in a nonclinically ascertained sample of young people.

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