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1.
Bioinformatics ; 2019 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-31710672

RESUMO

MOTIVATION: Eosinophils are phagocytic white blood cells with a variety of roles in the immune system. In situations where actual counts are not available, high quality approximations of their cell proportions using indirect markers are critical. RESULTS: We develop a Bayesian measurement error model to estimate proportions of eosinophils in cord blood, using the cord blood DNA methylation profiles, based on markers of eosinophil cell heterogeneity in blood of adults. The proposed method can be directly extended to other cells across different reference panels. We demonstrate the method's estimation accuracy using B cells and show that the findings support the proposed approach. The method has been incorporated into the estimateCellCounts function in the minfi package to estimate eosinophil cells proportions in cord blood. AVAILABILITY: estimateCellCounts function is implemented and available in Bioconductor package minfi. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

2.
Nat Commun ; 10(1): 3902, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31467281

RESUMO

Systemic lupus erythematous (SLE) is a heterogeneous autoimmune disease in which outcomes vary among different racial groups. Here, we aim to identify SLE subgroups within a multiethnic cohort using an unsupervised clustering approach based on the American College of Rheumatology (ACR) classification criteria. We identify three patient clusters that vary according to disease severity. Methylation association analysis identifies a set of 256 differentially methylated CpGs across clusters, including 101 CpGs in genes in the Type I Interferon pathway, and we validate these associations in an external cohort. A cis-methylation quantitative trait loci analysis identifies 744 significant CpG-SNP pairs. The methylation signature is enriched for ethnic-associated CpGs suggesting that genetic and non-genetic factors may drive outcomes and ethnic-associated methylation differences. Our computational approach highlights molecular differences associated with clusters rather than single outcome measures. This work demonstrates the utility of applying integrative methods to address clinical heterogeneity in multifactorial multi-ethnic disease settings.


Assuntos
Biologia Computacional , Grupos Étnicos/genética , Genômica , Lúpus Eritematoso Sistêmico/genética , Família Multigênica , Estudos de Coortes , Metilação de DNA , Epigenômica , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Locos de Características Quantitativas , Índice de Gravidade de Doença , Estados Unidos
3.
Mol Autism ; 9: 40, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29988321

RESUMO

Background: Several reports have suggested a role for epigenetic mechanisms in ASD etiology. Epigenome-wide association studies (EWAS) in autism spectrum disorder (ASD) may shed light on particular biological mechanisms. However, studies of ASD cases versus controls have been limited by post-mortem timing and severely small sample sizes. Reports from in-life sampling of blood or saliva have also been very limited in sample size and/or genomic coverage. We present the largest case-control EWAS for ASD to date, combining data from population-based case-control and case-sibling pair studies. Methods: DNA from 968 blood samples from children in the Study to Explore Early Development (SEED 1) was used to generate epigenome-wide array DNA methylation (DNAm) data at 485,512 CpG sites for 453 cases and 515 controls, using the Illumina 450K Beadchip. The Simons Simplex Collection (SSC) provided 450K array DNAm data on an additional 343 cases and their unaffected siblings. We performed EWAS meta-analysis across results from the two data sets, with adjustment for sex and surrogate variables that reflect major sources of biological variation and technical confounding such as cell type, batch, and ancestry. We compared top EWAS results to those from a previous brain-based analysis. We also tested for enrichment of ASD EWAS CpGs for being targets of meQTL associations using available SNP genotype data in the SEED sample. Findings: In this meta-analysis of blood-based DNA from 796 cases and 858 controls, no single CpG met a Bonferroni discovery threshold of p < 1.12 × 10- 7. Seven CpGs showed differences at p < 1 × 10- 5 and 48 at 1 × 10- 4. Of the top 7, 5 showed brain-based ASD associations as well, often with larger effect sizes, and the top 48 overall showed modest concordance (r = 0.31) in direction of effect with cerebellum samples. Finally, we observed suggestive evidence for enrichment of CpG sites controlled by SNPs (meQTL targets) among the EWAS CpG hits, which was consistent across EWAS and meQTL discovery p value thresholds. Conclusions: No single CpG site showed a large enough DNAm difference between cases and controls to achieve epigenome-wide significance in this sample size. However, our results suggest the potential to observe disease associations from blood-based samples. Among the seven sites achieving suggestive statistical significance, we observed consistent, and stronger, effects at the same sites among brain samples. Discovery-oriented EWAS for ASD using blood samples will likely need even larger samples and unified genetic data to further understand DNAm differences in ASD.


Assuntos
Transtorno do Espectro Autista/genética , Metilação de DNA , Transtorno do Espectro Autista/sangue , Estudos de Casos e Controles , Pré-Escolar , Ilhas de CpG , Epigênese Genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino
4.
Genome Med ; 10(1): 19, 2018 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-29587883

RESUMO

BACKGROUND: Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder characterized by deficits in social communication and restricted, repetitive behaviors, interests, or activities. The etiology of ASD involves both inherited and environmental risk factors, with epigenetic processes hypothesized as one mechanism by which both genetic and non-genetic variation influence gene regulation and pathogenesis. The aim of this study was to identify DNA methylation biomarkers of ASD detectable at birth. METHODS: We quantified neonatal methylomic variation in 1263 infants-of whom ~ 50% went on to subsequently develop ASD-using DNA isolated from archived blood spots taken shortly after birth. We used matched genotype data from the same individuals to examine the molecular consequences of ASD-associated genetic risk variants, identifying methylomic variation associated with elevated polygenic burden for ASD. In addition, we performed DNA methylation quantitative trait loci (mQTL) mapping to prioritize target genes from ASD GWAS findings. RESULTS: We identified robust epigenetic signatures of gestational age and prenatal tobacco exposure, confirming the utility of DNA methylation data generated from neonatal blood spots. Although we did not identify specific loci showing robust differences in neonatal DNA methylation associated with later ASD, there was a significant association between increased polygenic burden for autism and methylomic variation at specific loci. Each unit of elevated ASD polygenic risk score was associated with a mean increase in DNA methylation of - 0.14% at two CpG sites located proximal to a robust GWAS signal for ASD on chromosome 8. CONCLUSIONS: This study is the largest analysis of DNA methylation in ASD undertaken and the first to integrate genetic and epigenetic variation at birth. We demonstrate the utility of using a polygenic risk score to identify molecular variation associated with disease, and of using mQTL to refine the functional and regulatory variation associated with ASD risk variants.


Assuntos
Transtorno do Espectro Autista/genética , Metilação de DNA/genética , Herança Multifatorial/genética , Parto , Transtorno do Espectro Autista/sangue , Estudos de Coortes , Teste em Amostras de Sangue Seco , Epigênese Genética , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Masculino , Locos de Características Quantitativas/genética , Reprodutibilidade dos Testes , Tabaco/efeitos adversos
5.
Nat Commun ; 8(1): 1011, 2017 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-29066808

RESUMO

Integration of emerging epigenetic information with autism spectrum disorder (ASD) genetic results may elucidate functional insights not possible via either type of information in isolation. Here we use the genotype and DNA methylation (DNAm) data from cord blood and peripheral blood to identify SNPs associated with DNA methylation (meQTL lists). Additionally, we use publicly available fetal brain and lung meQTL lists to assess enrichment of ASD GWAS results for tissue-specific meQTLs. ASD-associated SNPs are enriched for fetal brain (OR = 3.55; P < 0.001) and peripheral blood meQTLs (OR = 1.58; P < 0.001). The CpG targets of ASD meQTLs across cord, blood, and brain tissues are enriched for immune-related pathways, consistent with other expression and DNAm results in ASD, and reveal pathways not implicated by genetic findings. This joint analysis of genotype and DNAm demonstrates the potential of both brain and blood-based DNAm for insights into ASD and psychiatric phenotypes more broadly.


Assuntos
Transtorno do Espectro Autista/genética , Ilhas de CpG/genética , Metilação de DNA/genética , Epigênese Genética , Transtorno do Espectro Autista/sangue , Encéfalo/embriologia , Encéfalo/metabolismo , Estudos de Casos e Controles , Pré-Escolar , Epigenômica/métodos , Sangue Fetal/metabolismo , Seguimentos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Lactente , Recém-Nascido , Pulmão/embriologia , Pulmão/metabolismo , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Cordão Umbilical/metabolismo
6.
Artigo em Inglês | MEDLINE | ID: mdl-27980682

RESUMO

BACKGROUND: The Illumina 450k array has been widely used in epigenetic association studies. Current quality-control (QC) pipelines typically remove certain sets of probes, such as those containing a SNP or with multiple mapping locations. An additional set of potentially problematic probes are those with DNA methylation distributions characterized by two or more distinct clusters separated by gaps. Data-driven identification of such probes may offer additional insights for downstream analyses. RESULTS: We developed a procedure, termed "gap hunting," to identify probes showing clustered distributions. Among 590 peripheral blood samples from the Study to Explore Early Development, we identified 11,007 "gap probes." The vast majority (9199) are likely attributed to an underlying SNP(s) or other variant in the probe, although SNP-affected probes exist that do not produce a gap signals. Specific factors predict which SNPs lead to gap signals, including type of nucleotide change, probe type, DNA strand, and overall methylation state. These expected effects are demonstrated in paired genotype and 450k data on the same samples. Gap probes can also serve as a surrogate for the local genetic sequence on a haplotype scale and can be used to adjust for population stratification. CONCLUSIONS: The characteristics of gap probes reflect potentially informative biology. QC pipelines may benefit from an efficient data-driven approach that "flags" gap probes, rather than filtering such probes, followed by careful interpretation of downstream association analyses. Our results should translate directly to the recently released Illumina EPIC array given the similar chemistry and content design.


Assuntos
Metilação de DNA , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Algoritmos , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/patologia , Estudos de Casos e Controles , Pré-Escolar , Ilhas de CpG , Bases de Dados Genéticas , Epigenômica , Genoma Humano , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único
7.
Epigenetics ; 11(5): 354-62, 2016 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-27019159

RESUMO

Epigenome-wide association studies of disease widely use DNA methylation measured in blood as a surrogate tissue. Cell proportions can vary between people and confound associations of exposure or outcome. An adequate reference panel for estimating cell proportions from adult whole blood for DNA methylation studies is available, but an analogous cord blood cell reference panel is not yet available. Cord blood has unique cell types and the epigenetic signatures of standard cell types may not be consistent throughout the life course. Using magnetic bead sorting, we isolated cord blood cell types (nucleated red blood cells, granulocytes, monocytes, natural killer cells, B cells, CD4(+)T cells, and CD8(+)T cells) from 17 live births at Johns Hopkins Hospital. We confirmed enrichment of the cell types using fluorescence assisted cell sorting and ran DNA from the separated cell types on the Illumina Infinium HumanMethylation450 BeadChip array. After filtering, the final analysis was on 104 samples at 429,794 probes. We compared cell type specific signatures in cord to each other and methylation at 49.2% of CpG sites on the array differed by cell type (F-test P < 10(-8)). Differences between nucleated red blood cells and the remainder of the cell types were most pronounced (36.9% of CpG sites at P < 10(-8)) and 99.5% of these sites were hypomethylated relative to the other cell types. We also compared the mean-centered sorted cord profiles to the available adult reference panel and observed high correlation between the overlapping cell types for granulocytes and monocytes (both r=0.74), and poor correlation for CD8(+)T cells and NK cells (both r=0.08). We further provide an algorithm for estimating cell proportions in cord blood using the newly developed cord reference panel, which estimates biologically plausible cell proportions in whole cord blood samples.


Assuntos
Metilação de DNA/genética , Epigenômica , Sangue Fetal/metabolismo , Genoma Humano , Linfócitos B/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Ilhas de CpG/genética , Eritroblastos/metabolismo , Feminino , Sangue Fetal/citologia , Granulócitos/metabolismo , Humanos , Recém-Nascido , Células Matadoras Naturais/metabolismo , Nascimento Vivo/genética , Masculino , Monócitos/metabolismo
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