A machine learning case–control classifier for schizophrenia based on DNA methylation in blood

Epigenetic dysregulation is thought to contribute to the etiology of schizophrenia (SZ), but the cell type-specificity of DNA methylation makes population-based epigenetic studies of SZ challenging. To train an SZ case–control classifier based on DNA methylation in blood, therefore, we focused on human genomic regions of systemic interindividual epigenetic variation (CoRSIVs), a subset of which are represented on the Illumina Human Methylation 450K (HM450) array. HM450 DNA methylation data on whole blood of 414 SZ cases and 433 non-psychiatric controls were used as training data for a classification algorithm with built-in feature selection, sparse partial least squares discriminate analysis (SPLS-DA); application of SPLS-DA to HM450 data has not been previously reported. Using the first two SPLS-DA dimensions we calculated a “risk distance” to identify individuals with the highest probability of SZ. The model was then evaluated on an independent HM450 data set on 353 SZ cases and 322 non-psychiatric controls. Our CoRSIV-based model classified 303 individuals as cases with a positive predictive value (PPV) of 80%, far surpassing the performance of a model based on polygenic risk score (PRS). Importantly, risk distance (based on CoRSIV methylation) was not associated with medication use, arguing against reverse causality. Risk distance and PRS were positively correlated (Pearson r = 0.28, P = 1.28 × 10−12), and mediational analysis suggested that genetic effects on SZ are partially mediated by altered methylation at CoRSIVs. Our results indicate two innate dimensions of SZ risk: one based on genetic, and the other on systemic epigenetic variants

Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort

Data from epidemiological and animal model studies suggest that nutrition during pregnancy may affect the health status of subsequent generations. These transgenerational effects are now being explained by disruptions at the level of the epigenetic machinery. Besides in vitro environmental exposures, the possible impact on the reprogramming of methylation profiles at imprinted genes at a much earlier time point, such as during spermatogenesis or oogenesis, has not previously been considered. In this study, our aim was to determine associations between preconceptional obesity and DNA methylation profiles in the offspring, particularly at the differentially methylated regions (DMRs) of the imprinted Insulin-like Growth Factor 2 (IGF2) gene

A Sustained Dietary Change Increases Epigenetic Variation in Isogenic Mice

Epigenetic changes can be induced by adverse environmental exposures, such as nutritional imbalance, but little is known about the nature or extent of these changes. Here we have explored the epigenomic effects of a sustained nutritional change, excess dietary methyl donors, by assessing genomic CpG methylation patterns in isogenic mice exposed for one or six generations. We find stochastic variation in methylation levels at many loci; exposure to methyl donors increases the magnitude of this variation and the number of variable loci. Several gene ontology categories are significantly overrepresented in genes proximal to these methylation-variable loci, suggesting that certain pathways are susceptible to environmental influence on their epigenetic states. Long-term exposure to the diet (six generations) results in a larger number of loci exhibiting epigenetic variability, suggesting that some of the induced changes are heritable. This finding presents the possibility that epigenetic variation within populations can be induced by environmental change, providing a vehicle for disease predisposition and possibly a substrate for natural selection

Comparison of sequencing-based methods to profile DNA methylation and identification of monoallelic epigenetic modifications.

Analysis of DNA methylation patterns relies increasingly on sequencing-based profiling methods. The four most frequently used sequencing-based technologies are the bisulfite-based methods MethylC-seq and reduced representation bisulfite sequencing (RRBS), and the enrichment-based techniques methylated DNA immunoprecipitation sequencing (MeDIP-seq) and methylated DNA binding domain sequencing (MBD-seq). We applied all four methods to biological replicates of human embryonic stem cells to assess their genome-wide CpG coverage, resolution, cost, concordance and the influence of CpG density and genomic context. The methylation levels assessed by the two bisulfite methods were concordant (their difference did not exceed a given threshold) for 82% for CpGs and 99% of the non-CpG cytosines. Using binary methylation calls, the two enrichment methods were 99% concordant and regions assessed by all four methods were 97% concordant. We combined MeDIP-seq with methylation-sensitive restriction enzyme (MRE-seq) sequencing for comprehensive methylome coverage at lower cost. This, along with RNA-seq and ChIP-seq of the ES cells enabled us to detect regions with allele-specific epigenetic states, identifying most known imprinted regions and new loci with monoallelic epigenetic marks and monoallelic expression

A realistic example of chaotic tunneling: The hydrogen atom in parallel static electric and magnetic fields

Statistics of tunneling rates in the presence of chaotic classical dynamics is discussed on a realistic example: a hydrogen atom placed in parallel uniform static electric and magnetic fields, where tunneling is followed by ionization along the fields direction. Depending on the magnetic quantum number, one may observe either a standard Porter-Thomas distribution of tunneling rates or, for strong scarring by a periodic orbit parallel to the external fields, strong deviations from it. For the latter case, a simple model based on random matrix theory gives the correct distribution.Comment: Submitted to Phys. Rev.

The Iowa Homemaker vol.26, no.2

Alma Mater, J. C. Harris, page 2 Travel With Poise, Mary Ann Hakes, page 3 Report From Athens, Joan Kelleher, page 4 Blanche Pederson Interviews an Aussie Bride, Blanche Pederson, page 5 Coeds are Veterans, Too, Mary Margaret Ryan, page 6 Future Home Economics Classroom, Helen Hochriem, page 7 Vicky Grins at the Sun, Breta Soldat, page 9 What’s New in Home Economics, Marjorie Clampitt, page 10 Wardrobe Worries? Here’s What We Wear, Textiles and Clothing Club, page 12 “I Have a Dozen Bosses”, Genevieve Callahan, page 14 Albino Rats Get in on the Ground Floor, Margaret Waterland, page 17 Alums Prove Chemistry can Pay, June Welch, page 18 Education Begins Egyptian Modernizing, Lois Bronson, page 19 Across Alumnae Desks, Mary Neff, page 21 Keeping Up With Today, Joyce Edgar, page 22 How Does Your Garden Grow?, Irene Meyer, page 23 Alums in the News, Goldie Rouse, page 2

Independent genomewide screens identify the tumor suppressor VTRNA2-1 as a human epiallele responsive to periconceptional environment

Background: Interindividual epigenetic variation that occurs systemically must be established prior to gastrulation in the very early embryo and, because it is systemic, can be assessed in easily biopsiable tissues. We employ two independent genome-wide approaches to search for such variants. Results: First, we screen for metastable epialleles by performing genomewide bisulfite sequencing in peripheral blood lymphocyte (PBL) and hair follicle DNA from two Caucasian adults. Second, we conduct a genomewide screen for genomic regions at which PBL DNA methylation is affected by season of conception in rural Gambia. Remarkably, both approaches identify the genomically imprinted VTRNA2-1 as a top environmentally responsive epiallele. We demonstrate systemic and stochastic interindividual variation in DNA methylation at the VTRNA2-1 differentially methylated region in healthy Caucasian and Asian adults and show, in rural Gambians, that periconceptional environment affects offspring VTRNA2-1 epigenotype, which is stable over at least 10 years. This unbiased screen also identifies over 100 additional candidate metastable epialleles, and shows that these are associated with cis genomic features including transposable elements. Conclusions: The non-coding VTRNA2-1 transcript (also called nc886) is a putative tumor suppressor and modulator of innate immunity. Thus, these data indicating environmentally induced loss of imprinting at VTRNA2-1 constitute a plausible causal pathway linking early embryonic environment, epigenetic alteration, and human disease. More broadly, the list of candidate metastable epialleles provides a resource for future studies of epigenetic variation and human disease

Prenatal Famine and Genetic Variation Are Independently and Additively Associated with DNA Methylation at Regulatory Loci within IGF2/H19

Both the early environment and genetic variation may affect DNA methylation, which is one of the major molecular marks of the epigenome. The combined effect of these factors on a well-defined locus has not been studied to date. We evaluated the association of periconceptional exposure to the Dutch Famine of 1944–45, as an example of an early environmental exposure, and single nucleotide polymorphisms covering the genetic variation (tagging SNPs) with DNA methylation at the imprinted IGF2/H19 region, a model for an epigenetically regulated genomic region. DNA methylation was measured at five differentially methylated regions (DMRs) that regulate the imprinted status of the IGF2/H19 region. Small but consistent differences in DNA methylation were observed comparing 60 individuals with periconceptional famine exposure with unexposed same-sex siblings at all IGF2 DMRs (PBH<0.05 after adjustment for multiple testing), but not at the H19 DMR. IGF2 DMR0 methylation was associated with IGF2 SNP rs2239681 (PBH = 0.027) and INS promoter methylation with INS SNPs, including rs689, which tags the INS VNTR, suggesting a mechanism for the reported effect of the VNTR on INS expression (PBH = 3.4×10−3). Prenatal famine and genetic variation showed similar associations with IGF2/H19 methylation and their contributions were additive. They were small in absolute terms (<3%), but on average 0.5 standard deviations relative to the variation in the population. Our analyses suggest that environmental and genetic factors could have independent and additive similarly sized effects on DNA methylation at the same regulatory site

Intergenerational Transmission of Glucose Intolerance and Obesity by In Utero Undernutrition in Mice

OBJECTIVE—Low birth weight (LBW) is associated with increased risk of obesity, diabetes, and cardiovascular disease during adult life. Moreover, this programmed disease risk can progress to subsequent generations. We previously described a mouse model of LBW, produced by maternal caloric undernutrition (UN) during late gestation. LBW offspring (F1-UN generation) develop progressive obesity and impaired glucose tolerance (IGT) with aging. We aimed to determine whether such metabolic phenotypes can be transmitted to subsequent generations in an experimental model, even in the absence of altered nutrition during the second pregnancy

Current opportunities to catalyze research in nutrition and cancer prevention – an interdisciplinary perspective

Cancer Research UK and Ludwig Cancer Research convened an inaugural international Cancer Prevention and Nutrition Conference in London on December 3–4, 2018. Much of the discussion focused on the need for systematic, interdisciplinary approaches to better understand the relationships of nutrition, exercise, obesity and metabolic dysfunction with cancer development. Scientists at the meeting underscored the importance of studying the temporal natural history of exposures that may cumulatively impact cancer risk later in life. A robust dialogue identified obesity as a major risk for cancer, and the food environment, especially high energy and low nutrient processed foods, as strong and prevalent risk factors for obesity. Further engagement highlighted challenges in the post-diagnostic setting, where similar opportunities to understand the complex interplay of nutrition, physical activity, and weight will inform better health outcomes. Going forward, holistic research approaches, encompassing insights from multiple disciplines and perspectives, will catalyze progress urgently needed to prevent cancer and improve public health