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Dive into the research topics where Christine Ladd-Acosta is active.

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Featured researches published by Christine Ladd-Acosta.


Nature Genetics | 2009

The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores

Rafael A. Irizarry; Christine Ladd-Acosta; Bo Wen; Zhijin Wu; Carolina Montano; Patrick Onyango; Hengmi Cui; Kevin Gabo; Michael Rongione; Maree J. Webster; Hong-Fei Ji; James B. Potash; Sarven Sabunciyan; Andrew P. Feinberg

Alterations in DNA methylation (DNAm) in cancer have been known for 25 years, including hypomethylation of oncogenes and hypermethylation of tumor suppressor genes1. However, most studies of cancer methylation have assumed that functionally important DNAm will occur in promoters, and that most DNAm changes in cancer occur in CpG islands2,3. Here we show that most methylation alterations in colon cancer occur not in promoters, and also not in CpG islands but in sequences up to 2 kb distant which we term “CpG island shores.” CpG island shore methylation was strongly related to gene expression, and it was highly conserved in mouse, discriminating tissue types regardless of species of origin. There was a surprising overlap (45-65%) of the location of colon cancer-related methylation changes with those that distinguished normal tissues, with hypermethylation enriched closer to the associated CpG islands, and hypomethylation enriched further from the associated CpG island and resembling non-colon normal tissues. Thus, methylation changes in cancer are at sites that vary normally in tissue differentiation, and they are consistent with the epigenetic progenitor model of cancer4, that epigenetic alterations affecting tissue-specific differentiation are the predominant mechanism by which epigenetic changes cause cancer.


Nature Genetics | 2009

Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts

Akiko Doi; In-Hyun Park; Bo Wen; Peter Murakami; Martin J. Aryee; Rafael A. Irizarry; Brian Herb; Christine Ladd-Acosta; Junsung Rho; Sabine Loewer; Justine D. Miller; Thorsten M. Schlaeger; George Q. Daley; Andrew P. Feinberg

Induced pluripotent stem (iPS) cells are derived by epigenetic reprogramming, but their DNA methylation patterns have not yet been analyzed on a genome-wide scale. Here, we find substantial hypermethylation and hypomethylation of cytosine-phosphate-guanine (CpG) island shores in nine human iPS cell lines as compared to their parental fibroblasts. The differentially methylated regions (DMRs) in the reprogrammed cells (denoted R-DMRs) were significantly enriched in tissue-specific (T-DMRs; 2.6-fold, P < 10−4) and cancer-specific DMRs (C-DMRs; 3.6-fold, P < 10−4). Notably, even though the iPS cells are derived from fibroblasts, their R-DMRs can distinguish between normal brain, liver and spleen cells and between colon cancer and normal colon cells. Thus, many DMRs are broadly involved in tissue differentiation, epigenetic reprogramming and cancer. We observed colocalization of hypomethylated R-DMRs with hypermethylated C-DMRs and bivalent chromatin marks, and colocalization of hypermethylated R-DMRs with hypomethylated C-DMRs and the absence of bivalent marks, suggesting two mechanisms for epigenetic reprogramming in iPS cells and cancer.


Molecular Psychiatry | 2014

Common DNA methylation alterations in multiple brain regions in autism

Christine Ladd-Acosta; Kasper D. Hansen; Eirikur Briem; Margaret Daniele Fallin; Walter E. Kaufmann; Andrew P. Feinberg

Autism spectrum disorders (ASD) are increasingly common neurodevelopmental disorders defined clinically by a triad of features including impairment in social interaction, impairment in communication in social situations and restricted and repetitive patterns of behavior and interests, with considerable phenotypic heterogeneity among individuals. Although heritability estimates for ASD are high, conventional genetic-based efforts to identify genes involved in ASD have yielded only few reproducible candidate genes that account for only a small proportion of ASDs. There is mounting evidence to suggest environmental and epigenetic factors play a stronger role in the etiology of ASD than previously thought. To begin to understand the contribution of epigenetics to ASD, we have examined DNA methylation (DNAm) in a pilot study of postmortem brain tissue from 19 autism cases and 21 unrelated controls, among three brain regions including dorsolateral prefrontal cortex, temporal cortex and cerebellum. We measured over 485 000 CpG loci across a diverse set of functionally relevant genomic regions using the Infinium HumanMethylation450 BeadChip and identified four genome-wide significant differentially methylated regions (DMRs) using a bump hunting approach and a permutation-based multiple testing correction method. We replicated 3/4 DMRs identified in our genome-wide screen in a different set of samples and across different brain regions. The DMRs identified in this study represent suggestive evidence for commonly altered methylation sites in ASD and provide several promising new candidate genes.


Nature Communications | 2015

Genome-wide association study identifies peanut allergy-specific loci and evidence of epigenetic mediation in US children

Xiumei Hong; Ke Hao; Christine Ladd-Acosta; Kasper D. Hansen; Hui Ju Tsai; Xin Liu; Xin Xu; Timothy A. Thornton; Deanna Caruso; Corinne A. Keet; Yifei Sun; Guoying Wang; Wei Luo; Rajesh Kumar; Ramsay L. Fuleihan; Anne Marie Singh; Jennifer S. Kim; Rachel E. Story; Ruchi S. Gupta; Peisong Gao; Zhu Chen; Sheila O. Walker; Tami R. Bartell; Terri H. Beaty; M. Daniele Fallin; Robert P. Schleimer; Patrick G. Holt; Kari C. Nadeau; Robert A. Wood; Jacqueline A. Pongracic

Food allergy (FA) affects 2–10% of U.S. children and is a growing clinical and public health problem. Here we conduct the first genome-wide association study of well-defined FA, including specific subtypes (peanut, milk, and egg) in 2,759 U.S. participants (1,315 children; 1,444 parents) from the Chicago Food Allergy Study; and identify peanut allergy (PA)-specific loci in the HLA-DR and -DQ gene region at 6p21.32, tagged by rs7192 (p=5.5×10−8) and rs9275596 (p=6.8×10−10), in 2,197 participants of European ancestry. We replicate these associations in an independent sample of European ancestry. These associations are further supported by meta-analyses across the discovery and replication samples. Both single-nucleotide polymorphisms (SNPs) are associated with differential DNA methylation levels at multiple CpG sites (p<5×10−8); and differential DNA methylation of the HLA-DQB1 and HLA-DRB1 genes partially mediate the identified SNP-PA associations. This study suggests that the HLA-DR and -DQ gene region likely poses significant genetic risk for PA.


Genome Research | 2008

SNP-specific array-based allele-specific expression analysis

Hans T. Bjornsson; Thomas J. Albert; Christine Ladd-Acosta; Roland D. Green; Michael Rongione; Christina Middle; Rafael A. Irizarry; Karl W. Broman; Andrew P. Feinberg

We have developed an optimized array-based approach for customizable allele-specific gene expression (ASE) analysis. The central features of the approach are the ability to select SNPs at will for detection, and the absence of need to PCR amplify the target. A surprisingly long probe length (39-49 nt) was needed for allelic discrimination. Reconstitution experiments demonstrate linearity of ASE over a broad range. Using this approach, we have discovered at least two novel imprinted genes, NLRP2, which encodes a member of the inflammasome, and OSBPL1A, which encodes a presumed oxysterol-binding protein, were both preferentially expressed from the maternal allele. In contrast, ERAP2, which encodes an aminopeptidase, did not show preferential parent-of-origin expression, but rather, cis-acting nonimprinted differential allelic control. The approach is scalable to the whole genome and can be used for discovery of functional epigenetic modifications in patient samples.


Annual Review of Public Health | 2017

The Changing Epidemiology of Autism Spectrum Disorders

Kristen Lyall; Lisa A. Croen; Julie L. Daniels; M. Daniele Fallin; Christine Ladd-Acosta; Brian K. Lee; Bo Y. Park; Nathaniel W. Snyder; Diana E. Schendel; Heather E. Volk; Gayle C. Windham; Craig J. Newschaffer

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with lifelong impacts. Genetic and environmental factors contribute to ASD etiology, which remains incompletely understood. Research on ASD epidemiology has made significant advances in the past decade. Current prevalence is estimated to be at least 1.5% in developed countries, with recent increases primarily among those without comorbid intellectual disability. Genetic studies have identified a number of rare de novo mutations and gained footing in the areas of polygenic risk, epigenetics, and gene-by-environment interaction. Epidemiologic investigations focused on nongenetic factors have established advanced parental age and preterm birth as ASD risk factors, indicated that prenatal exposure to air pollution and short interpregnancy interval are potential risk factors, and suggested the need for further exploration of certain prenatal nutrients, metabolic conditions, and exposure to endocrine-disrupting chemicals. We discuss future challenges and goals for ASD epidemiology as well as public health implications.


Environmental Research | 2016

Presence of an epigenetic signature of prenatal cigarette smoke exposure in childhood

Christine Ladd-Acosta; Chang Shu; Brian K. Lee; Nicole B. Gidaya; Alison B. Singer; Laura A. Schieve; Diana E. Schendel; Nicole M. Jones; Julie L. Daniels; Gayle C. Windham; Craig J. Newschaffer; Lisa A. Croen; Andrew P. Feinberg; M. Daniele Fallin

Prenatal exposure to tobacco smoke has lifelong health consequences. Epigenetic signatures such as differences in DNA methylation (DNAm) may be a biomarker of exposure and, further, might have functional significance for how in utero tobacco exposure may influence disease risk. Differences in infant DNAm associated with maternal smoking during pregnancy have been identified. Here we assessed whether these infant DNAm patterns are detectible in early childhood, whether they are specific to smoking, and whether childhood DNAm can classify prenatal smoke exposure status. Using the Infinium 450K array, we measured methylation at 26 CpG loci that were previously associated with prenatal smoking in infant cord blood from 572 children, aged 3-5, with differing prenatal exposure to cigarette smoke in the Study to Explore Early Development (SEED). Striking concordance was found between the pattern of prenatal smoking associated DNAm among preschool aged children in SEED and those observed at birth in other studies. These DNAm changes appear to be tobacco-specific. Support vector machine classification models and 10-fold cross-validation were applied to show classification accuracy for childhood DNAm at these 26 sites as a biomarker of prenatal smoking exposure. Classification models showed prenatal exposure to smoking can be assigned with 81% accuracy using childhood DNAm patterns at these 26 loci. These findings support the potential for blood-derived DNAm measurements to serve as biomarkers for prenatal exposure.


Epigenomics | 2016

The role of epigenetics in genetic and environmental epidemiology

Christine Ladd-Acosta; M. Daniele Fallin

Epidemiology is the branch of science that investigates the causes and distribution of disease in populations in order to provide preventative measures and promote human health. The fields of genetic and environmental epidemiology primarily seek to identify genetic and environmental risk factors for disease, respectively. Epigenetics is emerging as an important piece of molecular data to include in these studies because it can provide mechanistic insights into genetic and environmental risk factors for disease, identify potential intervention targets, provide biomarkers of exposure, illuminate gene-environment interactions and help localize disease-relevant genomic regions. Here, we describe the importance of including epigenetics in genetic and environmental epidemiology studies, provide a conceptual framework when considering epigenetic data in population-based studies and touch upon the many challenges that lie ahead.


Current Environmental Health Reports | 2015

Epigenetic Signatures as Biomarkers of Exposure

Christine Ladd-Acosta

To advance our knowledge of the influence of environmental exposures on human health and disease, robust studies are needed. However, for many exposures, robust studies are not feasible due to limitations with current ascertainment methods and/or study designs. Epigenetics, the study of mitotically heritable, reversible information that regulates critical cell processes, has gained much attention because it offers a potential mechanism to explain how exposures can influence cell states. Therefore, most studies have focused on epigenetics as a mechanism for disease. However, emerging evidence also suggests that epigenetic marks may also serve as biomarkers of exposure. Here, we highlight findings showing that the epigenome is labile to the environment and that these exposure-associated changes show long-term stability, are specific, are detectable in accessible tissues, can predict exposure status, and can be practically implemented, thus supporting the potential for epigenetic patterns to serve as robust measures of environmental exposure.


PLOS Genetics | 2016

Pleiotropic Mechanisms Indicated for Sex Differences in Autism

Ileena Mitra; Kathryn Tsang; Christine Ladd-Acosta; Lisa A. Croen; Kimberly A. Aldinger; Robert L. Hendren; Michela Traglia; Alinoë Lavillaureix; Noah Zaitlen; Michael C. Oldham; Pat Levitt; Stanley F. Nelson; David G. Amaral; Irva Herz-Picciotto; M. Daniele Fallin; Lauren A. Weiss

Sexual dimorphism in common disease is pervasive, including a dramatic male preponderance in autism spectrum disorders (ASDs). Potential genetic explanations include a liability threshold model requiring increased polymorphism risk in females, sex-limited X-chromosome contribution, gene-environment interaction driven by differences in hormonal milieu, risk influenced by genes sex-differentially expressed in early brain development, or contribution from general mechanisms of sexual dimorphism shared with secondary sex characteristics. Utilizing a large single nucleotide polymorphism (SNP) dataset, we identify distinct sex-specific genome-wide significant loci. We investigate genetic hypotheses and find no evidence for increased genetic risk load in females, but evidence for sex heterogeneity on the X chromosome, and contribution of sex-heterogeneous SNPs for anthropometric traits to ASD risk. Thus, our results support pleiotropy between secondary sex characteristic determination and ASDs, providing a biological basis for sex differences in ASDs and implicating non brain-limited mechanisms.

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Deanna Caruso

Johns Hopkins University

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Xiumei Hong

Johns Hopkins University

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