Search

BackgroundPrenatal folate supplementation has been consistently associated with a reduced risk of childhood acute lymphoblastic leukemia (ALL). Previous germline genetic studies examining the one carbon (folate) metabolism pathway were limited in sample size, scope, and population diversity and led to inconclusive results.MethodsWe evaluated whether ∼2,900 single-nucleotide polymorphisms (SNP) within 46 candidate genes involved in the folate metabolism pathway influence the risk of childhood ALL, using genome-wide data from nine case-control studies in the Childhood Cancer and Leukemia International Consortium (n = 9,058 cases including 4,510 children of European ancestry, 3,018 Latinx, and 1,406 Asians, and 92,364 controls). Each study followed a standardized protocol for quality control and imputation of genome-wide data and summary statistics were meta-analyzed for all children combined and by major ancestry group using METAL software.ResultsNone of the selected SNPs reached statistical significance, overall and for major ancestry groups (using adjusted Bonferroni P-value of 5 × 10-6 and less-stringent P-value of 3.5 × 10-5 accounting for the number of "independent" SNPs). None of the 10 top (nonsignificant) SNPs and corresponding genes overlapped across ancestry groups.ConclusionsThis large meta-analysis of original data does not reveal associations between many common genetic variants in the folate metabolism pathway and childhood ALL in various ancestry groups.ImpactGenetic variants in the folate pathway alone do not appear to substantially influence childhood acute lymphoblastic leukemia risk. Other mechanisms such as gene-folate interaction, DNA methylation, or maternal genetic effects may explain the observed associations with self-reported prenatal folate intake.

Although recent studies have demonstrated associations between nonchromosomal birth defects and several pediatric cancers, less is known about their role on childhood leukemia susceptibility. Using data from the Childhood Cancer and Leukemia International Consortium, we evaluated associations between nonchromosomal birth defects and childhood leukemia. Pooling consortium data from 18 questionnaire-based and three registry-based case-control studies across 13 countries, we used multivariable logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between a spectrum of birth defects and leukemia. Our analyses included acute lymphoblastic leukemia (ALL, n = 13 115) and acute myeloid leukemia (AML, n = 2120) cases, along with 46 172 controls. We used the false discovery rate to account for multiple comparisons. In the questionnaire-based studies, the prevalence of birth defects was 5% among cases vs 4% in controls, whereas, in the registry-based studies, the prevalence was 11% among cases vs 7% in controls. In pooled adjusted analyses, there were several notable associations, including (1) digestive system defects and ALL (OR = 2.70, 95% CI: 1.46-4.98); (2) congenital anomalies of the heart and circulatory system and AML (OR = 2.86, 95% CI: 1.81-4.52) and (3) nervous system defects and AML (OR = 4.23, 95% CI: 1.50-11.89). Effect sizes were generally larger in registry-based studies. Overall, our results could point to novel genetic and environmental factors associated with birth defects that could also increase leukemia susceptibility. Additionally, differences between questionnaire- and registry-based studies point to the importance of complementary sources of birth defect phenotype data when exploring these associations.

BackgroundCongenital heart defects (CHDs) affect approximately half of individuals with Down syndrome (DS), but the molecular reasons for incomplete penetrance are unknown. Previous studies have largely focused on identifying genetic risk factors associated with CHDs in individuals with DS, but comprehensive studies of the contribution of epigenetic marks are lacking. We aimed to identify and characterize DNA methylation differences from newborn dried blood spots (NDBS) of DS individuals with major CHDs compared to DS individuals without CHDs.MethodsWe used the Illumina EPIC array and whole-genome bisulfite sequencing (WGBS) to quantitate DNA methylation for 86 NDBS samples from the California Biobank Program: (1) 45 DS-CHD (27 female, 18 male) and (2) 41 DS non-CHD (27 female, 14 male). We analyzed global CpG methylation and identified differentially methylated regions (DMRs) in DS-CHD versus DS non-CHD comparisons (both sex-combined and sex-stratified) corrected for sex, age of blood collection, and cell-type proportions. CHD DMRs were analyzed for enrichment in CpG and genic contexts, chromatin states, and histone modifications by genomic coordinates and for gene ontology enrichment by gene mapping. DMRs were also tested in a replication dataset and compared to methylation levels in DS versus typical development (TD) WGBS NDBS samples.ResultsWe found global CpG hypomethylation in DS-CHD males compared to DS non-CHD males, which was attributable to elevated levels of nucleated red blood cells and not seen in females. At a regional level, we identified 58, 341, and 3938 CHD-associated DMRs in the Sex Combined, Females Only, and Males Only groups, respectively, and used machine learning algorithms to select 19 Males Only loci that could distinguish CHD from non-CHD. DMRs in all comparisons were enriched for gene exons, CpG islands, and bivalent chromatin and mapped to genes enriched for terms related to cardiac and immune functions. Lastly, a greater percentage of CHD-associated DMRs than background regions were differentially methylated in DS versus TD samples.ConclusionsA sex-specific signature of DNA methylation was detected in NDBS of DS-CHD compared to DS non-CHD individuals. This supports the hypothesis that epigenetics can reflect the variability of phenotypes in DS, particularly CHDs.

Children and adolescents diagnosed with cancer can now expect an average 85% 5-year overall survival, with significant improvements in longer-term morbidity and mortality reported over the past several decades. However, the long-term impact of therapeutic agents and modalities introduced in recent years remains unclear and will require dedicated follow-up in the years ahead. The Children's Oncology Group (COG), a part of the NCI's National Clinical Trials Network, with over 200 sites across North America and beyond, enrolls more than 10,000 patients onto research protocols annually, inclusive of first-line clinical trials and nontherapeutic studies. COG provides a platform to conduct survivorship research with several unique strengths: (i) a huge catchment to ascertain relatively rare but important adverse events, (ii) study populations that are otherwise too rare to study in smaller consortia, including access to highly diverse patient populations, (iii) long-term follow-up of clinical trial populations linked to the original trial data, and (iv) a natural platform for intervention research. Enhancements in COG infrastructure facilitate survivorship research, including a COG patient registry (Project:EveryChild), availability of a long-term follow-up tracking resource, and successful deployment of various remote-based study procedures to reduce the burden on participants and participating institutions.

MotivationCpG sites within the same genomic region often share similar methylation patterns and tend to be co-regulated by multiple genetic variants that may interact with one another.ResultsWe propose a multi-trait methylation random field (multi-MRF) method to evaluate the joint association between a set of CpG sites and a set of genetic variants. The proposed method has several advantages. First, it is a multi-trait method that allows flexible correlation structures between neighboring CpG sites (e.g. distance-based correlation). Second, it is also a multi-locus method that integrates the effect of multiple common and rare genetic variants. Third, it models the methylation traits with a beta distribution to characterize their bimodal and interval properties. Through simulations, we demonstrated that the proposed method had improved power over some existing methods under various disease scenarios. We further illustrated the proposed method via an application to a study of congenital heart defects (CHDs) with 83 cardiac tissue samples. Our results suggested that gene BACE2, a methylation quantitative trait locus (QTL) candidate, colocalized with expression QTLs in artery tibial and harbored genetic variants with nominal significant associations in two genome-wide association studies of CHD.Availability and implementationhttps://github.com/chenlyu2656/Multi-MRF.Supplementary informationSupplementary data are available at Bioinformatics online.

BackgroundMost congenital heart defects (CHDs) result from complex interactions among genetic susceptibilities, epigenetic modifications, and maternal environmental exposures. Characterizing the complex relationship between genetic, epigenetic, and transcriptomic variation will enhance our understanding of pathogenesis in this important type of congenital disorder. We investigated cis-acting effects of genetic single nucleotide polymorphisms (SNPs) on local DNA methylation patterns within 83 cardiac tissue samples and prioritized their contributions to CHD risk by leveraging results of CHD genome-wide association studies (GWAS) and their effects on cardiac gene expression.ResultsWe identified 13,901 potential methylation quantitative trait loci (mQTLs) with a false discovery threshold of 5%. Further co-localization analyses and Mendelian randomization indicated that genetic variants near the HLA-DRB6 gene on chromosome 6 may contribute to CHD risk by regulating the methylation status of nearby CpG sites. Additional SNPs in genomic regions on chromosome 10 (TNKS2-AS1 gene) and chromosome 14 (LINC01629 gene) may simultaneously influence epigenetic and transcriptomic variations within cardiac tissues.ConclusionsOur results support the hypothesis that genetic variants may influence the risk of CHDs through regulating the changes of DNA methylation and gene expression. Our results can serve as an important source of information that can be integrated with other genetic studies of heart diseases, especially CHDs.

DNA methylation may be regulated by genetic variants within a genomic region, referred to as methylation quantitative trait loci (mQTLs). The changes of methylation levels can further lead to alterations of gene expression, and influence the risk of various complex human diseases. Detecting mQTLs may provide insights into the underlying mechanism of how genotypic variations may influence the disease risk. In this article, we propose a methylation random field (MRF) method to detect mQTLs by testing the association between the methylation level of a CpG site and a set of genetic variants within a genomic region. The proposed MRF has two major advantages over existing approaches. First, it uses a beta distribution to characterize the bimodal and interval properties of the methylation trait at a CpG site. Second, it considers multiple common and rare genetic variants within a genomic region to identify mQTLs. Through simulations, we demonstrated that the MRF had improved power over other existing methods in detecting rare variants of relatively large effect, especially when the sample size is small. We further applied our method to a study of congenital heart defects with 83 cardiac tissue samples and identified two mQTL regions, MRPS10 and PSORS1C1, which were colocalized with expression QTL in cardiac tissue. In conclusion, the proposed MRF is a useful tool to identify novel mQTLs, especially for studies with limited sample sizes.

Down syndrome is associated with genome-wide perturbation of gene expression, which may be mediated by epigenetic changes. We perform an epigenome-wide association study on neonatal bloodspots comparing 196 newborns with Down syndrome and 439 newborns without Down syndrome, adjusting for cell-type heterogeneity, which identifies 652 epigenome-wide significant CpGs (P

PurposeHaploinsufficiency of USP7, located at chromosome 16p13.2, has recently been reported in seven individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), seizures, and hypogonadism. Further, USP7 was identified to critically incorporate into the MAGEL2-USP7-TRIM27 (MUST), such that pathogenic variants in USP7 lead to altered endosomal F-actin polymerization and dysregulated protein recycling.MethodsWe report 16 newly identified individuals with heterozygous USP7 variants, identified by genome or exome sequencing or by chromosome microarray analysis. Clinical features were evaluated by review of medical records. Additional clinical information was obtained on the seven previously reported individuals to fully elucidate the phenotypic expression associated with USP7 haploinsufficiency.ResultsThe clinical manifestations of these 23 individuals suggest a syndrome characterized by DD/ID, hypotonia, eye anomalies,feeding difficulties, GERD, behavioral anomalies, and ASD, and more specific phenotypes of speech delays including a nonverbal phenotype and abnormal brain magnetic resonance image findings including white matter changes based on neuroradiologic examination.ConclusionThe consistency of clinical features among all individuals presented regardless of de novo USP7 variant type supports haploinsufficiency as a mechanism for pathogenesis and refines the clinical impact faced by affected individuals and caregivers.

Background: Coloboma is a rare congenital malformation in which part of the tissue that makes up the eye is missing and may cause visual impairment or blindness. Little is known about the epidemiology of this condition. Therefore, we obtained data from the Texas Birth Defects Registry on children identified with coloboma for the period 1999–2014. Methods: Using information on all live births from the same period, prevalence ratios (PRs) for selected demographic and clinical factors were used to estimate associations using Poisson regression among cases with coloboma. Coloboma cases were divided into subgroups to explore patterns of co‐occurring defects and syndromes. All variables significant in unadjusted models (p < 0.05) were included in multivariable models to evaluate adjusted PRs (aPRs). Results: We identified 1587 cases with coloboma, of whom 934 (58.8%) were nonsyndromic, and 474 (29.9%) were isolated. When considering all identified cases, factors associated with significant differences in prevalence included plurality (multiple vs. singleton aPR = 1.4, 95% CI: 1.1–1.8); maternal education (college or greater vs. less than high school aPR = 0.7, 95% CI: 0.6–0.9); maternal race/ethnicity (Hispanic vs. non‐Hispanic White aPR = 0.9, 95% CI: 0.8–1.0); and maternal diabetes (yes vs. no aPR = 1.3, 95% CI: 1.0–1.6). There was a notable increase in the birth prevalence of coloboma during the study period (p‐for‐trend < 0.001). Effect estimates were similar across the different subgroups. Conclusion: In our large population, we identified several factors associated with the prevalence of coloboma. These findings may help define subgroups of women more likely to have children affected by coloboma, which could inform improved screening efforts. [ABSTRACT FROM AUTHOR]

Background: Environmental toxicants may impact survival in children with cancer, but the literature investigating these associations remains limited. Because oil and gas developments emit several hazardous air pollutants, the authors evaluated the relationship between residential proximity to oil or gas development and survival across 21 different pediatric cancers. Methods: The Texas Cancer Registry had 29,730 children (≤19 years old) diagnosed with a primary cancer between 1995 to 2017. Geocoded data were available for 285,266 active oil or gas wells and 109,965 horizontal wells. The authors calculated whether each case lived within 1000 m (yes/no) from each type of oil or gas development. Survival analyses were conducted using Cox regression, adjusting for potential confounders. Results: A total of 14.2% of cases lived within 1000 m of an oil or gas well or horizontal well. Living within 1000 m of an oil or gas well was associated with risk of mortality in cases with acute myeloid leukemia (AML) (adjusted hazard ratio [aHR], 1.36; 95% confidence interval [CI], 1.01–1.84) and hepatoblastoma (aHR, 2.13; 95% CI, 1.03–4.39). An inverse association was observed with Ewing sarcoma (aHR, 0.35; 95% CI, 0.13–0.95). No associations were observed with horizontal well. There was evidence of a dose‐response effect in children with AML or hepatoblastoma and residential proximity to oil or gas wells. In general, the magnitude of association increased with decreasing distance and with higher number of wells across the three distances. Conclusions: Residential proximity to oil or gas wells at diagnosis is associated with the risk of mortality in children with AML or hepatoblastoma. [ABSTRACT FROM AUTHOR]

Introduction: Fertility after cancer is a top concern for adolescents and young adults with cancer (AYAs) (15–39 years old at diagnosis). The authors characterized live births after cancer by race and ethnicity ("race/ethnicity") in a population‐based sample of female AYAs. Methods: This study used Texas Cancer Registry data linked to birth certificates (1995–2016) to estimate cumulative incidence of live birth, based on first live birth after cancer, and compared differences by race/ethnicity. Proportional subdistribution hazards models were used to estimate associations between race/ethnicity and live birth, adjusted for diagnosis age, cancer type, stage, year, and prior live birth, overall and for each cancer type. Results: Among 65,804 AYAs, 10‐year cumulative incidence of live birth was lower among non‐Hispanic Black AYAs than other racial/ethnic groups: 10.2% (95% confidence interval [CI], 9.4–10.9) compared to 15.9% (95% CI, 14.1–17.9) among Asian or Pacific Islander, 14.7% (95% CI, 14.2–15.3) among Hispanic, and 15.2% (95% CI, 14.8–15.6) among non‐Hispanic White AYAs (p <.01). In the adjusted overall model, Black AYAs were less likely to have a live birth after cancer than all other groups. In adjusted models for each cancer type, live birth was significantly less likely for Black AYAs with gynecologic cancers or lymphomas (compared to White AYAs) or thyroid cancers (compared to Hispanic AYAs). Conclusion: Black AYAs are less likely than AYAs of other races/ethnicities to have a live birth after cancer, in contrast to patterns of live birth in the general population. Research and action to promote childbearing equity after cancer are imperative. The authors used Texas Cancer Registry data linked to live birth certificates (1995–2016) to characterize live births after cancer by race and ethnicity ("race/ethnicity") among females diagnosed with cancer as adolescents and young adults (AYAs) (15–39 years old at diagnosis). Overall and within certain cancer types, Black AYAs were less likely than AYAs of other races or ethnicities to have a live birth after cancer, in contrast to general population birth patterns. [ABSTRACT FROM AUTHOR]

The Inaugural Symposium on Childhood Cancer Health Disparities was held in Houston, Texas, on November 2, 2016. The symposium was attended by 109 scientists and clinicians from diverse disciplinary backgrounds with interests in pediatric cancer disparities and focused on reviewing our current knowledge of disparities in cancer risk and outcomes for select childhood cancers. Following a full day of topical sessions, everyone participated in a brainstorming session to develop a working strategy for the continued expansion of research in this area. This meeting was designed to serve as a springboard for examination of childhood cancer disparities from a more unified and systematic approach and to enhance awareness of this area of need.

Background: Emerging evidence suggests newborn screening analytes may yield insights into the etiologies of birth defects, yet no effort has evaluated associations between a range of newborn screening analytes and birth defects. Methods: This population-based study pooled statewide data on birth defects, birth certificates, and newborn screening analytes from Texas occurring between January 1, 2007 and December 31, 2009. Associations between a panel of thirty-six newborn screening analytes, collected by the statewide Texas Newborn Screening Program, and the presence of a birth defect, defined as at least one of 39 birth defects diagnoses recorded by the Texas Birth Defects Registry, were assessed using regression analysis. Findings: Of the 27,643 births identified, 20,205 had at least one of the 39 birth defects of interest (cases) as identified by the Texas Birth Defects Registry, while 7,438 did not have a birth defect (controls). Among 1,404 analyte-birth defect associations evaluated, 377 were significant in replication analysis. Analytes most consistently associated with birth defects included the phenylalanine/tyrosine ratio (N = 29 birth defects), tyrosine (N = 28 birth defects), and thyroxine (N = 25 birth defects). Birth defects most frequently associated with a range of analytes included gastroschisis (N = 29 analytes), several cardiovascular defects (N = 26 analytes), and spina bifida (N = 23 analytes). Conclusions: Several significant and novel associations were observed between newborn screening analytes and birth defects. While some findings could be consequences of the defects themselves or to the care provided to infants with these defects, these findings could help to elucidate mechanisms underlying the etiology of some birth defects. [ABSTRACT FROM AUTHOR]

Background: Prior studies report associations of maternal serum Lamin A, encoded by the LMNA gene, with fetal congenital heart disease (CHD). It is unknown whether DNA methylation (DNAm) of cytosine‐phosphate‐guanine (CpG) sites in LMNA impacts the CHD susceptibility. Methods: We investigated the associations of LMNA DNAm with CHD using publicly available data of CHD cases (n = 197) and controls (n = 134) from the Gene Expression Omnibus repository. Peripheral blood DNAm was measured using Illumina 850 K BeadChip for cases and 450 K BeadChip for controls. We tested 31 LMNA CpGs to identify differences in DNAm between cases and controls using linear regression correcting for multiple testing with false discovery rate (FDR). In a case‐only analysis, we tested the variations in LMNA DNAm between CHD subtypes. To identify the consistency of DNAm across tissue types we compared peripheral blood (n = 197) and heart tissue DNAm (n = 20) in CHD cases. Results: After adjusting for age, sex, and cell types there were significant differences in 17 of the 31 LMNA CpGs between CHD cases and controls (FDR p ≤.05). We identified lower DNAm of cg09820673 at 3′ UTR for hypoplastic left heart syndrome compared to other CHD subtypes. Three CpGs exhibited uniform DNAm in blood and heart tissues in cases. Eleven CpGs showed changes in the same direction in blood and heart tissues in cases compared to controls. Conclusion: We identify statistically significant differences in LMNA DNAm between CHD cases and controls. Future studies should investigate the role of maternal LMNA DNAm in CHD development. [ABSTRACT FROM AUTHOR]

Background Air pollution is positively associated with some childhood cancers, whereas greenness is inversely associated with some adult cancers. The interplay between air pollution and greenness in childhood cancer etiology is unclear. We estimated the association between early-life air pollution and greenness exposure and childhood cancer in Texas (1995 to 2011). Methods We included 6101 cancer cases and 109 762 controls (aged 0 to 16 years). We linked residential birth address to census tract annual average fine particulate matter <2.5 µg/m³ (PM2.5) and Normalized Difference Vegetation Index (NDVI). We estimated odds ratios (ORs) and 95% confidence intervals (CIs) between PM2.5/NDVI interquartile range increases and cancer. We assessed statistical interaction between PM2.5 and NDVI (likelihood ratio tests). Results Increasing residential early-life PM2.5 exposure was associated with all childhood cancers (OR = 1.10, 95% CI = 1.06 to 1.15), lymphoid leukemias (OR = 1.15, 95% CI = 1.07 to 1.23), Hodgkin lymphomas (OR = 1.27, 95% CI = 1.02 to 1.58), non-Hodgkin lymphomas (OR = 1.24, 95% CI = 1.02 to 1.51), ependymoma (OR = 1.27, 95% CI = 1.01 to 1.60), and others. Increasing NDVI exposure was inversely associated with ependymoma (0- to 4-year-old OR = 0.75, 95% CI = 0.58 to 0.97) and medulloblastoma (OR = 0.75, 95% CI = 0.62 to 0.91) but positively associated with malignant melanoma (OR = 1.75, 95% CI = 1.23 to 2.47) and Langerhans cell histiocytosis (OR = 1.56, 95% CI = 1.07 to 2.28). There was evidence of statistical interaction between NDVI and PM2.5 (P  < .04) for all cancers. Conclusion Increasing early-life exposure to PM2.5 increased the risk of childhood cancers. NDVI decreased the risk of 2 cancers yet increased the risk of others. These findings highlight the complexity between PM2.5 and NDVI in cancer etiology. [ABSTRACT FROM AUTHOR]

Common genetic variants identified in the general population have been found to increase phenotypic risks among individuals with certain genetic conditions. Up to 90% of individuals with tuberous sclerosis complex (TSC) are affected by some type of epilepsy, yet the common variants contributing to epilepsy risk in the general population have not been evaluated in the context of TSC‐associated epilepsy. Such knowledge is important to help uncover the underlying pathogenesis of epilepsy in TSC which is not fully understood, and critical as uncontrolled epilepsy is a major problem in this population. To evaluate common genetic modifiers of epilepsy, our study pooled phenotypic and genotypic data from 369 individuals with TSC to evaluate known and novel epilepsy common variants. We did not find evidence of enhanced genetic penetrance for known epilepsy variants identified across the largest genome‐wide association studies of epilepsy in the general population, but identified support for novel common epilepsy variants in the context of TSC. Specifically, we have identified a novel signal in SLC7A1 that may be functionally involved in pathways relevant to TSC and epilepsy. Our study highlights the need for further evaluation of genetic modifiers in TSC to aid in further understanding of epilepsy in TSC and improve outcomes. [ABSTRACT FROM AUTHOR]