scholarly journals Epigenome-wide association study of seizures in childhood and adolescence

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Doretta Caramaschi ◽  
Charlie Hatcher ◽  
Rosa H. Mulder ◽  
Janine F. Felix ◽  
Charlotte A. M. Cecil ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
Independent Study ◽  
Childhood And Adolescence ◽  
Parents And Children ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
The Brain ◽  
Avon Longitudinal Study

AbstractThe occurrence of seizures in childhood is often associated with neurodevelopmental impairments and school underachievement. Common genetic variants associated with epilepsy have been identified and epigenetic mechanisms have also been suggested to play a role. In this study, we analyzed the association of genome-wide blood DNA methylation with the occurrence of seizures in ~ 800 children from the Avon Longitudinal Study of Parents and Children, UK, at birth (cord blood), during childhood, and adolescence (peripheral blood). We also analyzed the association between the lifetime occurrence of any seizures before age 13 with blood DNA methylation levels. We sought replication of the findings in the Generation R Study and explored causality using Mendelian randomization, i.e., using genetic variants as proxies. The results showed five CpG sites which were associated cross-sectionally with seizures either in childhood or adolescence (1–5% absolute methylation difference at pFDR < 0.05), although the evidence of replication in an independent study was weak. One of these sites was located in the BDNF gene, which is highly expressed in the brain, and showed high correspondence with brain methylation levels. The Mendelian randomization analyses suggested that seizures might be causal for changes in methylation rather than vice-versa. In conclusion, we show a suggestive link between seizures and blood DNA methylation while at the same time exploring the limitations of conducting such study.

scholarly journals Epigenome-wide association study of seizures in childhood and adolescence

2019 ◽  
Author(s):  
Doretta Caramaschi ◽  
Charlie Hatcher ◽  
Rosa H. Mulder ◽  
Janine F. Felix ◽  
Charlotte A. M. Cecil ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Genetic Variants ◽  
Cognitive Skills ◽  
Mendelian Randomization ◽  
Independent Study ◽  
Childhood And Adolescence ◽  
Parents And Children ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
The Brain

ABSTRACTThe occurrence of seizures in childhood is often associated with neurodevelopmental impairments and school underachievement. Common genetic variants associated with epilepsy have been identified and epigenetic mechanisms have also been suggested to play a role. In this study we analysed the association of genome-wide blood DNA methylation with the occurrence of seizures in ∼800 children from the Avon Longitudinal Study of Parents and Children, UK, at birth (cord blood), during childhood and adolescence (peripheral blood). We also analysed the association between the lifetime occurrence of any seizures before age 13 with blood DNA methylation levels. We sought replication of the findings in the Generation R Study and explored causality using Mendelian randomization, i.e. using genetic variants as proxies. The results showed five CpG sites which were associated cross-sectionally with seizures either in childhood or adolescence (1-5% absolute methylation difference at pFDR<0.05), although the evidence of replication in an independent study was weak. One of these sites was located in the BDNF gene, which is highly expressed in the brain, and showed high correspondence with brain methylation levels. The Mendelian randomization analyses suggested that seizures might be causal for changes in methylation rather than vice-versa. In addition, seizure-associated methylation changes could affect other outcomes such as growth, cognitive skills and educational attainment. In conclusion, we present a link between seizures and DNA methylation which suggests that DNA methylation changes might mediate some of the effects of seizures on growth and neurodevelopment.

scholarly journals Testing the principles of Mendelian randomization: Opportunities and complications on a genomewide scale

2017 ◽  
Author(s):  
M Taylor ◽  
KE Tansey ◽  
DA Lawlor ◽  
J Bowden ◽  
DM Evans ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Mendelian Randomization ◽  
Phenotypic Correlation ◽  
Causal Relationships ◽  
Biological Phenomena ◽  
Parents And Children ◽  
Multiple Variables ◽  
Using Data ◽  
Avon Longitudinal Study ◽  
Gwas Catalog

ABSTRACTBackgroundMendelian randomization (MR) uses genetic variants as instrumental variables to assess whether observational associations between exposures and disease reflect causal relationships. MR requires genetic variants to be independent of factors that confound observational associations.MethodsUsing data from the Avon Longitudinal Study of Parents and Children, associations within and between 121 phenotypes and 13,720 genetic variants (from the NHGRI-EBI GWAS catalog) were examined to assess the validity of MR assumptions.ResultsAmongst 7,260 pairwise comparisons between the 121 phenotypes, 2,188 (30%) provided evidence of association, where 363 were expected at the 5% level (observed:expected ratio=6.03; 95% CI: 5.42, 6.70; χ2=9682.29; d.f. =1, P≤1x10-50). Amongst 1,660,120 pairwise associations between phenotypes and genotypes, 86,748 (5.2%) gave evidence of association at the same threshold, where 83,006 were expected (observed:expected ratio=1.05; 95% CI: 1.04, 1.05; χ2=117.57; d.f. =1, P=2.15x10-27). Amongst 1,171,764 pairwise associations between the phenotypes and LD pruned independent genetic variants, 60,136 (5.1%) gave evidence of association, where 58,588 were expected (observed:expected ratio=1.03; 95% CI: 1.03, 1.08; χ2= 43.05; d.f. = 1, P=5.33x10-11).ConclusionThese results confirm previously observed patterns of phenotypic correlation. They also provide evidence of a substantially lower level of association between genetic variants and phenotypes, with residual inflation the likely product of indistinguishable real genetic association, multiple variables measuring the same biological phenomena, or pleiotropy. These results reflect the favorable properties of genetic instruments for estimating causal relationships, but confirm the need for functional information or analytical methods to account for pleiotropic events.

scholarly journals The molecular genetics of participation in the Avon Longitudinal Study of Parents and Children

2017 ◽  
Author(s):  
Amy E. Taylor ◽  
Hannah J. Jones ◽  
Hannah Sallis ◽  
Jack Euesden ◽  
Evie Stergiakouli ◽  
...  
Keyword(s):  
Longitudinal Study ◽  
Association Studies ◽  
Genetic Data ◽  
Polygenic Score ◽  
Parents And Children ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
Polygenic Scores ◽  
Avon Longitudinal Study

AbstractBackgroundIt is often assumed that selection (including participation and dropout) does not represent an important source of bias in genetic studies. However, there is little evidence to date on the effect of genetic factors on participation.MethodsUsing data on mothers (N=7,486) and children (N=7,508) from the Avon Longitudinal Study of Parents and Children, we 1) examined the association of polygenic risk scores for a range of socio-demographic, lifestyle characteristics and health conditions related to continued participation, 2) investigated whether associations of polygenic scores with body mass index (BMI; derived from self-reported weight and height) and self-reported smoking differed in the largest sample with genetic data and a sub-sample who participated in a recent follow-up and 3) determined the proportion of variation in participation explained by common genetic variants using genome-wide data.ResultsWe found evidence that polygenic scores for higher education, agreeableness and openness were associated with higher participation and polygenic scores for smoking initiation, higher BMI, neuroticism, schizophrenia, ADHD and depression were associated with lower participation. Associations between the polygenic score for education and self-reported smoking differed between the largest sample with genetic data (OR for ever smoking per SD increase in polygenic score:0.85, 95% CI:0.81,0.89) and sub-sample (OR:0.95, 95% CI:0.88,1.02). In genome-wide analysis, single nucleotide polymorphism based heritability explained 17-31% of variability in participation.ConclusionsGenetic association studies, including Mendelian randomization, can be biased by selection, including loss to follow-up. Genetic risk for dropout should be considered in all analyses of studies with selective participation.

scholarly journals A prospective study of time-dependent exposures to childhood adversity and DNA methylation in childhood and adolescence

2021 ◽  
Author(s):  
Alexandre A Lussier ◽  
Yiwen Zhu ◽  
Brooke J Smith ◽  
Janine Cerutti ◽  
Andrew Simpkin ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Childhood Adversity ◽  
Time Dependent ◽  
Childhood And Adolescence ◽  
Parents And Children ◽  
Genome Wide ◽  
Latent Effects ◽  
Underlying Mechanisms ◽  
A Prospective Study ◽  
The Relationship

Background: Childhood adversity influences long-term health, particularly if experienced during sensitive periods in development when physiological systems are more responsive to environmental influences. Although the underlying mechanisms remain unclear, prior studies suggest that DNA methylation (DNAm) may capture these time-dependent effects of childhood adversity. However, it remains unknown whether DNAm alterations persist into adolescence and how the timing of adversity might influence DNAm trajectories across development. Methods: We examined the relationship between time-dependent adversity and genome-wide DNAm measured at three waves from birth to adolescence using prospective data from the Avon Longitudinal Study of Parents and Children. We first assessed the relationship between the timing of exposure to seven types of adversity (measured 5-8 times between ages 0-11) and DNAm at age 15 using a structured life course modeling approach. We also characterized the persistence into adolescence of associations identified from age 7 DNAm, as well as the influence of adversity on DNAm trajectories from ages 0-15. Results: Adversity was associated with differences in age 15 DNAm at 24 loci (FDR<0.05). Most loci (19 of 24) were associated with adversity (i.e., physical/sexual abuse, one-adult households, caregiver abuse) that occurred between ages 3-5. Although no DNAm differences present at age 7 persisted into adolescence, we identified seven unique types of DNAm trajectories across development, which highlighted diverse effects of childhood adversity on DNAm. Conclusions: Our results suggest that childhood adversity, particularly between ages 3-5, can influence the trajectories of DNAm across development, exerting both immediate and latent effects on the epigenome.

scholarly journals Pre-adolescence DNA methylation is associated with BMI status change from pre- to post-adolescence

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Jiajing Wang ◽  
Hongmei Zhang ◽  
Faisal I. Rezwan ◽  
Caroline Relton ◽  
S. Hasan Arshad ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Status Change ◽  
Status Transition ◽  
Parents And Children ◽  
Genome Wide ◽  
Logistic Regressions ◽  
And Gender ◽  
Gender Specific ◽  
Avon Longitudinal Study ◽  
Independent Cohort

Abstract Background Previous studies have shown that DNA methylation (DNAm) is associated with body mass index (BMI). However, it is unknown whether DNAm at pre-adolescence is associated with BMI status transition from pre- to post-adolescence. In the Isle of Wight (IoW) birth cohort, genome-wide DNA methylation in whole blood was measured using Illumina Infinium Human450 and EPIC BeadChip arrays in n = 325 subjects, and pre- to post-adolescence BMI transition was classified into four groups: (1) normal to normal, (2) normal to overweight or obese, (3) overweight or obese to normal, and (4) persistent overweight or obese. We used recursive random forest to screen genome-wide Cytosine-phosphate-Guanine (CpG) sites with DNAm potentially associated with BMI transition for each gender, and the association of BMI status transition with DNAm at an earlier age was assessed via logistic regressions. To evaluate gender specificity, interactions between DNAm and gender were included in the model. Findings in the IoW cohort were further tested in an independent cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC). Results In total, 174 candidate CpGs were selected including CpGs from screening and CpGs previously associated correctionally with BMI in children and adults. Of these 174 CpGs, pre-adolescent DNAm of 38 CpGs in the IoW cohort was associated with BMI status transition, including 30 CpGs showing gender-specific associations. Thirteen CpGs showed consistent associations between the IoW cohort and the ALSPAC cohort (11 of which were gender-specific). Conclusion Pre-adolescence DNAm is associated with the change in BMI status from pre- to post-adolescence and such associations are likely to be gender-specific.

scholarly journals Association between Breastfeeding and DNA Methylation over the Life Course: Findings from the Avon Longitudinal Study of Parents and Children (ALSPAC)

Nutrients ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3309 ◽  
Author(s):  
Fernando Pires Hartwig ◽  
George Davey Smith ◽  
Andrew J. Simpkin ◽  
Cesar Gomes Victora ◽  
Caroline L. Relton ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Longitudinal Study ◽  
Negative Control ◽  
Childhood And Adolescence ◽  
Long Term Effects ◽  
Parents And Children ◽  
Short And Long Term ◽  
The Life Course ◽  
Avon Longitudinal Study

Background: Breastfeeding is associated with short and long-term health benefits. Long-term effects might be mediated by epigenetic mechanisms, yet the literature on this topic is scarce. We performed the first epigenome-wide association study of infant feeding, comparing breastfed vs non-breastfed children. We measured DNA methylation in children from peripheral blood collected in childhood (age 7 years, N = 640) and adolescence (age 15–17 years, N = 709) within the Accessible Resource for Integrated Epigenomic Studies (ARIES) project, part of the larger Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Cord blood methylation (N = 702) was used as a negative control for potential pre-natal residual confounding. Results: Two differentially-methylated sites presented directionally-consistent associations with breastfeeding at ages 7 and 15–17 years, but not at birth. Twelve differentially-methylated regions in relation to breastfeeding were identified, and for three of them there was evidence of directional concordance between ages 7 and 15–17 years, but not between birth and age 7 years. Conclusions: Our findings indicate that DNA methylation in childhood and adolescence may be predicted by breastfeeding, but further studies with sufficiently large samples for replication are required to identify robust associations.

scholarly journals Association between breastfeeding and DNA methylation over the life course: findings from the Avon Longitudinal Study of Parents and Children (ALSPAC)

2019 ◽  
Author(s):  
Fernando Pires Hartwig ◽  
George Davey Smith ◽  
Andrew J Simpkin ◽  
Cesar Gomes Victora ◽  
Caroline L. Relton ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Longitudinal Study ◽  
Negative Control ◽  
Childhood And Adolescence ◽  
Long Term Effects ◽  
Parents And Children ◽  
Short And Long Term ◽  
The Life Course ◽  
Avon Longitudinal Study

AbstractBackgroundBreastfeeding is associated with short and long-term health benefits. Long-term effects might be mediated by epigenetic mechanisms, yet a recent systematic review indicated that the literature on this topic is scarce. We performed the first epigenome-wide association study of infant feeding, comparing breastfed vs non-breastfed children. We measured DNA methylation in children from peripheral blood collected in childhood (age 7, N=640) and adolescence (age 15-17, N=709) within the Accessible Resource for Integrated Epigenomic Studies (ARIES) project, part of the larger Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Cord blood methylation (N=702) was used as a negative control for potential pre-natal residual confounding.ResultsTwo differentially-methylated sites presented directionally-consistent associations with breastfeeding at ages 7 and 15-17, but not at birth. Twelve differentially-methylated regions in relation to breastfeeding were identified, and for three of them there was evidence of directional concordance between ages 7 and 15-17, but not between birth and age 7.ConclusionsOur findings indicate that DNA methylation in childhood and adolescence may be predicted by breastfeeding, but further studies with sufficiently large samples for replication are required to identify robust associations.

scholarly journals Imprinted loci may be more widespread in humans than previously appreciated and enable limited assignment of parental allelic transmissions in unrelated individuals

2017 ◽  
Author(s):  
Gabriel Cuellar Partida ◽  
Charles Laurin ◽  
Susan M. Ring ◽  
Tom R. Gaunt ◽  
Caroline L. Relton ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Epigenetic Mechanism ◽  
Childhood And Adolescence ◽  
The Novel ◽  
Time Points ◽  
Parents And Children ◽  
Genome Wide ◽  
Parent Of Origin ◽  
Dominance Pattern ◽  
Genomic Regions

AbstractGenomic imprinting is an epigenetic mechanism leading to parent-of-origin dependent gene expression. So far, the precise number of imprinted genes in humans is uncertain. In this study, we leveraged genome-wide DNA methylation in whole blood measured longitudinally at 3 time points (birth, childhood and adolescence) and GWAS data in 740 Mother-Child duos from the Avon Longitudinal Study of Parents and Children (ALSPAC) to systematically identify 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 35 novel and 50 known imprinted regions (10−10< P <10−300). Among the novel loci, we observed signals near genes implicated in cardiovascular disease (PCSK9), and Alzheimer’s disease (CR1), amongst others. Most of the significant regions exhibited imprinting patterns consistent with uniparental expression, with the exception of twelve loci (including the IGF2, IGF1R, and IGF2R genes), where we observed a bipolar-dominance pattern. POEs were remarkably consistent across time points and were so strong at some loci that methylation levels enabled good discrimination of parental transmissions at these and surrounding genomic regions. The implication is that parental allelic transmissions could be modelled at many imprinted (and linked) loci and hence POEs detected in GWAS of unrelated individuals given a combination of genetic and methylation data. Our results indicate that modelling POEs on DNA methylation is effective to identify loci that may be affected by imprinting.

scholarly journals Developmental cannabidiol exposure increases anxiety and modifies genome-wide brain DNA methylation in adult female mice

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Nicole M. Wanner ◽  
Mathia Colwell ◽  
Chelsea Drown ◽  
Christopher Faulk
Keyword(s):  
Dna Methylation ◽  
Molecular Mechanisms ◽  
Coat Color ◽  
Brain Regions ◽  
Functional Enrichment ◽  
Positive Effects ◽  
Genome Wide ◽  
Nulliparous Female ◽  
The Impact ◽  
The Brain

Abstract Background Use of cannabidiol (CBD), the primary non-psychoactive compound found in cannabis, has recently risen dramatically, while relatively little is known about the underlying molecular mechanisms of its effects. Previous work indicates that direct CBD exposure strongly impacts the brain, with anxiolytic, antidepressant, antipsychotic, and other effects being observed in animal and human studies. The epigenome, particularly DNA methylation, is responsive to environmental input and can direct persistent patterns of gene regulation impacting phenotype. Epigenetic perturbation is particularly impactful during embryogenesis, when exogenous exposures can disrupt critical resetting of epigenetic marks and impart phenotypic effects lasting into adulthood. The impact of prenatal CBD exposure has not been evaluated; however, studies using the psychomimetic cannabinoid Δ9-tetrahydrocannabinol (THC) have identified detrimental effects on psychological outcomes in developmentally exposed adult offspring. We hypothesized that developmental CBD exposure would have similar negative effects on behavior mediated in part by the epigenome. Nulliparous female wild-type Agouti viable yellow (Avy) mice were exposed to 20 mg/kg CBD or vehicle daily from two weeks prior to mating through gestation and lactation. Coat color shifts, a readout of DNA methylation at the Agouti locus in this strain, were measured in F1 Avy/a offspring. Young adult F1 a/a offspring were then subjected to tests of working spatial memory and anxiety/compulsive behavior. Reduced-representation bisulfite sequencing was performed on both F0 and F1 cerebral cortex and F1 hippocampus to identify genome-wide changes in DNA methylation for direct and developmental exposure, respectively. Results F1 offspring exposed to CBD during development exhibited increased anxiety and improved memory behavior in a sex-specific manner. Further, while no significant coat color shift was observed in Avy/a offspring, thousands of differentially methylated loci (DMLs) were identified in both brain regions with functional enrichment for neurogenesis, substance use phenotypes, and other psychologically relevant terms. Conclusions These findings demonstrate for the first time that despite positive effects of direct exposure, developmental CBD is associated with mixed behavioral outcomes and perturbation of the brain epigenome.

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