Publications by authors named "Jenny van Dongen"

61 Publications

Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation.

Nat Genet 2021 Sep 6;53(9):1311-1321. Epub 2021 Sep 6.

Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.
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http://dx.doi.org/10.1038/s41588-021-00923-xDOI Listing
September 2021

Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression.

Nat Genet 2021 Sep 2;53(9):1300-1310. Epub 2021 Sep 2.

Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.

Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.
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http://dx.doi.org/10.1038/s41588-021-00913-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432599PMC
September 2021

Predicting Complex Traits and Exposures From Polygenic Scores and Blood and Buccal DNA Methylation Profiles.

Front Psychiatry 2021 29;12:688464. Epub 2021 Jul 29.

Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.

We examined the performance of methylation scores (MS) and polygenic scores (PGS) for birth weight, BMI, prenatal maternal smoking exposure, and smoking status to assess the extent to which MS could predict these traits and exposures over and above the PGS in a multi-omics prediction model. MS may be seen as the epigenetic equivalent of PGS, but because of their dynamic nature and sensitivity of non-genetic exposures may add to complex trait prediction independently of PGS. MS and PGS were calculated based on genotype data and DNA-methylation data in blood samples from adults (Illumina 450 K; = 2,431; mean age 35.6) and in buccal samples from children (Illumina EPIC; = 1,128; mean age 9.6) from the Netherlands Twin Register. Weights to construct the scores were obtained from results of large epigenome-wide association studies (EWASs) based on whole blood or cord blood methylation data and genome-wide association studies (GWASs). In adults, MSs in blood predicted independently from PGSs, and outperformed PGSs for BMI, prenatal maternal smoking, and smoking status, but not for birth weight. The largest amount of variance explained by the multi-omics prediction model was for current vs. never smoking (54.6%) of which 54.4% was captured by the MS. The two predictors captured 16% of former vs. never smoking initiation variance (MS:15.5%, PGS: 0.5%), 17.7% of prenatal maternal smoking variance (MS:16.9%, PGS: 0.8%), 11.9% of BMI variance (MS: 6.4%, PGS 5.5%), and 1.9% of birth weight variance (MS: 0.4%, PGS: 1.5%). In children, MSs in buccal samples did not show independent predictive value. The largest amount of variance explained by the two predictors was for prenatal maternal smoking (2.6%), where the MSs contributed 1.5%. These results demonstrate that blood DNA MS in adults explain substantial variance in current smoking, large variance in former smoking, prenatal smoking, and BMI, but not in birth weight. Buccal cell DNA methylation scores have lower predictive value, which could be due to different tissues in the EWAS discovery studies and target sample, as well as to different ages. This study illustrates the value of combining polygenic scores with information from methylation data for complex traits and exposure prediction.
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http://dx.doi.org/10.3389/fpsyt.2021.688464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357987PMC
July 2021

Examining the Vanishing Twin Hypothesis of Neural Tube Defects: Application of an Epigenetic Predictor for Monozygotic Twinning.

Twin Res Hum Genet 2021 Jun 26;24(3):155-159. Epub 2021 Jul 26.

Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

Strong associations between neural tube defects (NTDs) and monozygotic (MZ) twinning have long been noted, and it has been suggested that NTD cases who do not present as MZ twins may be the survivors of MZ twinning events. We have recently shown that MZ twins carry a strong, distinctive DNA methylation signature and have developed an algorithm based on genomewide DNA methylation array data that distinguishes MZ twins from dizygotic twins and other relatives at well above chance level. We have applied this algorithm to published methylation data from five fetal tissues (placental chorionic villi, kidney, spinal cord, brain and muscle) collected from spina bifida cases (n = 22), anencephalic cases (n = 15) and controls (n = 19). We see no difference in signature between cases and controls, providing no support for a common etiological role of MZ twinning in NTDs. The strong associations therefore continue to await elucidation.
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http://dx.doi.org/10.1017/thg.2021.25DOI Listing
June 2021

Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging.

Genome Biol 2021 06 29;22(1):194. Epub 2021 Jun 29.

Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.

Background: Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field.

Results: Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels.

Conclusion: This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.
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http://dx.doi.org/10.1186/s13059-021-02398-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243879PMC
June 2021

Genome-wide association study of circulating interleukin 6 levels identifies novel loci.

Hum Mol Genet 2021 04;30(5):393-409

Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK.

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
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http://dx.doi.org/10.1093/hmg/ddab023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098112PMC
April 2021

DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan.

Mol Psychiatry 2021 Jun 8;26(6):2148-2162. Epub 2021 Jan 8.

Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, 33520, Finland.

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.
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http://dx.doi.org/10.1038/s41380-020-00987-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263810PMC
June 2021

Genetics and Not Shared Environment Explains Familial Resemblance in Adult Metabolomics Data.

Twin Res Hum Genet 2020 06;23(3):145-155

Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.

Metabolites are small molecules involved in cellular metabolism where they act as reaction substrates or products. The term 'metabolomics' refers to the comprehensive study of these molecules. The concentrations of metabolites in biological tissues are under genetic control, but this is limited by environmental factors such as diet. In adult mono- and dizygotic twin pairs, we estimated the contribution of genetic and shared environmental influences on metabolite levels by structural equation modeling and tested whether the familial resemblance for metabolite levels is mainly explained by genetic or by environmental factors that are shared by family members. Metabolites were measured across three platforms: two based on proton nuclear magnetic resonance techniques and one employing mass spectrometry. These three platforms comprised 237 single metabolic traits of several chemical classes. For the three platforms, metabolites were assessed in 1407, 1037 and 1116 twin pairs, respectively. We carried out power calculations to establish what percentage of shared environmental variance could be detected given these sample sizes. Our study did not find evidence for a systematic contribution of shared environment, defined as the influence of growing up together in the same household, on metabolites assessed in adulthood. Significant heritability was observed for nearly all 237 metabolites; significant contribution of the shared environment was limited to 6 metabolites. The top quartile of the heritability distribution was populated by 5 of the 11 investigated chemical classes. In this quartile, metabolites of the class lipoprotein were significantly overrepresented, whereas metabolites of classes glycerophospholipids and glycerolipids were significantly underrepresented.
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http://dx.doi.org/10.1017/thg.2020.53DOI Listing
June 2020

Identification, Heritability, and Relation With Gene Expression of Novel DNA Methylation Loci for Blood Pressure.

Hypertension 2020 07 10;76(1):195-205. Epub 2020 Jun 10.

Department of Endocrinology (B.H.R.W., J.V.v.V.-O.), University Medical Center Groningen, University of Groningen, The Netherlands.

We conducted an epigenome-wide association study meta-analysis on blood pressure (BP) in 4820 individuals of European and African ancestry aged 14 to 69. Genome-wide DNA methylation data from peripheral leukocytes were obtained using the Infinium Human Methylation 450k BeadChip. The epigenome-wide association study meta-analysis identified 39 BP-related CpG sites with <1×10. In silico replication in the CHARGE consortium of 17 010 individuals validated 16 of these CpG sites. Out of the 16 CpG sites, 13 showed novel association with BP. Conversely, out of the 126 CpG sites identified as being associated (<1×10) with BP in the CHARGE consortium, 21 were replicated in the current study. Methylation levels of all the 34 CpG sites that were cross-validated by the current study and the CHARGE consortium were heritable and 6 showed association with gene expression. Furthermore, 9 CpG sites also showed association with BP with <0.05 and consistent direction of the effect in the meta-analysis of the Finnish Twin Cohort (199 twin pairs and 4 singletons; 61% monozygous) and the Netherlands Twin Register (266 twin pairs and 62 singletons; 84% monozygous). Bivariate quantitative genetic modeling of the twin data showed that a majority of the phenotypic correlations between methylation levels of these CpG sites and BP could be explained by shared unique environmental rather than genetic factors, with 100% of the correlations of systolic BP with cg19693031 () and cg00716257 () determined by environmental effects acting on both systolic BP and methylation levels.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.14973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295009PMC
July 2020

Urinary Amine and Organic Acid Metabolites Evaluated as Markers for Childhood Aggression: The ACTION Biomarker Study.

Front Psychiatry 2020 31;11:165. Epub 2020 Mar 31.

Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.

Biomarkers are of interest as potential diagnostic and predictive instruments in personalized medicine. We present the first urinary metabolomics biomarker study of childhood aggression. We aim to examine the association of urinary metabolites and neurotransmitter ratios involved in key metabolic and neurotransmitter pathways in a large cohort of twins ( = 1,347) and clinic-referred children ( = 183) with an average age of 9.7 years. This study is part of ACTION (Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies), in which we developed a standardized protocol for large-scale collection of urine samples in children. Our analytical design consisted of three phases: a discovery phase in twins scoring low or high on aggression ( = 783); a replication phase in twin pairs discordant for aggression ( = 378); and a validation phase in clinical cases and matched twin controls ( = 367). In the discovery phase, 6 biomarkers were significantly associated with childhood aggression, of which the association of O-phosphoserine (β = 0.36; = 0.09; = 0.004), and gamma-L-glutamyl-L-alanine (β = 0.32; = 0.09; = 0.01) remained significant after multiple testing. Although non-significant, the directions of effect were congruent between the discovery and replication analyses for six biomarkers and two neurotransmitter ratios and the concentrations of 6 amines differed between low and high aggressive twins. In the validation analyses, the top biomarkers and neurotransmitter ratios, with congruent directions of effect, showed no significant associations with childhood aggression. We find suggestive evidence for associations of childhood aggression with metabolic dysregulation of neurotransmission, oxidative stress, and energy metabolism. Although replication is required, our findings provide starting points to investigate causal and pleiotropic effects of these dysregulations on childhood aggression.
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http://dx.doi.org/10.3389/fpsyt.2020.00165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138132PMC
March 2020

Heritability estimates for 361 blood metabolites across 40 genome-wide association studies.

Nat Commun 2020 01 7;11(1):39. Epub 2020 Jan 7.

Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Metabolomics examines the small molecules involved in cellular metabolism. Approximately 50% of total phenotypic differences in metabolite levels is due to genetic variance, but heritability estimates differ across metabolite classes. We perform a review of all genome-wide association and (exome-) sequencing studies published between November 2008 and October 2018, and identify >800 class-specific metabolite loci associated with metabolite levels. In a twin-family cohort (N = 5117), these metabolite loci are leveraged to simultaneously estimate total heritability (h), and the proportion of heritability captured by known metabolite loci (h) for 309 lipids and 52 organic acids. Our study reveals significant differences in h among different classes of lipids and organic acids. Furthermore, phosphatidylcholines with a high degree of unsaturation have higher h estimates than phosphatidylcholines with low degrees of unsaturation. This study highlights the importance of common genetic variants for metabolite levels, and elucidates the genetic architecture of metabolite classes.
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http://dx.doi.org/10.1038/s41467-019-13770-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946682PMC
January 2020

Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group.

Mol Psychiatry 2019 Dec 6. Epub 2019 Dec 6.

University Medical Centre Hamburg-Eppendorf, House W34, 3.OG, Martinistr. 52, 20246, Hamburg, Germany.

DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)-three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.
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http://dx.doi.org/10.1038/s41380-019-0605-zDOI Listing
December 2019

DNA Methylation Signatures of Breastfeeding in Buccal Cells Collected in Mid-Childhood.

Nutrients 2019 Nov 17;11(11). Epub 2019 Nov 17.

Department of Biological Psychology, Vrije Universiteit Amsterdam, 1081 BT Amsterdam, The Netherlands.

Breastfeeding has long-term benefits for children that may be mediated via the epigenome. This pathway has been hypothesized, but the number of empirical studies in humans is small and mostly done by using peripheral blood as the DNA source. We performed an epigenome-wide association study (EWAS) in buccal cells collected around age nine (mean = 9.5) from 1006 twins recruited by the Netherlands Twin Register (NTR). An age-stratified analysis examined if effects attenuate with age (median split at 10 years; = 517, mean age = 7.9; = 489, mean age = 11.2). We performed replication analyses in two independent cohorts from the NTR (buccal cells) and the Avon Longitudinal Study of Parents and Children (ALSPAC) (peripheral blood), and we tested loci previously associated with breastfeeding in epigenetic studies. Genome-wide DNA methylation was assessed with the Illumina Infinium MethylationEPIC BeadChip (Illumina, San Diego, CA, USA) in the NTR and with the HumanMethylation450 Bead Chip in the ALSPAC. The duration of breastfeeding was dichotomized ('never' vs. 'ever'). In the total sample, no robustly associated epigenome-wide significant CpGs were identified (α = 6.34 × 10). In the sub-group of children younger than 10 years, four significant CpGs were associated with breastfeeding after adjusting for child and maternal characteristics. In children older than 10 years, methylation differences at these CpGs were smaller and non-significant. The findings did not replicate in the NTR sample ( = 98; mean age = 7.5 years), and no nearby sites were associated with breastfeeding in the ALSPAC study ( = 938; mean age = 7.4). Of the CpG sites previously reported in the literature, three were associated with breastfeeding in children younger than 10 years, thus showing that these CpGs are associated with breastfeeding in buccal and blood cells. Our study is the first to show that breastfeeding is associated with epigenetic variation in buccal cells in children. Further studies are needed to investigate if methylation differences at these loci are caused by breastfeeding or by other unmeasured confounders, as well as what mechanism drives changes in associations with age.
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http://dx.doi.org/10.3390/nu11112804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893543PMC
November 2019

Evaluation of commonly used analysis strategies for epigenome- and transcriptome-wide association studies through replication of large-scale population studies.

Genome Biol 2019 11 14;20(1):235. Epub 2019 Nov 14.

Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.

Background: A large number of analysis strategies are available for DNA methylation (DNAm) array and RNA-seq datasets, but it is unclear which strategies are best to use. We compare commonly used strategies and report how they influence results in large cohort studies.

Results: We tested the associations of DNAm and RNA expression with age, BMI, and smoking in four different cohorts (n = ~ 2900). By comparing strategies against the base model on the number and percentage of replicated CpGs for DNAm analyses or genes for RNA-seq analyses in a leave-one-out cohort replication approach, we find the choice of the normalization method and statistical test does not strongly influence the results for DNAm array data. However, adjusting for cell counts or hidden confounders substantially decreases the number of replicated CpGs for age and increases the number of replicated CpGs for BMI and smoking. For RNA-seq data, the choice of the normalization method, gene expression inclusion threshold, and statistical test does not strongly influence the results. Including five principal components or excluding correction of technical covariates or cell counts decreases the number of replicated genes.

Conclusions: Results were not influenced by the normalization method or statistical test. However, the correction method for cell counts, technical covariates, principal components, and/or hidden confounders does influence the results.
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http://dx.doi.org/10.1186/s13059-019-1878-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857161PMC
November 2019

The Netherlands Twin Register: Longitudinal Research Based on Twin and Twin-Family Designs.

Twin Res Hum Genet 2019 12 31;22(6):623-636. Epub 2019 Oct 31.

Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.

The Netherlands Twin Register (NTR) is a national register in which twins, multiples and their parents, siblings, spouses and other family members participate. Here we describe the NTR resources that were created from more than 30 years of data collections; the development and maintenance of the newly developed database systems, and the possibilities these resources create for future research. Since the early 1980s, the NTR has enrolled around 120,000 twins and a roughly equal number of their relatives. The majority of twin families have participated in survey studies, and subsamples took part in biomaterial collection (e.g., DNA) and dedicated projects, for example, for neuropsychological, biomarker and behavioral traits. The recruitment into the NTR is all inclusive without any restrictions on enrollment. These resources - the longitudinal phenotyping, the extended pedigree structures and the multigeneration genotyping - allow for future twin-family research that will contribute to gene discovery, causality modeling, and studies of genetic and cultural inheritance.
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http://dx.doi.org/10.1017/thg.2019.93DOI Listing
December 2019

A characterization of cis- and trans-heritability of RNA-Seq-based gene expression.

Eur J Hum Genet 2020 02 26;28(2):253-263. Epub 2019 Sep 26.

Department of Biological Psychology, Amsterdam Public Health research institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Insights into individual differences in gene expression and its heritability (h) can help in understanding pathways from DNA to phenotype. We estimated the heritability of gene expression of 52,844 genes measured in whole blood in the largest twin RNA-Seq sample to date (1497 individuals including 459 monozygotic twin pairs and 150 dizygotic twin pairs) from classical twin modeling and identity-by-state-based approaches. We estimated for each gene h, composed of cis-heritability (h, the variance explained by single nucleotide polymorphisms in the cis-window of the gene), and trans-heritability (h, the residual variance explained by all other genome-wide variants). Mean h was 0.26, which was significantly higher than heritability estimates earlier found in a microarray-based study using largely overlapping (>60%) RNA samples (mean h = 0.14, p = 6.15 × 10). Mean h was 0.06 and strongly correlated with beta of the top cis expression quantitative loci (eQTL, ρ = 0.76, p < 10) and with estimates from earlier RNA-Seq-based studies. Mean h was 0.20 and correlated with the beta of the corresponding trans-eQTL (ρ = 0.04, p < 1.89 × 10) and was significantly higher for genes involved in cytokine-cytokine interactions (p = 4.22 × 10), many other immune system pathways, and genes identified in genome-wide association studies for various traits including behavioral disorders and cancer. This study provides a thorough characterization of cis- and trans-h estimates of gene expression, which is of value for interpretation of GWAS and gene expression studies.
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http://dx.doi.org/10.1038/s41431-019-0511-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974598PMC
February 2020

Validated inference of smoking habits from blood with a finite DNA methylation marker set.

Eur J Epidemiol 2019 Nov 7;34(11):1055-1074. Epub 2019 Sep 7.

Department of Genetic Identification, Erasmus MC University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.

Inferring a person's smoking habit and history from blood is relevant for complementing or replacing self-reports in epidemiological and public health research, and for forensic applications. However, a finite DNA methylation marker set and a validated statistical model based on a large dataset are not yet available. Employing 14 epigenome-wide association studies for marker discovery, and using data from six population-based cohorts (N = 3764) for model building, we identified 13 CpGs most suitable for inferring smoking versus non-smoking status from blood with a cumulative Area Under the Curve (AUC) of 0.901. Internal fivefold cross-validation yielded an average AUC of 0.897 ± 0.137, while external model validation in an independent population-based cohort (N = 1608) achieved an AUC of 0.911. These 13 CpGs also provided accurate inference of current (average AUC 0.925 ± 0.021, AUC0.914), former (0.766 ± 0.023, 0.699) and never smoking (0.830 ± 0.019, 0.781) status, allowed inferring pack-years in current smokers (10 pack-years 0.800 ± 0.068, 0.796; 15 pack-years 0.767 ± 0.102, 0.752) and inferring smoking cessation time in former smokers (5 years 0.774 ± 0.024, 0.760; 10 years 0.766 ± 0.033, 0.764; 15 years 0.767 ± 0.020, 0.754). Model application to children revealed highly accurate inference of the true non-smoking status (6 years of age: accuracy 0.994, N = 355; 10 years: 0.994, N = 309), suggesting prenatal and passive smoking exposure having no impact on model applications in adults. The finite set of DNA methylation markers allow accurate inference of smoking habit, with comparable accuracy as plasma cotinine use, and smoking history from blood, which we envision becoming useful in epidemiology and public health research, and in medical and forensic applications.
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http://dx.doi.org/10.1007/s10654-019-00555-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861351PMC
November 2019

Pre- and Perinatal Characteristics Associated with Apgar Scores in a Review and in a New Study of Dutch Twins.

Twin Res Hum Genet 2019 06 14;22(3):164-176. Epub 2019 Jun 14.

Department of Biological Psychology,Vrije Universiteit Amsterdam,Amsterdam,the Netherlands.

A literature review was carried out to identify pre and perinatal characteristics associated with variation in Apgar scores in population-based studies. The parameters identified in the literature search were included in the classical twin design study to estimate effects of pre and perinatal factors shared and nonshared by twins and to test for a contribution of genetic factors in 1- and 5-min Apgar scores in a large sample of Dutch monozygotic (MZ) and dizygotic (DZ) twins. The sample included MZ and DZ twins (N = 5181 pairs) recruited by the Netherlands Twin Register shortly after birth, with data on prenatal characteristics and Apgar scores at first and/or fifth minutes. The ordinal regression and structural equation modeling were used to analyze the effects of characteristics identified in the literature review and to estimate genetic and nongenetic variance components. The literature review identified 63 papers. Consistent with the review, we observed statistically significant effects of birth order, zygosity and gestational age (GA) for 1- and 5-min Apgar scores of both twins. Apgar scores are higher in first-born versus second-born twins and DZ first-born versus MZ first-born twins. Birth weight had an effect on the 5-min Apgar of the first born. Fetal presentation and mode of delivery had different effects on Apgar scores of first- and second-born twins. Parental characteristics and chorionicity did not have significant main effects on Apgar scores. The MZ twins' Apgar correlations equaled the DZ Apgar correlations. Our analyses suggest that individual differences in 1- and 5-min Apgar scores are attributable to shared and nonshared pre and perinatal factors, but not to genotypic factors of the newborns. The main predictors of Apgar scores are birth order, zygosity, GA, birth weight, mode of delivery and fetal presentation.
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http://dx.doi.org/10.1017/thg.2019.24DOI Listing
June 2019

An integrative cross-omics analysis of DNA methylation sites of glucose and insulin homeostasis.

Nat Commun 2019 06 13;10(1):2581. Epub 2019 Jun 13.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, 48109, USA.

Despite existing reports on differential DNA methylation in type 2 diabetes (T2D) and obesity, our understanding of its functional relevance remains limited. Here we show the effect of differential methylation in the early phases of T2D pathology by a blood-based epigenome-wide association study of 4808 non-diabetic Europeans in the discovery phase and 11,750 individuals in the replication. We identify CpGs in LETM1, RBM20, IRS2, MAN2A2 and the 1q25.3 region associated with fasting insulin, and in FCRL6, SLAMF1, APOBEC3H and the 15q26.1 region with fasting glucose. In silico cross-omics analyses highlight the role of differential methylation in the crosstalk between the adaptive immune system and glucose homeostasis. The differential methylation explains at least 16.9% of the association between obesity and insulin. Our study sheds light on the biological interactions between genetic variants driving differential methylation and gene expression in the early pathogenesis of T2D.
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http://dx.doi.org/10.1038/s41467-019-10487-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565679PMC
June 2019

eFORGE v2.0: updated analysis of cell type-specific signal in epigenomic data.

Bioinformatics 2019 11;35(22):4767-4769

Medical Genomics Group, UCL Cancer Institute, University College London, London WC1E 6BT, UK.

Summary: The Illumina Infinium EPIC BeadChip is a new high-throughput array for DNA methylation analysis, extending the earlier 450k array by over 400 000 new sites. Previously, a method named eFORGE was developed to provide insights into cell type-specific and cell-composition effects for 450k data. Here, we present a significantly updated and improved version of eFORGE that can analyze both EPIC and 450k array data. New features include analysis of chromatin states, transcription factor motifs and DNase I footprints, providing tools for epigenome-wide association study interpretation and epigenome editing.

Availability And Implementation: eFORGE v2.0 is implemented as a web tool available from https://eforge.altiusinstitute.org and https://eforge-tf.altiusinstitute.org/.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btz456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853678PMC
November 2019

Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight.

Nat Commun 2019 04 23;10(1):1893. Epub 2019 Apr 23.

Department of Biological Psychology, Netherlands Twin Register, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (P < 1.06 x 10). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10) and BMI in pregnancy (3/914, p = 1.13x10), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.
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http://dx.doi.org/10.1038/s41467-019-09671-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478731PMC
April 2019

Epigenome-wide Association Study of Attention-Deficit/Hyperactivity Disorder Symptoms in Adults.

Biol Psychiatry 2019 10 1;86(8):599-607. Epub 2019 Mar 1.

Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam.

Background: Previous studies have reported associations between attention-deficit/hyperactivity disorder symptoms and DNA methylation in children. We report the first epigenome-wide association study meta-analysis of adult attention-deficit/hyperactivity disorder symptoms, based on peripheral blood DNA methylation (Infinium HumanMethylation450K array) in three population-based adult cohorts.

Methods: An epigenome-wide association study was performed in the Netherlands Twin Register (N = 2258, mean age 37 years), Dunedin Multidisciplinary Health and Development Study (N = 800, age 38 years), and Environmental Risk Longitudinal Twin Study (N = 1631, age 18 years), and results were combined through meta-analysis (total sample size N = 4689). Region-based analyses accounting for the correlation between nearby methylation sites were also performed.

Results: One epigenome-wide significant differentially methylated position was detected in the Dunedin study, but meta-analysis did not detect differentially methylated positions that were robustly associated across cohorts. In region-based analyses, six significant differentially methylation regions (DMRs) were identified in the Netherlands Twin Register, 19 in the Dunedin study, and none in the Environmental Risk Longitudinal Twin Study. Of these DMRs, 92% were associated with methylation quantitative trait loci, and 68% showed moderate to large blood-brain correlations for DNA methylation levels. DMRs included six nonoverlapping DMRs (three in the Netherlands Twin Register, three in the Dunedin study) in the major histocompatibility complex, which were associated with expression of genes in the major histocompatibility complex, including C4A and C4B, previously implicated in schizophrenia.

Conclusions: Our findings point at new candidate loci involved in immune and neuronal functions that await further replication. Our work also illustrates the need for further research to examine to what extent epigenetic associations with psychiatric traits depend on characteristics such as age, comorbidities, exposures, and genetic background.
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http://dx.doi.org/10.1016/j.biopsych.2019.02.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717697PMC
October 2019

Multivariate genome-wide analyses of the well-being spectrum.

Nat Genet 2019 03 14;51(3):445-451. Epub 2019 Jan 14.

Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.

We introduce two novel methods for multivariate genome-wide-association meta-analysis (GWAMA) of related traits that correct for sample overlap. A broad range of simulation scenarios supports the added value of our multivariate methods relative to univariate GWAMA. We applied the novel methods to life satisfaction, positive affect, neuroticism, and depressive symptoms, collectively referred to as the well-being spectrum (N = 2,370,390), and found 304 significant independent signals. Our multivariate approaches resulted in a 26% increase in the number of independent signals relative to the four univariate GWAMAs and in an ~57% increase in the predictive power of polygenic risk scores. Supporting transcriptome- and methylome-wide analyses (TWAS and MWAS, respectively) uncovered an additional 17 and 75 independent loci, respectively. Bioinformatic analyses, based on gene expression in brain tissues and cells, showed that genes differentially expressed in the subiculum and GABAergic interneurons are enriched in their effect on the well-being spectrum.
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http://dx.doi.org/10.1038/s41588-018-0320-8DOI Listing
March 2019

DNA methylation signatures of educational attainment.

NPJ Sci Learn 2018 23;3. Epub 2018 Mar 23.

1Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Educational attainment is a key behavioural measure in studies of cognitive and physical health, and socioeconomic status. We measured DNA methylation at 410,746 CpGs ( = 4152) and identified 58 CpGs associated with educational attainment at loci characterized by pleiotropic functions shared with neuronal, immune and developmental processes. Associations overlapped with those for smoking behaviour, but remained after accounting for smoking at many CpGs: Effect sizes were on average 28% smaller and genome-wide significant at 11 CpGs after adjusting for smoking and were 62% smaller in never smokers. We examined sources and biological implications of education-related methylation differences, demonstrating correlations with maternal prenatal folate, smoking and air pollution signatures, and associations with gene expression in cis, dynamic methylation in foetal brain, and correlations between blood and brain. Our findings show that the methylome of lower-educated people resembles that of smokers beyond effects of their own smoking behaviour and shows traces of various other exposures.
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http://dx.doi.org/10.1038/s41539-018-0020-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220239PMC
March 2018

Epigenome-wide association study of serum cotinine in current smokers reveals novel genetically driven loci.

Clin Epigenetics 2019 01 5;11(1). Epub 2019 Jan 5.

Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.

Background: DNA methylation alteration extensively associates with smoking and is a plausible link between smoking and adverse health. We examined the association between epigenome-wide DNA methylation and serum cotinine levels as a proxy of nicotine exposure and smoking quantity, assessed the role of SNPs in these associations, and evaluated molecular mediation by methylation in a sample of biochemically verified current smokers (N = 310).

Results: DNA methylation at 50 CpG sites was associated (FDR < 0.05) with cotinine levels, 17 of which are novel associations. As cotinine levels are influenced not only by nicotine intake but also by CYP2A6-mediated nicotine metabolism rate, we performed secondary analyses adjusting for genetic risk score of nicotine metabolism rate and identified five additional novel associations. We further assessed the potential role of genetic variants in the detected association between methylation and cotinine levels observing 124 cis and 3898 trans methylation quantitative trait loci (meQTLs). Nineteen of these SNPs were also associated with cotinine levels (FDR < 0.05). Further, at seven CpG sites, we observed a trend (P < 0.05) that altered DNA methylation mediates the effect of SNPs on nicotine exposure rather than a direct consequence of smoking. Finally, we performed replication of our findings in two independent cohorts of biochemically verified smokers (N = 450 and N = 79).

Conclusions: Using cotinine, a biomarker of nicotine exposure, we replicated and extended identification of novel epigenetic associations in smoking-related genes. We also demonstrated that DNA methylation in some of the identified loci is driven by the underlying genotype and may mediate the causal effect of genotype on cotinine levels.
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http://dx.doi.org/10.1186/s13148-018-0606-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321663PMC
January 2019

DNA methylation and associated gene expression in blood prior to lung cancer diagnosis in the Norwegian Women and Cancer cohort.

Sci Rep 2018 11 13;8(1):16714. Epub 2018 Nov 13.

MRC/PHE Centre for Environmental Health, Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom.

The majority of lung cancer is caused by tobacco smoking, and lung cancer-relevant epigenetic markers have been identified in relation to smoking exposure. Still, smoking-related markers appear to mediate little of the effect of smoking on lung cancer. Thus in order to identify disease-relevant markers and enhance our understanding of pathways, a wide search is warranted. Through an epigenome-wide search within a case-control study (131 cases, 129 controls) nested in a Norwegian prospective cohort of women, we found 25 CpG sites associated with lung cancer. Twenty-three were classified as associated with smoking (LC-AwS), and two were classified as unassociated with smoking (LC-non-AwS), as they remained associated with lung cancer after stringent adjustment for smoking exposure using the comprehensive smoking index (CSI): cg10151248 (PC, CSI-adjusted odds ratio (OR) = 0.34 [0.23-0.52] per standard deviation change in methylation) and cg13482620 (B3GNTL1, CSI-adjusted OR = 0.33 [0.22-0.50]). Analysis among never smokers and a cohort of smoking-discordant twins confirmed the classification of the two LC-non-AwS CpG sites. Gene expression profiles demonstrated that the LC-AwS CpG sites had different enriched pathways than LC-non-AwS sites. In conclusion, using blood-derived DNA methylation and gene expression profiles from a prospective lung cancer case-control study in women, we identified 25 CpG lung cancer markers prior to diagnosis, two of which were LC-non-AwS markers and related to distinct pathways.
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http://dx.doi.org/10.1038/s41598-018-34334-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233189PMC
November 2018

Genome-wide analysis of DNA methylation in buccal cells: a study of monozygotic twins and mQTLs.

Epigenetics Chromatin 2018 09 25;11(1):54. Epub 2018 Sep 25.

Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Van Der Boechorststraat 1, 1081BT, Amsterdam, The Netherlands.

Background: DNA methylation arrays are widely used in epigenome-wide association studies and methylation quantitative trait locus (mQTL) studies. Here, we performed the first genome-wide analysis of monozygotic (MZ) twin correlations and mQTLs on data obtained with the Illumina MethylationEPIC BeadChip (EPIC array) and compared the performance of the EPIC array to the Illumina HumanMethylation450 BeadChip (HM450 array) for buccal-derived DNA.

Results: Good-quality EPIC data were obtained for 102 buccal-derived DNA samples from 49 MZ twin pairs (mean age = 7.5 years, range = 1-10). Differences between MZ twins in the cellular content of buccal swabs were a major driver for differences in their DNA methylation profiles, highlighting the importance to adjust for cellular composition in DNA methylation studies of buccal-derived DNA. After adjusting for cellular composition, the genome-wide mean correlation (r) between MZ twins was 0.21 for the EPIC array, and cis mQTL analysis in 84 twins identified 1,296,323 significant associations (FDR 5%), encompassing 33,749 methylation sites and 616,029 genetic variants. MZ twin correlations were slightly larger (p < 2.2 × 10) for novel EPIC probes (N = 383,066, mean r = 0.22) compared to probes that are also present on HM450 (N = 406,822, mean r = 0.20). In line with this observation, a larger percentage of novel EPIC probes was associated with genetic variants (novel EPIC probes with significant mQTL 4.7%, HM450 probes with mQTL 3.9%, p < 2.2 × 10). Methylation sites with a large MZ correlation and sites associated with mQTLs were most strongly enriched in epithelial cell DNase I hypersensitive sites (DHSs), enhancers, and histone mark H3K4me3.

Conclusions: We conclude that the contribution of familial factors to individual differences in DNA methylation and the effect of mQTLs are larger for novel EPIC probes, especially those within regulatory elements connected to active regions specific to the investigated tissue.
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http://dx.doi.org/10.1186/s13072-018-0225-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156977PMC
September 2018

DNA methylation age is associated with an altered hemostatic profile in a multiethnic meta-analysis.

Blood 2018 10 24;132(17):1842-1850. Epub 2018 Jul 24.

Cardiovascular Health Research Unit, University of Washington, Seattle, WA.

Many hemostatic factors are associated with age and age-related diseases; however, much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we performed European and African ancestry-specific meta-analyses which were then combined via a random effects meta-analysis. For all other measures we could not estimate ancestry-specific effects and used a single fixed effects meta-analysis. We found that 1-year higher extrinsic epigenetic age as compared with chronological age was associated with higher fibrinogen (0.004 g/L/y; 95% confidence interval, 0.001-0.007; = .01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL/y; 95% confidence interval, 0.07-0.20; = 6.6 10) concentrations, as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms, we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene () and the 3 fibrinogen subunit-encoding genes (, , and ) in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a procoagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.
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http://dx.doi.org/10.1182/blood-2018-02-831347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202911PMC
October 2018

Childhood aggression and the co-occurrence of behavioural and emotional problems: results across ages 3-16 years from multiple raters in six cohorts in the EU-ACTION project.

Eur Child Adolesc Psychiatry 2018 Sep 29;27(9):1105-1121. Epub 2018 May 29.

Netherlands Twin Register, Department of Biological Psychology, Vrije Universiteit Amsterdam, van der Boechorststraat 1, 1081 BT, Amsterdam, The Netherlands.

Childhood aggression and its resulting consequences inflict a huge burden on affected children, their relatives, teachers, peers and society as a whole. Aggression during childhood rarely occurs in isolation and is correlated with other symptoms of childhood psychopathology. In this paper, we aim to describe and improve the understanding of the co-occurrence of aggression with other forms of childhood psychopathology. We focus on the co-occurrence of aggression and other childhood behavioural and emotional problems, including other externalising problems, attention problems and anxiety-depression. The data were brought together within the EU-ACTION (Aggression in Children: unravelling gene-environment interplay to inform Treatment and InterventiON strategies) project. We analysed the co-occurrence of aggression and other childhood behavioural and emotional problems as a function of the child's age (ages 3 through 16 years), gender, the person rating the behaviour (father, mother or self) and assessment instrument. The data came from six large population-based European cohort studies from the Netherlands (2x), the UK, Finland and Sweden (2x). Multiple assessment instruments, including the Child Behaviour Checklist (CBCL), the Strengths and Difficulties Questionnaire (SDQ) and Multidimensional Peer Nomination Inventory (MPNI), were used. There was a good representation of boys and girls in each age category, with data for 30,523 3- to 4-year-olds (49.5% boys), 20,958 5- to 6-year-olds (49.6% boys), 18,291 7- to 8-year-olds (49.0% boys), 27,218 9- to 10-year-olds (49.4% boys), 18,543 12- to 13-year-olds (48.9% boys) and 10,088 15- to 16-year-olds (46.6% boys). We replicated the well-established gender differences in average aggression scores at most ages for parental ratings. The gender differences decreased with age and were not present for self-reports. Aggression co-occurred with the majority of other behavioural and social problems, from both externalising and internalising domains. At each age, the co-occurrence was particularly prevalent for aggression and oppositional and ADHD-related problems, with correlations of around 0.5 in general. Aggression also showed substantial associations with anxiety-depression and other internalizing symptoms (correlations around 0.4). Co-occurrence for self-reported problems was somewhat higher than for parental reports, but we found neither rater differences, nor differences across assessment instruments in co-occurrence patterns. There were large similarities in co-occurrence patterns across the different European countries. Finally, co-occurrence was generally stable across age and sex, and if any change was observed, it indicated stronger correlations when children grew older. We present an online tool to visualise these associations as a function of rater, gender, instrument and cohort. In addition, we present a description of the full EU-ACTION projects, its first results and the future perspectives.
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http://dx.doi.org/10.1007/s00787-018-1169-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133086PMC
September 2018
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