@inbook {372, title = {Chapter 32 - Twins and omics: the role of twin studies in multi-omics}, booktitle = {Twin Research for Everyone}, year = {2022}, pages = {547-584}, publisher = {Academic Press}, organization = {Academic Press}, abstract = {

Genomics, transcriptomics, proteomics, and metabolomics are the four main omics domains, referring to high-throughput studies of the genome (DNA), transcriptome (RNA), proteome (proteins), and metabolome (metabolites). Together, these omics domains describe how proteins are formed by the transcription and translation of genetic information and how cells, tissues, and organisms\’ function at the molecular level. Other omics layers reflect regulatory and modulatory processes or exposures to the environment. Twin designs offer powerful analytical tools to study variation in omics data and the influence of omics on phenotypes and phenotypic development. Here, we review and discuss the contribution of twin studies to omics and argue that twin research plays a valuable role in omics research.

}, keywords = {epigenome, Genome, Metabolome, Omics, Transcriptome, Twin design, twins}, isbn = {978-0-12-821514-2}, doi = {https://doi.org/10.1016/B978-0-12-821514-2.00029-5}, url = {https://www.sciencedirect.com/science/article/pii/B9780128215142000295}, author = {Fiona A. Hagenbeek and Jenny van Dongen and Ren{\`e} Pool and Dorret I. Boomsma}, editor = {Adam Tarnoki and David Tarnoki and Jennifer Harris and Nancy Segal} } @article {236, title = {Adult aggressive behavior in humans and biomarkers: a focus on lipids and methylation}, journal = {Journal of Pediatric and Neonatal Individualized Medicine (JPNIM)}, volume = {7}, year = {2018}, month = {04/2018}, abstract = {

Aggression shows large variation between individuals, with about 50\% explained by genetic factors. Biomarkers related to aggression have been reported for lipid metabolism and for epigenetic marks. Methylation and blood lipid levels are not independent and differential methylation can be a consequence of variation in blood lipid levels. We hypothesized that the methylation level of such loci in blood can inform us if aggression is associated with long-term exposure to lipid levels. If this is the case, we expect to find that loci where methylation levels are influenced by lipid levels to show differential methylation in aggressive individuals. Such loci might complement classic lipid level measures as a biomarker for lipid-related disturbances in aggression. As a first step, we examined the association of lipid levels and related biomarkers with aggression in a large adult population cohort (N = 5,588) and in 31 monozygotic (MZ) twin pairs who were discordant for aggression, as well as 12 extremely discordant MZ pairs. Biomarkers were not significantly associated with aggression in the population cohort. In the discordant MZ pairs we identified significant within-pair differences for glucose and marginally significant differences for lipids and cytokines, with the more aggressive twin showing lower levels of glucose and low density lipoprotein cholesterol and higher levels of fibrinogen, C-reactive protein and interleukin-6. The analysis of epigenetic data in the MZ pairs discordant for aggression did not show enrichment for lipid cytosine guanine dinucleotides (CpGs) and we observed no enrichment of lipid CpGs in an epigenome-wide association study of aggression in the population cohort. These results did not support the hypothesis that lipid CpGs show differential methylation in adult aggression. A next step will be to examine the role of biomarkers in aggression across the lifespan, including childhood, and to explore a more holistic biomarker approach, such as offered by metabolomics.

PDF Available here

}, keywords = {adult aggression, biomarkers, discordant twin pairs, epigenetics, lipids}, doi = {10.7363/070204}, url = {http://www.jpnim.com/index.php/jpnim/article/view/070204}, author = {Fiona Hagenbeek and Jenny van Dongen and Kluft, Cornelis and Thomas Hankemeier and Lannie Ligthart and Gonneke Willemsen and de Geus, Eco J.C. and Vink, Jacqueline M. and Meike Bartels and Dorret I. Boomsma} } @article {230, title = {Childhood aggression and the co-occurrence of behavioural and emotional problems: results across ages 3{\textendash}16~years from multiple raters in six cohorts in the EU-ACTION project}, journal = {European Child {\&} Adolescent Psychiatry}, year = {2018}, month = {May}, abstract = {

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\&$\#$39;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.

Related interactive tool here.

}, issn = {1435-165X}, doi = {10.1007/s00787-018-1169-1}, url = {https://doi.org/10.1007/s00787-018-1169-1}, author = {Meike Bartels and Anne Hendriks and Matteo Mauri and Eva Krapohl and Alyce Whipp and Koen Bolhuis and Conde, Lucia Colodro and Luningham, Justin and Fung Ip, Hill and Fiona Hagenbeek and Roetman, Peter and Gatej, Raluca and Lamers, Audri and Michel G. Nivard and Jenny van Dongen and Lu, Yi and Christel Middeldorp and van Beijsterveldt, Toos and Vermeiren, Robert and Thomas Hankemeier and Kluft, Cees and Medland, Sarah and Lundstr{\"o}m, Sebastian and Richard J. Rose and Pulkkinen, Lea and Vuoksimaa, Eero and Korhonen, Tellervo and Martin, Nicholas G. and Gitta Lubke and Catrin Finkenauer and Vassilios Fanos and Henning Tiemeier and Lichtenstein, Paul and Robert Plomin and Kaprio, Jaakko and Dorret I. Boomsma} } @article {227, title = {DNA methylation signatures of educational attainment}, volume = {3}, year = {2018}, month = {2018/03/23}, pages = {7}, abstract = {

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 (N\ =\ 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.

}, isbn = {2056-7936}, url = {https://doi.org/10.1038/s41539-018-0020-2}, author = {Jenny van Dongen and Bonder, Marc Jan and Dekkers, Koen F. and Michel G. Nivard and van Iterson, Maarten and Gonneke Willemsen and Beekman, Marian and van der Spek, Ashley and Joyce B.J. Van Meurs and Franke, Lude and Bastiaan T. Heijmans and van Duijn, Cornelia M. and Slagboom, P. Eline and Dorret I. Boomsma} } @article {235, title = {Genome-wide analysis of DNA methylation in buccal cells: a study of monozygotic twins and mQTLs}, journal = {Epigenetics {\&} Chromatin}, volume = {11}, year = {2018}, month = {Sep}, pages = {54}, abstract = {

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.

}, issn = {1756-8935}, doi = {10.1186/s13072-018-0225-x}, url = {https://doi.org/10.1186/s13072-018-0225-x}, author = {Jenny van Dongen and Ehli, Erik A. and Jansen, Rick and Catharina E. M. van Beijsterveldt and Gonneke Willemsen and Hottenga, Jouke J. and Kallsen, Noah A. and Peyton, Shanna A. and Breeze, Charles E. and Kluft, Cornelis and Bastiaan T. Heijmans and Meike Bartels and Gareth E Davies and Dorret I. Boomsma} } @article {211, title = {Selected Lectures of the 13th International Workshop on Neonatology. LECT 39, Self-reported aggressive behavior in humans and biomarkers: a focus on lipids and methylation}, journal = {Journal of Pediatric and Neonatal Individualized Medicine (JPNIM)}, volume = {6}, year = {2017}, month = {10/2017}, pages = {52-55}, type = {Proceedings of the 13{\textdegree} International Workshop on Neonatology, Twins: identical but different, Cagliari (Italy), October 25-28}, abstract = {

PDF Available here

}, keywords = {13th International Workshop on Neonatology, 2017, Aggression, Cagliari}, doi = {10.7363/060235}, url = {http://www.jpnim.com/index.php/jpnim/article/view/060235/467}, author = {Fiona Hagenbeek and Jenny van Dongen and Kluft, Cornelis and Lannie Ligthart} } @article {128, title = {Genetic and environmental influences interact with age and sex in shaping the human methylome}, journal = {Nat Commun}, volume = {7}, year = {2016}, month = {2016/04/07}, abstract = {

The methylome is subject to genetic and environmental effects. Their impact may depend on sex and age, resulting in sex- and age-related physiological variation and disease susceptibility. Here we estimate the total heritability of DNA methylation levels in whole blood and estimate the variance explained by common single nucleotide polymorphisms at 411,169 sites in 2,603 individuals from twin families, to establish a catalogue of between-individual variation in DNA methylation. Heritability estimates vary across the genome (mean=19\%) and interaction analyses reveal thousands of sites with sex-specific heritability as well as sites where the environmental variance increases with age. Integration with previously published data illustrates the impact of genome and environment across the lifespan at methylation sites associated with metabolic traits, smoking and ageing. These findings demonstrate that our catalogue holds valuable information on locations in the genome where methylation variation between people may reflect disease-relevant environmental exposures or genetic variation.

}, url = {http://dx.doi.org/10.1038/ncomms11115}, author = {Jenny van Dongen and Michel G. Nivard and Gonneke Willemsen and Hottenga, Jouke-Jan and Helmer, Quinta and Conor V Dolan and Ehli, Erik A. and Gareth E Davies and van Iterson, Maarten and Breeze, Charles E. and Beck, Stephan and BIOS Consortium and Suchiman, H. Eka and Jansen, Rick and Joyce B.J. Van Meurs and Bastiaan T. Heijmans and Slagboom, P. Eline and Dorret I. Boomsma} } @article {94, title = {Epigenome-Wide Association Study of Aggressive Behavior}, journal = {Twin Research and Human Genetics}, volume = {FirstView}, year = {2015}, month = {11}, pages = {1{\textendash}13}, issn = {1839-2628}, doi = {10.1017/thg.2015.74}, url = {http://journals.cambridge.org/article_S1832427415000742}, author = {Jenny van Dongen and Michel G. Nivard and Bart M. L. Baselmans and Zilh{\~a}o,Nuno R. and Lannie Ligthart and Bastiaan T. Heijmans and Meike Bartels and Dorret I. Boomsma} } @article {95, title = {Methylation as an epigenetic source of random genetic effects in the classical twin design}, journal = {Advances in Genomics and Genetics, Dove Medical Press}, volume = {5}, year = {2015}, month = {09/2015}, pages = {305{\textendash}315}, abstract = {

The epigenetic effects of cytosine methylation on gene expression are an acknowledged source of phenotypic variance. The discordant monozygotic (MZ) twin design has been used to demonstrate the role of methylation in disease. Application of the classical twin design, featuring both monozygotic and dizygotic twins, has demonstrated that individual differences in methylation levels are attributable to genetic and environmental (including stochastic) factors, with the latter explaining most of the variance. What implications epigenetic sources of variance have for the twin modeling of (non-epigenetic) phenotypes such as height and IQ is an open question. One possibility is that epigenetic effects are absorbed by the variance component attributable to unshared environmental. Another possibility is that such effects form an independent source of variance distinguishable in principle from standard genetic and environmental sources. In the present paper, we conceptualized epigenetic processes as giving rise to randomness in the effects of polygenetic influences. This means that the regression coefficient in the regression of the phenotype on the polygenic factor, as specified in the twin model, varies over individuals. We investigate the consequences of ignoring this randomness in the standard twin model.

}, keywords = {classical twin design, epigenetics, heritability, methylation, parameter randomness}, doi = {http://dx.doi.org/10.2147/AGG.S46909}, url = {https://www.dovepress.com/methylation-as-an-epigenetic-source-of-random-genetic-effects-in-the-c-peer-reviewed-article-AGG}, author = {Conor V Dolan and Michel G. Nivard and Jenny van Dongen and van der Sluis,Sophie and Dorret I. Boomsma} }