@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.

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}, 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 {261, title = {DNA methylation age is associated with an altered hemostatic profile in a multi-ethnic meta-analysis}, journal = {Blood}, year = {2018}, abstract = {

Elevated epigenetic age is associated with an altered hemostatic factor profile and lower clotting time (aPTT).DNA methylation age is associated with mRNA levels of fibrinogen in multiple tissues. 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 used European and African-ancestry participants who were meta-analyzed separately and combined via a random effects meta-analysis. All other measures only included participants of European-ancestry. We found that 1-year higher extrinsic epigenetic age as compared to chronological age was associated with higher fibrinogen (0.004 g/L per year; 95\% CI: 0.001, 0.007; P = 0.01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL per year; 95\% CI: 0.07, 0.20; P = 6.6x10-5) 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 (SERPINE1) and the three fibrinogen subunit-encoding genes (FGA, FGG, and FGB), in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGG in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a pro-coagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.

}, issn = {0006-4971}, doi = {10.1182/blood-2018-02-831347}, url = {http://www.bloodjournal.org/content/early/2018/07/24/blood-2018-02-831347}, author = {Ward-Caviness, Cavin K. and Huffman, Jennifer E. and Evertt, Karl and Germain, Marine and van Dongen, Jenny and Hill, W. David and Jhun, Min A. and Brody, Jennifer A. and Ghanbari, Mohsen and Du, Lei and Roetker, Nicholas S. and de Vries, Paul S. and Waldenberger, Melanie and Gieger, Christian and Wolf, Petra and Prokisch, Holger and Koenig, Wolfgang and O{\textquoteright}Donnell, Christopher J. and Levy, Daniel and Liu, Chunyu and Truong, Vinh and Wells, Philip S. and Tr{\'e}gou{\"e}t, David-Alexandre and Tang, Weihong and Morrison, Alanna C. and Boerwinkle, Eric and Wiggins, Kerri L. and McKnight, Barbara and Guo, Xiuqing and Psaty, Bruce M. and Sotoodenia, Nona and Dorret I. Boomsma and Gonneke Willemsen and Lannie Ligthart and Deary, Ian J. and Zhao, Wei and Ware, Erin B. and Kardia, Sharon L.R. and Joyce B.J. Van Meurs and Uitterlinden, Andre G. and Franco, Oscar H. and Eriksson, Per and Franco-Cereceda, Anders and Pankow, James S. and Johnson, Andrew D. and Gagnon, France and Morange, Pierre-Emmanuel and de Geus, Eco J.C. and Starr, John M. and Smith, Jennifer A. and Dehghan, Abbas and Bj{\"o}rck, Hanna M. and Smith, Nicholas L. and Peters, Annette} } @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 {283, title = {Unraveling the Genetic and Environmental Relationship Between Well-Being and Depressive Symptoms Throughout the Lifespan}, journal = {Frontiers in Psychiatry}, volume = {9}, year = {2018}, pages = {261}, abstract = {

Whether well-being and depressive symptoms can be considered as two sides of the same coin is widely debated. The aim of this study was to gain insight into the etiology of the association between well-being and depressive symptoms across the lifespan. In a large twin-design, including data from 43,427 twins between age 7 and 99, we estimated the association between well-being and depressive symptoms throughout the lifespan and assessed genetic and environmental contributions to the observed overlap. For both well-being (range 31\% \–47\%) and depressive symptoms (range 50\%-61\%), genetic factors explained a substantial part of the phenotypic variance across the lifespan. Phenotypic correlations between well-being and depressive symptoms across ages ranged from -.34 in childhood to -.49 in adulthood. In children, genetic effects explained 49\% of the phenotypic correlation while in adolescents and young adults, genetic effects explained 60\% to 77\% of the phenotypic correlations. Moderate to high genetic correlations (ranging from -0.60 to -0.66) were observed in adolescence and adulthood, while in childhood environmental correlations were substantial but genetic correlations small. Our results suggest that in childhood genetic and environmental effects are about equally important in explaining the relationship between well-being and depressive symptoms. From adolescence onwards, the role of genetic effects increases compared to environmental effects. These results provided more insights into the etiological underpinnings of well-being and depressive symptoms, possibly allowing to articulate better strategies for health promotion and resource allocation in the future.

}, issn = {1664-0640}, doi = {10.3389/fpsyt.2018.00261}, url = {https://www.frontiersin.org/article/10.3389/fpsyt.2018.00261}, author = {Bart M. L. Baselmans and Willems, Yayouk E. and Catharina E. M. van Beijsterveldt and Lannie Ligthart and Gonneke Willemsen and Conor V Dolan and Dorret I. Boomsma and Meike Bartels} } @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 {258, title = {Spousal resemblance in psychopathology: A comparison of parents of children with and without psychopathology}, journal = {European PsychiatryEuropean Psychiatry}, volume = {34}, year = {2016}, month = {2016/04/01}, pages = {49 - 55}, abstract = {

BACKGROUND:

Spouses resemble each other for psychopathology, but data regarding spousal resemblance in externalizing psychopathology, and data regarding spousal resemblance across different syndromes (e.g. anxiety in wives and attention deficit/hyperactivity disorder [ADHD] in husbands) are limited. Moreover, knowledge is lacking regarding spousal resemblance in parents of children with psychiatric disorders. We investigated and compared spousal resemblance within and across internalizing and externalizing symptom domains in parents of children with and without psychopathology.

METHODS:

Symptoms of depression, anxiety, avoidant personality, ADHD, and antisocial personality were assessed with the Adult Self Report in 728 mothers and 544 fathers of 778 children seen in child and adolescent psychiatric outpatient clinics and in 2075 mothers and 1623 fathers of 2784 children from a population-based sample. Differences in symptom scores and spousal correlations between the samples were tested.

RESULTS:

Parents in the clinical sample had higher symptom scores than in the population-based sample. In both samples, correlations within and across internalizing and externalizing domains of psychopathology were significant. Importantly, correlations were significantly higher in the clinical sample (P=0.03). Correlations, within and across symptoms, ranged from 0.14 to 0.30 in the clinical sample and from 0.05 to 0.23 in the population-based sample.

CONCLUSIONS:

This large study shows that spousal resemblance is not only present within but also across symptom domains. Especially in the clinical sample, ADHD symptoms in fathers and antisocial personality symptoms in mothers were correlated with a range of psychiatric symptoms in their spouses. Clinicians need to be alert of these multiple affected families.

}, isbn = {0924-9338}, url = {https://doi.org/10.1016/j.eurpsy.2016.01.2423}, author = {Laura W. Wesseldijk and Dieleman, G.C. and Lindauer, R.J.L. and Meike Bartels and Gonneke Willemsen and J.J. Hudziak and Dorret I. Boomsma and Christel Middeldorp} }