Eske M. Derks

The Relationship of DNA Methylation with Age, Gender and Genotype in Twins and Healthy Controls

Cytosine-5 methylation within CpG dinucleotides is a potentially important mechanism of epigenetic influence on human traits and disease. In addition to influences of age and gender, genetic control of DNA methylation levels has recently been described. We used whole blood genomic DNA in a twin set (23 MZ twin-pairs and 23 DZ twin-pairs, N = 92) as well as healthy controls (N = 96) to investigate heritability and relationship with age and gender of selected DNA methylation profiles using readily commercially available GoldenGate bead array technology. Despite the inability to detect meaningful methylation differences in the majority of CpG loci due to tissue type and locus selection issues, we found replicable significant associations of DNA methylation with age and gender. We identified associations of genetically heritable single nucleotide polymorphisms with large differences in DNA methylation levels near the polymorphism (cis effects) as well as associations with much smaller differences in DNA methylation levels elsewhere in the human genome (trans effects). Our results demonstrate the feasibility of array-based approaches in studies of DNA methylation and highlight the vast differences between individual loci. The identification of CpG loci of which DNA methylation levels are under genetic control or are related to age or gender will facilitate further studies into the role of DNA methylation and disease.

Prevalence and Genetic Architecture of Child Behavior Checklist-Juvenile Bipolar Disorder

BACKGROUND No consensus has been reached yet on how best to characterize children with juvenile bipolar disorder (JBD). Several groups have shown that children on the attention problems (AP), aggressive behavior (AGG), and anxious-depressed (AD) syndromes of the Child Behavior Checklist (CBCL) are likely to meet criteria for DSM-JBD. We aimed to use a large population-based twin sample to evaluate the prevalence and genetic architecture of the CBCL-JBD (deviant on AP, AGG, and AD) phenotype and compare these data to children who are deviant on just the CBCL-AP syndrome. METHODS Structural equation modeling (SEM) was applied to CBCL data from 5418, 3562, and 1971 Dutch twin pairs at ages 7, 10, and 12 years. RESULTS The CBCL-JBD phenotype occurs in approximately 1% of children at each age. Among the children who meet criteria for the CBCL-AP phenotype ( approximately 5%), between 13 and 20% also meet criteria for CBCL-JBD. The best SEM for CBCL-JBD includes additive genetic, shared and unique environmental factors. The best SEM for CBCL-AP includes dominant and additive genetic and unique environmental factors. CONCLUSIONS These data suggest that CBCL-JBD is common, and even more common among children who have severe attention problems. CBCL-JBD shows familial aggregation due to both genetic and shared environmental factors.

Individual Differences in Aggression: Genetic Analyses by age, gender, and informant in 3-, 7-, and 10-year-old Dutch Twins

Aggression in humans is associated with substantial morbidity and mortality. In this study we report on the aggressive behavior syndrome (AGG) in young children as defined by the Child Behavior Checklist (CBCL) and the Teacher Report Form (TRF). We assessed aggression in a large sample of Dutch twins at ages 3, 7, and 10 years. The purpose of this study was three-fold. First, we determined the number of children who are “clinically deviant” on the AGG scale. Second, we assessed the genetic and environmental contributions to AGG for the maternal, paternal, and teacher ratings at each age, for boys and girls. Third, we explored issues of rater bias by analyzing parental and teacher data simultaneously. CBCL data were available from mothers on 6436 three-year-old, 5451 seven-year-old, and 2972 ten-year-old twin pairs and CBCL data from fathers on 4207 three-year-old, 4269 seven-year-old, and 2295 ten-year-old twin pairs. Teacher report data from the TRF were collected for 1036 seven-year-old and 903 ten-year-old twin pairs from the Netherlands Twin Registry. Structural equation modeling was employed to obtain genetic and environmental estimates at each age. Analyses were conducted separately by age and informant, as well as simultaneously, for all informants. Differences in raw scores across gender were found, with boys being rated as more aggressive than girls by all informants. Mothers reported more symptoms than fathers, who reported more symptoms than teachers. Evidence for moderate to high genetic influence (51%–72%) was seen for AGG by all three informants at all ages with only small sex differences in heritability estimates. Best fitting models for AGG by parent reports also included a small contribution of common environment. The largest sex differences in heritabilities were seen at age 10. Contributions of common (13%–27%) and unique (16%–31%) environment were small to moderate. There was some evidence of genetic dominance by teacher report for 10-year-old girls.

Evidence-based psychiatric genetics, AKA the false dichotomy between common and rare variant hypotheses

In this article, we review some of the data that contribute to our understanding of the genetic architecture of psychiatric disorders. These include results from evolutionary modelling (hence no data), the observed recurrence risk to relatives and data from molecular markers. We briefly discuss the common-disease common-variant hypothesis, the success (or otherwise) of genome-wide association studies, the evidence for polygenic variance and the likely success of exome and whole-genome sequencing studies. We conclude that the perceived dichotomy between ‘common’ and ‘rare’ variants is not only false, but unhelpful in making progress towards increasing our understanding of the genetic basis of psychiatric disorders. Strong evidence has been accumulated that is consistent with the contribution of many genes to risk of disease, across a wide range of allele frequencies and with a substantial proportion of genetic variation in the population in linkage disequilibrium with single-nucleotide polymorphisms (SNPs) on commercial genotyping arrays. At the same time, most causal variants that segregate in the population are likely to be rare and in total these variants also explain a significant proportion of genetic variation. It is the combination of allele frequency, effect size and functional characteristics that will determine the success of new experimental paradigms such as whole exome/genome sequencing to detect such loci. Empirical results suggest that roughly half the genetic variance is tagged by SNPs on commercial genome-wide chips, but that individual causal variants have a small effect size, on average. We conclude that larger experimental sample sizes are essential to further our understanding of the biology underlying psychiatric disorders.

Maternal Ratings of Attention Problems in ADHD: Evidence for the Existence of a Continuum

OBJECTIVE To investigate whether items assessing attention problems provide evidence of quantitative differences or categorically distinct subtypes of attention problems (APs) and to investigate the relation of empirically derived latent classes to DSM-IV diagnoses of subtypes of attention-deficit/hyperactivity disorder (ADHD), for example, combined subtype, predominantly inattentive type, and predominantly hyperactive/impulsive type. METHOD Data on attention problems were obtained from maternal ratings on the Child Behavior Check List (CBCL). Latent class models, which assume categorically different subtypes, and factor mixture models, which permit severity differences, are fitted to data obtained from Dutch boys at age 7 (N = 8,079), 10 (N = 5,278), and 12 years (N = 3,139). The fit of the different models to the data is compared to decide which model, and hence, which corresponding interpretation of AP, is most appropriate. Next, ADHD diagnoses are regressed on latent class membership in a subsample of children. RESULTS At all the three ages, models that distinguish between three mainly quantitatively different classes (e.g., mild, moderate, and severe attention problems) provide the best fit to the data. Within each class, the CBCL items measure three correlated continuous factors that can be interpreted in terms of hyperactivity/impulsivity, inattentiveness/dreaminess, and nervous behavior. The AP severe class contains all of the subjects diagnosed with ADHD-combined subtype. Some subjects diagnosed with ADHD-predominantly inattentive type are in the moderate AP class. CONCLUSIONS Factor mixture analyses provide evidence that the CBCL AP syndrome varies along a severity continuum of mild to moderate to severe attention problems. Children affected with ADHD are at the extreme of the continuum. These data are important for clinicians, research scholars, and the framers of the DSM-V as they provide evidence that ADHD diagnoses exist on a continuum rather than as discrete categories.

Childhood trauma and auditory verbal hallucinations.

BACKGROUND Hallucinations have consistently been associated with traumatic experiences during childhood. This association appears strongest between physical and sexual abuse and auditory verbal hallucinations (AVH). It remains unclear whether traumatic experiences mainly colour the content of AVH or whether childhood trauma triggers the vulnerability to experience hallucinations in general. In order to investigate the association between hallucinations, childhood trauma and the emotional content of hallucinations, experienced trauma and phenomenology of AVH were investigated in non-psychotic individuals and in patients with a psychotic disorder who hear voices. METHOD A total of 127 non-psychotic individuals with frequent AVH, 124 healthy controls and 100 psychotic patients with AVH were assessed for childhood trauma. Prevalence of childhood trauma was compared between groups and the relation between characteristics of voices, especially emotional valence of content, and childhood trauma was investigated. RESULTS Both non-psychotic individuals with AVH and patients with a psychotic disorder and AVH experienced more sexual and emotional abuse compared with the healthy controls. No difference in the prevalence of traumatic experiences could be observed between the two groups experiencing AVH. In addition, no type of childhood trauma could distinguish between positive or negative emotional valence of the voices and associated distress. No correlations were found between sexual abuse and emotional abuse and other AVH characteristics. CONCLUSIONS These results suggest that sexual and emotional trauma during childhood render a person more vulnerable to experience AVH in general, which can be either positive voices without associated distress or negative voices as part of a psychotic disorder.

The Treatment of Hallucinations in Schizophrenia Spectrum Disorders

This article reviews the treatment of hallucinations in schizophrenia. The first treatment option for hallucinations in schizophrenia is antipsychotic medication, which can induce a rapid decrease in severity. Only 8% of first-episode patients still experience mild to moderate hallucinations after continuing medication for 1 year. Olanzapine, amisulpride, ziprasidone, and quetiapine are equally effective against hallucinations, but haloperidol may be slightly inferior. If the drug of first choice provides inadequate improvement, it is probably best to switch medication after 2-4 weeks of treatment. Clozapine is the drug of choice for patients who are resistant to 2 antipsychotic agents. Blood levels should be above 350-450 μg/ml for maximal effect. For relapse prevention, medication should be continued in the same dose. Depot medication should be considered for all patients because nonadherence is high. Cognitive-behavioral therapy (CBT) can be applied as an augmentation to antipsychotic medication. The success of CBT depends on the reduction of catastrophic appraisals, thereby reducing the concurrent anxiety and distress. CBT aims at reducing the emotional distress associated with auditory hallucinations and develops new coping strategies. Transcranial magnetic stimulation (TMS) is capable of reducing the frequency and severity of auditory hallucinations. Several meta-analyses found significantly better symptom reduction for low-frequency repetitive TMS as compared with placebo. Consequently, TMS currently has the status of a potentially useful treatment method for auditory hallucinations, but only in combination with state of the art antipsychotic treatment. Electroconvulsive therapy (ECT) is considered a last resort for treatment-resistant psychosis. Although several studies showed clinical improvement, a specific reduction in hallucination severity has never been demonstrated.

A systems medicine research approach for studying alcohol addiction

According to the World Health Organization, about 2 billion people drink alcohol. Excessive alcohol consumption can result in alcohol addiction, which is one of the most prevalent neuropsychiatric diseases afflicting our society today. Prevention and intervention of alcohol binging in adolescents and treatment of alcoholism are major unmet challenges affecting our health‐care system and society alike. Our newly formed German SysMedAlcoholism consortium is using a new systems medicine approach and intends (1) to define individual neurobehavioral risk profiles in adolescents that are predictive of alcohol use disorders later in life and (2) to identify new pharmacological targets and molecules for the treatment of alcoholism. To achieve these goals, we will use omics‐information from epigenomics, genetics transcriptomics, neurodynamics, global neurochemical connectomes and neuroimaging (IMAGEN; Schumann et al. ) to feed mathematical prediction modules provided by two Bernstein Centers for Computational Neurosciences (Berlin and Heidelberg/Mannheim), the results of which will subsequently be functionally validated in independent clinical samples and appropriate animal models. This approach will lead to new early intervention strategies and identify innovative molecules for relapse prevention that will be tested in experimental human studies. This research program will ultimately help in consolidating addiction research clusters in Germany that can effectively conduct large clinical trials, implement early intervention strategies and impact political and healthcare decision makers.

A test of the equal environment assumption (EEA) in multivariate twin studies.

In the classic twin design, estimation of genetic and environmental effects is based on the assumption that environmental influences are shared to the same extent by monozygotic and dizygotic twins (equal environment assumption, EEA). We explore the conditions in which the EEA can be tested based on multivariate phenotypic data. We focus on the test whether the correlation between shared environmental factors in dizygotic twins (r(C)) is less than 1. First, model identification was investigated analytically in Maple and Mx. Second, statistical power was examined in Mx. Third, the amount of bias caused by violation of the EEA was evaluated. Finally, applications to empirical data concern spatial ability in adolescents and aggression in children. Bivariate and trivariate models include several instances in which the EEA can be tested. The number of twin pairs that is needed to detect violation of the EEA with a statistical power of .80 (alpha = .05) varied between 508 and 3576 pairs for the situations considered. The bias in parameter estimates, given misspecification, ranged from 5% to 34% for additive genetic effects, and from 4% to 34% for shared environmental effects. Estimates of the nonshared environmental effects were not biased. The EEA was not violated for spatial ability or aggression. Multivariate data provide sufficient information to test the validity of the EEA. The number of twin pairs that is needed is no greater than the number typically available in most twin registries. The analysis of spatial ability and aggression indicated no detectable violation of the EEA.

Effects of Censoring on Parameter Estimates and Power in Genetic Modeling

Genetic and environmental influences on variance in phenotypic traits may be estimated with normal theory Maximum Likelihood (ML). However, when the assumption of multivariate normality is not met, this method may result in biased parameter estimates and incorrect likelihood ratio tests. We simulated multivariate normal distributed twin data under the assumption of three different genetic models. Genetic model fitting was performed in six data sets: multivariate normal data, discrete uncensored data, censored data, square root transformed censored data, normal scores of censored data, and categorical data. Estimates were obtained with normal theory ML (data sets 1-5) and with categorical data analysis (data set 6). Statistical power was examined by fitting reduced models to the data. When fitting an ACE model to censored data, an unbiased estimate of the additive genetic effect was obtained. However, the common environmental effect was underestimated and the unique environmental effect was overestimated. Transformations did not remove this bias. When fitting an ADE model, the additive genetic effect was underestimated while the dominant and unique environmental effects were overestimated. In all models, the correct parameter estimates were recovered with categorical data analysis. However, with categorical data analysis, the statistical power decreased. The analysis of L-shaped distributed data with normal theory ML results in biased parameter estimates. Unbiased parameter estimates are obtained with categorical data analysis, but the power decreases.