[Show abstract][Hide abstract] ABSTRACT: For most complex traits, results from genome-wide association studies show that the proportion of the phenotypic variance attributable to the additive effects of individual SNPs, that is, the heritability explained by the SNPs, is substantially less than the estimate of heritability obtained by standard methods using correlations between relatives. This difference has been called the "missing heritability". One explanation is that heritability estimates from family (including twin) studies are biased upwards. Zuk et al. revisited overestimation of narrow sense heritability from twin studies as a result of confounding with non-additive genetic variance. They propose a limiting pathway (LP) model that generates significant epistatic variation and its simple parametrization provides a convenient way to explore implications of epistasis. They conclude that over-estimation of narrow sense heritability from family data ('phantom heritability') may explain an important proportion of missing heritability. We show that for highly heritable quantitative traits large phantom heritability estimates from twin studies are possible only if a large contribution of common environment is assumed. The LP model is underpinned by strong assumptions that are unlikely to hold, including that all contributing pathways have the same mean and variance and are uncorrelated. Here, we relax the assumptions that underlie the LP model to be more biologically plausible. Together with theoretical, empirical, and pragmatic arguments we conclude that in outbred populations the contribution of additive genetic variance is likely to be much more important than the contribution of non-additive variance.
PLoS ONE 07/2013; 8(7):e68913. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Affective and non-affective psychoses are severe and frequent psychiatric disorders. Amongst others, they not only have a profound impact on affected individuals through their symptomatology, but also regarding cognition, brain structure and function. Cognitive impairment influences patients' quality of life as well as their ability to work and being employed. While exercise therapy has been implemented in the treatment of psychiatric conditions since the days of Kraepelin and Bleuler, the underlying mechanisms have never been systematically studied. Since the early 1990s, studies emerged examining the effect of physical exercise in animal models, revealing stimulation of neurogenesis, synaptogenesis and neurotransmission. Based on that body of work, clinical studies have been carried out in both healthy humans and in patient populations. These studies differ with regard to homogenous study samples, sample size, type and duration of exercise, outcome variables and measurement techniques. Based on their review, we draw conclusions regarding recommendations for future research strategies showing that modern therapeutic approaches should include physical exercise as part of a multimodal intervention programme to improve psychopathology and cognitive symptoms in schizophrenia and affective disorders.
European Archives of Psychiatry and Clinical Neuroscience 07/2013; · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Automatic classification of individuals at increased risk for schizophrenia can become an important screening method that allows for early intervention based on disease markers, if proven to be sufficiently accurate. Conventional classification methods typically consider information from single subjects, thereby ignoring (heritable) features of the person's relatives. In this paper we show that the inclusion of these features can lead to an increase in classification accuracy from 0.54 to 0.72 using a support vector machine model. This inclusion of contextual information is especially useful in diseases where the classification features carry a heritable component.
Schizophrenia Research 07/2013; · 4.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Serine and other amino acids that function as coagonists at the N-methyl-d-aspartate receptor (NMDAR) have been extensively investigated in schizophrenia (SCZ). However, studies comparing amino acid levels in body fluids of SCZ patients with healthy controls have yielded inconsistent results. We therefore conducted a meta-analysis (search: May 9, 2013) of serine, l-serine, d-serine, glycine, alanine, proline and aspartate levels in blood and cerebrospinal fluid (CSF) obtained from adult SCZ patients and healthy controls. Standardized differences of means (SDMs) were computed, and heterogeneity, subgroup, sensitivity, and publication bias analyses were conducted. Blood serine levels were found to be significantly higher in SCZ patients compared to healthy controls (SDM=0.280 (0.021-0.540), p=0.034; N=1671 subjects), whereas CSF serine, l-serine, d-serine, glycine, alanine, proline and aspartate levels did not differ. Stratification by sex suggested that the case-control difference in blood serine levels particularly applied to male subjects. These results provide support for blood serine level aberrations in SCZ patients and warrant further research to disentangle the involvement of serine with SCZ in both sexes.
[Show abstract][Hide abstract] ABSTRACT: Several large imaging-genetics consortia aim to identify genetic variants influencing subcortical brain volumes. We investigated the extent to which genetic variation accounts for the variation in subcortical volumes, including thalamus, amygdala, putamen, caudate nucleus, globus pallidus and nucleus accumbens and obtained the stability of these brain volumes over a five-year period. The heritability estimates for all subcortical regions were high, with the highest heritability estimates observed for the thalamus (.80) and caudate nucleus (.88) and lowest for the left nucleus accumbens (.44). Five-year stability was substantial and higher for larger [e.g., thalamus (.88), putamen (.86), caudate nucleus (.87)] compared to smaller [nucleus accumbens (.45)] subcortical structures. These results provide additional evidence that subcortical structures are promising starting points for identifying genetic variants that influence brain structure.
[Show abstract][Hide abstract] ABSTRACT: IMPORTANCE The human brain forms a large-scale structural network of regions and interregional pathways. Recent studies have reported the existence of a selective set of highly central and interconnected hub regions that may play a crucial role in the brain's integrative processes, together forming a central backbone for global brain communication. Abnormal brain connectivity may have a key role in the pathophysiology of schizophrenia. OBJECTIVE To examine the structure of the rich club in schizophrenia and its role in global functional brain dynamics. DESIGN Structural diffusion tensor imaging and resting-state functional magnetic resonance imaging were performed in patients with schizophrenia and matched healthy controls. SETTING Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands. PARTICIPANTS Forty-eight patients and 45 healthy controls participated in the study. An independent replication data set of 41 patients and 51 healthy controls was included to replicate and validate significant findings. MAIN OUTCOME(S) AND MEASURES Measures of rich club organization, connectivity density of rich club connections and connections linking peripheral regions to brain hubs, measures of global brain network efficiency, and measures of coupling between brain structure and functional dynamics. RESULTS Rich club organization between high-degree hub nodes was significantly affected in patients, together with a reduced density of rich club connections predominantly comprising the white matter pathways that link the midline frontal, parietal, and insular hub regions. This reduction in rich club density was found to be associated with lower levels of global communication capacity, a relationship that was absent for other white matter pathways. In addition, patients had an increase in the strength of structural connectivity-functional connectivity coupling. CONCLUSIONS Our findings provide novel biological evidence that schizophrenia is characterized by a selective disruption of brain connectivity among central hub regions of the brain, potentially leading to reduced communication capacity and altered functional brain dynamics.
[Show abstract][Hide abstract] ABSTRACT: The glutamatergic neurotransmission system and the N-methyl-D-aspartate receptor (NMDAR) have been implicated in smoking and alcohol consumption behavior. Preclinical studies have demonstrated that nicotine and ethanol influence NMDAR functionality, which may play a role in tendencies to consume these substances. Nonetheless, little is known about concentrations of NMDAR coagonists in the cerebrospinal fluid (CSF) and plasma of individuals who smoke or consume alcohol. Glycine and L and D-stereoisomers of Alanine, Serine and Proline were therefore measured using ultra-high performance liquid chromatography-tandem mass spectrometry in 403 healthy subjects. Nicotine and alcohol consumption were quantified using questionnaires. Possible differences in NMDAR coagonist concentrations in plasma and CSF were investigated using ANCOVA with age, BMI and storage duration as covariates. The significance threshold was Bonferroni-corrected (α=0.00625). Compared to non-smokers, smokers displayed lower levels of D-Proline in plasma (p=0.0027, Cohen's d=-0.41) and D-Proline in CSF (p=0.0026, Cohen's d=-0.43). D-Serine in CSF was higher in smokers than in non-smokers (p=0.0052, Cohen's d=0.41). After subdividing participants based on smoking quantity, dose-dependent decreases were demonstrated in smokers for D-Proline in plasma (F= 5.65, p = 0.0039) and D-Proline in CSF (F=5.20, p=0.0060). No differences in NMDAR coagonist levels between alcohol consumption groups were detected. To our knowledge, this is the first report to implicate D-amino acids in smoking behavior of humans. Whether such concentration differences lie at the root of or result from smoking habits may be addressed in prospective studies.Neuropsychopharmacology accepted article preview online, 24 April 2013; doi:10.1038/npp.2013.103.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 04/2013; · 8.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Cognitive deficits have been recognized as a key feature of schizophrenia, since the first description by Kraepelin. Specifically, lower intelligence is considered a core feature of the disorder and may represent a risk factor for its development. However, whether global intelligence decreases over time in schizophrenia is not known. The aims of this quantitative meta-analysis are to gather, integrate and estimate the overall mean effect size of IQ change over time in schizophrenia as compared to healthy individuals. METHODS: A systematic search was conducted to identify relevant studies. Longitudinal studies with at least two intelligence assessments in schizophrenia cohorts were retrieved. Studies had to report sufficient data on IQ-change and include data from healthy comparisons for computation of effect sizes. For each study, the Cohen d was calculated as well as a combined mean effect size. RESULTS: Fourteen studies were identified. Eight studies with a total of 280 patients and 306 healthy controls were suitable to be included. The mean weighted baseline IQ was 97.20 for patients and 109.26 for controls. The mean weighted IQ-change per year was +0.33 for patients and +2.08 for controls. The combined effect size was Cohen's d=-0.48, p=0.01. CONCLUSIONS: A global cognitive deficit is present in patients with schizophrenia expressed as a lower test score increase over repeated testing as compared to healthy subjects possibly due to the lack of practice effects in patients. Thus, schizophrenia is characterized by a relative lack of gain in global cognitive abilities over time.
Schizophrenia Research 03/2013; · 4.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: INTRODUCTION: Verbal auditory hallucinations (VAHs) are experienced as spoken voices which seem to originate in the extracorporeal environment or inside the head. Animal and human research has identified a 'where' pathway for sound processing comprising the planum temporale, the middle frontal gyrus and the inferior parietal lobule. We hypothesize that increased activity of that 'where' pathway mediates the exteriorization of VAHs. METHODS: The fMRI scans of 52 right-handed psychotic patients experiencing frequent VAHs were compared with the reported location of hallucinations, as rated with the aid of the PSYRATS-AHRS. For each subject, a unique VAH activation model was created based on the VAH timings, and subsequently convolved with a gamma function to model the hemodynamic response. In order to examine the neurofunctional equivalents of perceived VAH location, second-level group effects of subjects experiencing either internal (n=24) or external (n=28) VAHs were contrasted within planum temporale, middle frontal gyrus, and inferior parietal lobule regions of interest (ROIs). RESULTS: Three ROIs were tested for increased activity in relation with the exteriorization of VAHs. The analysis revealed a left-sided medial planum temporale and a right-sided middle frontal gyrus cluster of increased activity. No significant activity was found in the inferior parietal lobule. CONCLUSIONS: Our study indicates that internal and external VAHs are mediated by a fronto-temporal pattern of neuronal activity while the exteriorization of VAHs stems from additional brain activity in the auditory 'where' pathway, comprising the planum temporale and prefrontal regions.
Schizophrenia Research 03/2013; · 4.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Decisions are rarely made in social isolation. One phenomenon often observed in social interactions is altruistic punishment, i.e. the punishment of unfair behavior by others at a personal cost. The tendency for altruistic punishment is altered by affective states including those induced by stress exposure. Stress is thought to exert bi-directional effects on behavior: immediately after stress, reflex-like and habitual behavior is promoted while later on more far-sighted, flexible and goal-directed behavior is enhanced. We hypothesized that such time-dependent effects of stress would also be present in the context of altruistic punishment behavior. Healthy male participants (N=80) were exposed to either a grouped stress test or a control condition. Participants were tested in prosocial decision making tasks either directly after stress or 75min later. Altruistic punishment was assessed using the Ultimatum Game. General altruism was assessed with a one-shot version of the Dictator Game in which an anonymous donation could be offered to a charitable organization. We found that stress caused a bi-directional effect on altruistic punishment, with decreased rejection rates in the late aftermath of stress in response to ambiguous 30% offers. In the Dictator Game, stressed participants were less generous than controls, but no time-dependent effect was observed, indicating that the general reward sensitivity remained unchanged at various time-points after stress. Overall, during the late aftermath after acute stress exposure (i.e. 75min later), participants acted more consistent with their own material self-interest, and had a lower propensity for altruistic punishment, possibly through upregulation of cognitive self-control mechanisms. Thus, our findings underscore the importance of time as a factor in simple, real-life economic decisions in a stressful social context.
[Show abstract][Hide abstract] ABSTRACT: In psychiatric disorders, the effect of genetic and environmental factors may converge on molecular pathways and brain circuits related to growth factor functioning. In this review, we describe how disturbances in fibroblast growth factors (FGFs) and their receptors influence behavior by affecting brain development. Recently, several studies reported associations of members of the FGF family with psychiatric disorders. FGFs are key candidates to modulate the impact of environmental factors, such as stress. Mutant mice for FGF receptor 1 show schizophrenia-like behaviors that are related to general loss of neurons and postnatal glia dysfunction. Mice lacking FGF2, a FGFR1 ligand, show similar reductions in brain volume and hyperactivity, as well as increased anxiety behaviors. FGFR2 and FGF17 are involved in the development of frontal brain regions and impairments in cognitive and social behaviors, respectively. Moreover, treatment with FGF2 was beneficial for depressive and cognitive measures in several animal studies and one human study. These findings indicate the importance of the FGF system with respect to developing novel etiology-directed treatments for psychopathology.
[Show abstract][Hide abstract] ABSTRACT: Genomic copy number variations (CNVs) and increased parental age are both associated with the risk to develop a variety of clinical neuropsychiatric disorders such as autism, schizophrenia and bipolar disorder. At the same time, it has been shown that the rate of transmitted de novo single nucleotide mutations is increased with paternal age. To address whether paternal age also affects the burden of structural genomic deletions and duplications, we examined various types of CNV burden in a large population sample from the Netherlands. Healthy participants with parental age information (n = 6,773) were collected at different University Medical Centers. CNVs were called with the PennCNV algorithm using Illumina genome-wide SNP array data. We observed no evidence in support of a paternal age effect on CNV load in the offspring. Our results were negative for global measures as well as several proxies for de novo CNV events in this unique sample. While recent studies suggest de novo single nucleotide mutation rate to be dominated by the age of the father at conception, our results strongly suggest that at the level of global CNV burden there is no influence of increased paternal age. While it remains possible that local genomic effects may exist for specific phenotypes, this study indicates that global CNV burden and increased father's age may be independent disease risk factors.
[Show abstract][Hide abstract] ABSTRACT: In order to assess the importance of environmental and genetic risk on transition from health to psychotic disorder, a prospective study of individuals at average (n = 462) and high genetic risk (n = 810) was conducted.
A three-year cohort study examined the rate of transition to psychotic disorder. Binary measures indexing environmental exposure (combining urban birth, cannabis use, ethnicity and childhood trauma) and proxy genetic risk (high-risk sibling status) were used to model transition.
The majority of high-risk siblings (68%) and healthy comparison subjects (60%) had been exposed to one or more environmental risks. The risk of transition in siblings (n = 9, 1.1%) was higher than the risk in healthy comparison subjects (n = 2, 0.4%; ORadj = 2.2,95%CI:5-10.3). All transitions (100%) were associated with environmental exposure, compared to 65% of non-transitions (p = 0.014), with the greatest effects for childhood trauma (ORadj = 34.4,95%CI:4.4-267.4), cannabis use (OR = 4.1,95%CI:1.1, 15.4), minority ethnic group (OR = 3.8,95%CI:1.2,12.8) and urban birth (OR = 3.7,95%CI:0.9,15.4). The proportion of transitions in the population attributable to environmental and genetic risk ranged from 28% for minority ethnic group, 45% for urban birth, 57% for cannabis use, 86% for childhood trauma, and 50% for high-risk sibling status. Nine out of 11 transitions (82%) were exposed to both genetic and environmental risk, compared to only 43% of non-transitions (p = 0.03).
Environmental risk associated with transition to psychotic disorder is semi-ubiquitous regardless of genetic high risk status. Careful prospective documentation suggests most transitions can be attributed to powerful environmental effects that become detectable when analysed against elevated background genetic risk, indicating gene-environment interaction.
PLoS ONE 01/2013; 8(11):e76690. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In a previous study we reported on a non-invasive functional diffusion tensor imaging (fDTI) method to measure neuronal signals directly from subtle changes in fractional anisotropy along white matter tracts. We hypothesized that these fractional anisotropy changes relate to morphological changes of glial cells induced by axonal activity. In the present study we set out to replicate the results of the previous study with an improved fDTI scan acquisition scheme. A group of twelve healthy human participants were scanned on a 3 Tesla MRI scanner. Activation was revealed in the contralateral thalamo-cortical tract and optic radiations during tactile and visual stimulation, respectively. Mean percent signal change in FA was 3.47% for the tactile task and 3.79% for the visual task, while for the MD the mean percent signal change was only -0.10 and -0.09%. The results support the notion of different response functions for tactile and visual stimuli. With this study we successfully replicated our previous findings using the same types of stimuli but on a different group of healthy participants and at different field-strength. The successful replication of our first fDTI results suggests that the non-invasive fDTI method is robust enough to study the functional neural networks in the human brain within a practically feasible time period.
Frontiers in Human Neuroscience 01/2013; 7:817. · 2.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A putative pathway by which the BDNF Val66Met polymorphism (rs6265) leads to aberrant phenotypes is its influence on plasma BDNF. Research into the impact of rs6265 on plasma BDNF has given rise to conflicting results. Moreover, most such studies have compared Met-carriers with Val-homozygous subjects. We therefore genotyped subjects from a population-based cohort (the Utrecht Health Project, N=2,743) and assessed whether plasma BDNF differs between rs6265 homozygous groups. We maximized the number of Met-homozygous subjects in whom we measured plasma BDNF, resulting in plasma BDNF being available for 19 Met-homozygous and 42 matched Val-homozygous subjects. Mean concentrations (S.D.) were 1963.1 (750.1) and 2133.2 pg/ml (1164.3) for the Val/Val and Met/Met groups, respectively. Using ANOVA, no differences in plasma BDNF between the two groups were detected. In conclusion, these results add to a growing body of evidence indicating that allelic variation at rs6265 does not have medium to large effects on plasma BDNF concentrations.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 12/2012; 43:185. · 4.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Available data on antipsychotic-induced metabolic risks are often constrained by potential confounding effects due to prior antipsychotic treatment. In this study, we assessed the baseline prevalence of metabolic abnormalities and changes following treatment with five commonly-used antipsychotic drugs (haloperidol, amisulpride, olanzapine, quetiapine or ziprasidone) in first-episode, partially antipsychotic-naive patients with schizophrenia in the European first-episode schizophrenia trial (EUFEST). Overall baseline prevalence of metabolic syndrome (MetS) was 6.0%, with similar rates observed in the antipsychotic-naive patients (5.7%, 9/157) and in the other patients with only a brief prior exposure to antipsychotics (6.1%, 20/326). These results are consistent with the MetS prevalence rate estimated in a general population of similar age. Examination of individual risk factors showed 58.5% of subjects had one or more elevated metabolic risks at baseline: 28.5% demonstrated suboptimal HDL; 24.2% hypertension; 17.7% hypertriglyceridemia; 8.2% abdominal obesity; 7.3% hyperglycaemia. Increase in body weight (kg/month) occurred in patients treated with haloperidol (0.62 s.e. 0.11), amisulpride (0.76 s.e. 0.08), olanzapine (0.98 s.e. 0.07) and quetiapine (0.58 s.e. 0.09), which was significantly greater than that in the ziprasidone group (0.18 s.e. 0.10). The incidence rate of new diabetes cases over a 52-wk follow-up period was 0.82% (4/488). More patients experienced worsening rather than improvement of hypertriglyceridemia or hyperglycaemia in all treatment groups. Our findings suggest that in first-episode, partially antipsychotic-naive patients, the baseline prevalence rate of MetS appears to be no higher than that in the general population, but serious underlying individual risk factors nevertheless existed.
The International Journal of Neuropsychopharmacology 12/2012; · 5.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: People usually feel they cause their own actions and the consequences of those actions, i.e., they attribute behavior to the proper agent. Research suggests that there are two routes to the experience of self-agency: 1) an explicit route, where one has the intention to obtain a goal (if it occurs, I must have done it) and 2) an implicit route, where information about the goal is unconsciously available and increases the feeling of self-agency. Schizophrenia patients typically experience no behavioral control and exhibit difficulties in distinguishing one's own actions from those of others. The present study investigates differences in both routes to self-agency experiences between schizophrenia patients and controls. METHODS: Twenty-three schizophrenia patients and 23 controls performed a task where they performed an action (button press) and subsequently indicated whether or not they were the agent of the consequence of this action (the outcome) on a 9-point scale. The task can be manipulated to measure both the explicit and implicit route (by using priming) to the experience of self-agency. RESULTS: In the explicit condition (participants intended to produce a specific outcome, and this outcome matched their goal), both groups experienced enhanced self-agency. In the implicit condition (the outcome matched the primed outcome), healthy controls showed increased self-agency over the outcome, while patients did not. Potential differences in task motivation and attention did not explain these findings. CONCLUSIONS: These findings provide new evidence for the idea that implicit processes leading to feelings of self-agency may be disturbed in schizophrenia.
Schizophrenia Research 11/2012; · 4.43 Impact Factor