Klaus-Peter Lesch

Maastricht University, Maestricht, Limburg, Netherlands

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Publications (219)1082.11 Total impact

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    ABSTRACT: Objectives. Methylphenidate (MPH) is a commonly used stimulant medication for treating attention-deficit/hyperactivity disorder (ADHD). Besides inhibiting monoamine reuptake there is evidence that MPH also influences gene expression directly. Methods. We investigated the impact of MPH treatment on gene expression levels of lymphoblastoid cells derived from adult ADHD patients and healthy controls by hypothesis-free, genome-wide microarray analysis. Significant findings were subsequently confirmed by quantitative Real-Time PCR (qRT PCR) analysis. Results. The microarray analysis from pooled samples after correction for multiple testing revealed 138 genes to be marginally significantly regulated due to MPH treatment, and one gene due to diagnosis. By qRT PCR we could confirm that GUCY1B3 expression was differential due to diagnosis. We verified chronic MPH treatment effects on the expression of ATXN1, HEY1, MAP3K8 and GLUT3 in controls as well as acute treatment effects on the expression of NAV2 and ATXN1 specifically in ADHD patients. Conclusions. Our preliminary results demonstrate MPH treatment differences in ADHD patients and healthy controls in a peripheral primary cell model. Our results need to be replicated in larger samples and also using patient-derived neuronal cell models to validate the contribution of those genes to the pathophysiology of ADHD and mode of action of MPH.
    The World Journal of Biological Psychiatry 08/2014; · 3.57 Impact Factor
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    ABSTRACT: The monoamine oxidase A (MAO-A) gene has been suggested to be involved in the pathogenesis as well as the pharmacological treatment of major depressive disorder. In the present analysis, for the first time a pharmacoepigenetic approach was applied investigating the influence of DNA methylation patterns in the MAO-A regulatory and exon1/intron1 region on antidepressant treatment response. 94 patients of Caucasian descent with major depressive disorder (f = 61; DSM-IV) were analyzed for DNA methylation status at 43 MAO-A CpG sites via direct sequencing of sodium bisulfite treated DNA extracted from blood cells. Patients were also genotyped for the functional MAO-A VNTR. Clinical response to antidepressant treatment with escitalopram was assessed by intra-individual changes of HAM-D-21 scores after 6 weeks of treatment. Apart from two CpG sites, male subjects showed no or only very minor methylation. In female patients, lower methylation at two individual CpG sites in the MAO-A promoter region was nominally associated with impaired response to antidepressant treatment after 6 weeks (GRCh37/hg19: CpG 43.514.063, p = 0.04; CpG 43.514.684, p = 0.009), not, however, withstanding correction for multiple testing. MAO-A VNTR genotypes did not influence MAO-A methylation status. The present pilot data do not suggest a major influence of MAO-A DNA methylation on antidepressant treatment response. However, the presently observed trend towards CpG-specific MAO-A gene hypomethylation-possibly via increased gene expression and consecutively decreased serotonin and/or norepinephrine availability-to potentially drive impaired antidepressant treatment response in female patients might be worthwhile to be followed up in larger pharmacoepigenetic studies.
    Journal of Neural Transmission 05/2014; · 3.05 Impact Factor
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    ABSTRACT: Depression and diabetes are serious diseases with an increasing global prevalence. Intriguingly, recent meta-analyses have highlighted an asymmetrical relationship between the two conditions as depressed patients were found to display a higher risk of developing type 2 diabetes than those individuals suffering from diabetes are to become depressed. Based on recent findings, we favor a hypothesis where by decreased peripheral serotonin (5-HT) transporter (5-HTT) function is a reciprocal risk factor for the co-morbidity of depression and diabetes, as it can trigger inflammatory pathogenetic mechanisms of both conditions. Higher intestinal levels of 5-HT and 5-HT3 receptor stimulation lead to increased intestinal permeability in 5-HTT deficient mice, which is viewed one of the most relevant animal models of depression. We hypothesize that this leakage of bacterial endotoxins can activate both central and peripheral Toll-like receptor 4 (TLR4), which inhibits insulin signaling and IRS1/PI3K/Akt and thus, contribute to the pathogenesis of diabetes and depression that are associated with this pathway. Antidepressant therapies, which also suppress intestinal 5-HTT, may have potentiating effects on the association between depression and diabetes. It is also of interest that high carbohydrate and fat intake ("cafeteria-type diet") increases intestinal 5-HT leading to TLR4 activation. Thus, endotoxaemia and inflammation owing to increased intestinal 5-HT may underpin the depression and diabetes association, where the risk of the latter pathology becomes particularly preeminent after the onset of depression and not vice versa. The evidence presented here shows the further investigation into peripheral mechanisms that linked diabetes to depression is clearly warranted.
    Behavioural brain research 05/2014; · 3.22 Impact Factor
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    ABSTRACT: Antioxidant enzymes and lipid peroxidation in the brain are involved in neuropsychiatric pathologies, including depression.14- or 28-day chronic stress model induced a depressive syndrome defined by lowered reward sensitivity in C57BL/6J mice and changed gene expression of peroxidation enzymes as shown in microarray assays. We studied how susceptibility or resilience to anhedonia is related to lipid peroxidation in the prefrontal cortex (PFC). With 14-day stress, a comparison of the activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidise(GPX) and accumulation of malondialdehyde (MDA) revealed a decrease of the first two measures in susceptible, but not in resilient animals or in stressed mice chronically dosed with imipramine (7mg/kg/day). Acute stress elevated activity of CAT and SOD and dynamics of MDA accumulation in the PFC that was prevented by imipramine (30mg/kg). 28-day stress evoked anhedonia lasting two but not five weeks while behavioural invigoration was detected at the latter time point in anhedonic but not non-anhedonic mice; enhanced aggressive traits were observed in both groups. After two weeks of a stress-free period, CAT and SOD activity levels in the PFC were reduced in anhedonic animals; after five weeks, only CAT was diminished. Thus, in the present chronic stress depression paradigm, lasting alterations in brain peroxidation occur not only during anhedonia but also in the recovery period and are accompanied by behavioural abnormalities in mice. This mimics behavioural and neurochemical deficits observed in depressed patients during remission which could be used to develop remedies preventing their relapse.
    Behavioural brain research 04/2014; · 3.22 Impact Factor
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    ABSTRACT: A promoter variant of the serotonin transporter (SERT) gene is known to affect emotional and cognitive regulation. In particular, the "short" allelic variant is implicated in the etiology of multiple neuropsychiatric disorders. Heterozygous (SERT(+/-)) and homozygous (SERT(-/-)) SERT mutant mice are valuable tools for understanding the mechanisms of altered SERT levels. Although these genetic effects are well investigated in adulthood, the developmental trajectory of altered SERT levels for behavior has not been investigated. We assessed anxiety-like and cognitive behaviors in SERT mutant mice in early adolescence and adulthood to examine the developmental consequences of reduced SERT levels. Spine density of pyramidal neurons was also measured in corticolimbic brain regions. Adult SERT(-/-) mice exhibited increased anxiety-like behavior, but these differences were not observed in early adolescent SERT(-/-) mice. Conversely, SERT(+/-) and SERT(-/-) mice did display higher spontaneous alternation during early adolescence and adulthood. SERT(+/-) and SERT(-/-) also exhibited greater neuronal spine densities in the orbitofrontal but not the medial prefrontal cortices. Adult SERT(-/-) mice also showed an increased spine density in the basolateral amygdala. Developmental alterations of the serotonergic system caused by genetic inactivation of SERT can have different influences on anxiety-like and cognitive behaviors through early adolescence into adulthood, which may be associated with changes of spine density in the prefrontal cortex and amygdala. The altered maturation of serotonergic systems may lead to specific age-related vulnerabilities to psychopathologies that develop during adolescence.
    Psychopharmacology 04/2014; · 4.06 Impact Factor
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    ABSTRACT: Variation in the serotonin transporter gene (5-HTT; SERT; SLC6A4) has been suggested to pharmacogenetically drive interindividual differences in antidepressant treatment response. In the present analysis, a 'pharmaco-epigenetic' approach was applied by investigating the influence of DNA methylation patterns in the 5-HTT transcriptional control region on antidepressant treatment response. Ninety-four patients of Caucasian descent with major depressive disorder (MDD) (f = 61) were analysed for DNA methylation status at nine CpG sites in the 5-HTT transcriptional control region upstream of exon 1A via direct sequencing of sodium bisulfite treated DNA extracted from blood cells. Patients were also genotyped for the functional 5-HTTLPR/rs25531 polymorphisms. Clinical response to treatment with escitalopram was assessed by intra-individual changes of HAM-D-21 scores after 6 wk of treatment. Lower average 5-HTT methylation across all nine CpGs was found to be associated with impaired antidepressant treatment response after 6 wk (p = 0.005). This effect was particularly conferred by one individual 5-HTT CpG site (CpG2 (GRCh37 build, NC_000017.10 28.563.102; p = 0.002). 5-HTTLPR/rs25531 haplotype was neither associated with 5-HTT DNA methylation nor treatment response. This analysis suggests that DNA hypomethylation of the 5-HTT transcriptional control region - possibly via increased serotonin transporter expression and consecutively decreased serotonin availability - might impair antidepressant treatment response in Caucasian patients with MDD. This pharmaco-epigenetic approach could eventually aid in establishing epigenetic biomarkers of treatment response and thereby a more personalized treatment of MDD.
    The International Journal of Neuropsychopharmacology 03/2014; · 5.64 Impact Factor
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    ABSTRACT: Although there are many studies available investigating internalizing and externalizing behavior in childhood and adolescent manifestations of attention-deficit/hyperactivity disorder, there is limited information about their relevance in adults featuring persistence of the disease. We examined a large sample of 910 adults affected with attention-deficit/hyperactivity disorders (AADHD) for internalizing and externalizing behavior. Regarding correlates of internalizing behavior, AADHD probands showed significantly higher scores of the anxiety- and depression-related personality traits Neuroticism and Harm Avoidance, compared with reference values. The lifetime comorbidity of depressive disorders, anxiety disorders, and anxious or fearful Cluster C personality disorders (PDs) is elevated in AADHD patients compared with general population. Regarding correlates of externalizing behavior, patients affected with AADHD show significantly lower scores of Conscientiousness and significantly higher scores of Novelty Seeking than the published German reference values. Emotional, dramatic, or erratic Cluster B PDs were most frequent in AADHD. Internalizing and externalizing behavior notably affected psychosocial status to a similar extent. The frequency of both internalizing and externalizing behavior in AADHD might reflect an underlying emotional regulation disorder.
    ADHD Attention Deficit and Hyperactivity Disorders 02/2014;
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    ABSTRACT: Schizophrenia spectrum disorders and bipolar spectrum disorders are the product of both heritable and non-heritable factors, the impact of which converges at different biological levels. Recent evidence from molecular approaches has provided new insights about how environmental exposures cause persistent alterations in the regulation of gene expression, particularly by so-called epigenetic mechanisms. The aim of this review is to provide an overview of findings of epigenetic studies in psychotic disorders, summarizing findings of human and animal studies on epigenetic alterations due to postnatal environmental exposures associated with psychotic disorders. Electronic and manual literature search of MEDLINE, EMBASE and PSYCHINFO, using a range of search terms around epigenetics, DNA methylation, histone modifications, psychoses, schizophrenia, bipolar disorder and environmental risks associated with psychotic disorders as observed in human and experimental animal studies, complemented by review articles and cross-references. Despite several promising findings of differential epigenetic profiles in individuals with psychotic disorders in the studies published to date, the knowledge of the role of epigenetic processes in psychotic disorder remains very limited, and should be interpreted cautiously given various challenges in this rapidly evolving field of research. Integration of epigenetic findings into biopsychosocial models of the etiology of psychotic disorders eventually may yield important insights into the biological underpinnings of the onset and course of psychotic disorders.
    Social Psychiatry 02/2014; · 2.05 Impact Factor
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    ABSTRACT: Objective: Despite growing awareness of adult ADHD and its comorbidity with personality disorders (PDs), little is known about sex- and subtype-related differences. Method: In all, 910 patients (452 females, 458 males) affected with persistent adult ADHD were assessed for comorbid PDs with the Structured Clinical Interview of DSM-IV and for personality traits with the revised NEO personality inventory, and the Tridimensional Personality Questionnaire. Results: The most prevalent PDs were narcissistic PD in males and histrionic PD in females. Affected females showed higher Neuroticism, Openness to Experience, and Agreeableness scores as well as Harm Avoidance and Reward Dependence scores. Narcissistic PD and antisocial PD have the highest prevalence in the H-type, while Borderline PD is more frequent in the C-type. Conclusion: Sex- and subtype-related differences in Axis II disorder comorbidity as well as impairment-modifying personality traits have to be taken into account in epidemiological studies of persistent ADHD. (J. of Att. Dis. XXXX; XX(X) XX-XX).
    Journal of Attention Disorders 02/2014; · 2.16 Impact Factor
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    ABSTRACT: Cognitive bias, the altered information processing resulting from the background emotional state of an individual, has been suggested as a promising new indicator of animal emotion. Comparable to anxious or depressed humans, animals in a putatively negative emotional state are more likely to judge an ambiguous stimulus as if it predicts a negative event, than those in positive states. The present study aimed to establish a cognitive bias test for mice based on a spatial judgment task and to apply it in a pilot study to serotonin transporter (5-HTT) knockout mice, a well-established mouse model for the study of anxiety- and depression-related behavior. In a first step, we validated that our setup can assess different expectations about the outcome of an ambiguous stimulus: mice having learned to expect something positive within a maze differed significantly in their behavior towards an unfamiliar location than animals having learned to expect something negative. In a second step, the use of spatial location as a discriminatory stimulus was confirmed by showing that mice interpret an ambiguous stimulus depending on its spatial location, with a position exactly midway between a positive and a negative reference point provoking the highest level of ambiguity. Finally, the anxiety- and depression-like phenotype of the 5-HTT knockout mouse model manifested - comparable to human conditions - in a trend for a negatively distorted interpretation of ambiguous information, albeit this effect was not statistically significant. The results suggest that the present cognitive bias test provides a useful basis to study the emotional state in mice, which may not only increase the translational value of animal models in the study of human affective disorders, but which is also a central objective of animal welfare research.
    PLoS ONE 01/2014; 9(8):e105431. · 3.73 Impact Factor
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    ABSTRACT: Abstract Objectives. This study investigates an overall autonomic hypoactivity reflecting hypoarousal as important aetiological factor in ADHD at baseline during rest and in response towards stimuli. In addition, effects of methylphenidate (MPH) are examined. We further assessed whether this hypoarousal is a stable characteristic or ameliorated by arousing emotional stimuli. Methods. Boys with ADHD were examined with (n = 35) or without MPH (n = 45) and compared with healthy boys (n = 22) regarding skin conductance level (SCL) during rest and skin conductance responses (SCRs) as well as valence and arousal ratings in response to positive, neutral, and negative pictures. Results. ADHD children without MPH were characterized by reduced baseline SCL and overall reduced SCRs. ADHD children with MPH never differed from control children. All groups displayed normal valence and arousal ratings of the stimuli and enhanced SCRs to emotional in comparison to neutral pictures. Conclusions. This is the first study to unravel (1) a general autonomic hypoactivity in ADHD children at baseline and in response to low arousing neutral and highly arousing emotional stimuli, and (2) hints that MPH normalizes this hypoactivity. Results contribute to the understanding of ADHD aetiology and MPH functionality, and are consistent with the cognitive-energetic model of ADHD.
    The World Journal of Biological Psychiatry 01/2014; 15(1):56-65. · 3.57 Impact Factor
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    ABSTRACT: Environmental factors can significantly affect disease prevalence, including neuropsychiatric disorders such as depression. The ratio of deuterium to protium in water shows substantial geographical variation, which could affect disease susceptibility. Thus the link between deuterium content of water and depression was investigated, both epidemiologically, and in a mouse model of chronic mild stress. We performed a correlation analysis between deuterium content of tap water and rates of depression in regions of the USA. Next, we used a 10-day chronic stress paradigm to test whether 2-week deuterium-depleted water treatment (91 ppm) affects depressive-like behavior and hippocampal structure. The effect of deuterium-depletion on sleep electrophysiology was also evaluated in naïve mice. There was a geographic correlation between a content of deuterium and the prevalence of depression across the USA. In the chronic stress model, depressive-like features were reduced in mice fed with deuterium-depleted water, and SERT expression was decreased in mice treated with deuterium-treated water compared with regular water. Five days of predator stress also suppressed proliferation in the dentate gyrus; this effect was attenuated in mice fed with deuterium-depleted water. Finally, in naïve mice, deuterium-depleted water treatment increased EEG indices of wakefulness, and decreased duration of REM sleep, phenomena that have been shown to result from the administration of selective serotonin reuptake inhibitors (SSRI). Our data suggest that the deuterium content of water may influence the incidence of affective disorder-related pathophysiology and major depression, which might be mediated by the serotoninergic mechanisms.
    Behavioural Brain Research. 01/2014;
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    ABSTRACT: Neuropeptide S is involved in anxiety and arousal modulation, and the functional polymorphism Asn107Ile (rs324981, A > T) of the neuropeptide S receptor gene (NPSR1) is associated with panic disorder and anxiety/fear-related traits. NPSR1 also interacts with the environment in shaping personality and impulsivity. We therefore examined whether the NPSR1 A/T polymorphism is associated with affective and anxiety disorders in a population-representative sample. Lifetime psychiatric disorders were assessed by MINI interview (n = 501) in the older cohort of the longitudinal Estonian Children Personality, Behaviour and Health Study (ECPBHS). Anxiety (STAI), self-esteem (RSES), depression (MÅDRS), suicide attempts and environmental factors were self-reported in both the younger (original n = 583) and the older cohort (original n = 593). Most of the NPSR1 effects were sex-specific and depended on environmental factors. Females with the functionally least active NPSR1 AA genotype and exposed to environmental adversity had affective/anxiety disorders more frequently; they also exhibited higher anxiety and depressiveness, and lower self-esteem. Female AA homozygotes also reported suicidal behaviour more frequently, and this was further accentuated by adverse family environment. In the general population, the NPSR1 A/T polymorphism together with environmental factors is associated with anxious, depressive and activity-related traits, increased prevalence of affective/anxiety disorders and a higher likelihood of suicidal behaviour.
    The International Journal of Neuropsychopharmacology 12/2013; · 5.64 Impact Factor
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    ABSTRACT: Attention-deficit/hyperactivity disorder (ADHD) is the most frequent psychiatric disorder in children, where it displays a global prevalence of 5 %. In up to 50 % of the cases, ADHD may persist into adulthood (aADHD), where it is often comorbid with personality disorders. Due to a potentially heritable nature of this comorbidity, we hypothesized that their genetic framework may contain common risk-modifying genes. SPOCK3, a poorly characterized, putatively Ca(2+)-binding extracellular heparan/chondroitin sulfate proteoglycan gene encoded by the human chromosomal region 4q32.3, was found to be associated with polymorphisms among the top ranks in a genome-wide association study (GWAS) on ADHD and a pooled GWAS on personality disorder (PD). We therefore genotyped 48 single nucleotide polymorphisms (SNPs) representative of the SPOCK3 gene region in 1,790 individuals (n aADHD = 624, n PD = 630, n controls = 536). In this analysis, we found two SNPs to be nominally associated with aADHD (rs7689440, rs897511) and four PD-associated SNPs (rs7689440, rs897511, rs17052671 and rs1485318); the latter even reached marginal significance after rigorous Bonferroni correction. Bioinformatics tools predicted a possible influence of rs1485318 on transcription factor binding, whereas the other candidate SNPs may have effects on alternative splicing. Our results suggest that SPOCK3 may modify the genetic risk for ADHD and PD; further studies are, however, needed to identify the underlying mechanisms.
    European Archives of Psychiatry and Clinical Neuroscience 11/2013; · 2.75 Impact Factor
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    ABSTRACT: Objective: Comorbidity in adult ADHD (aADHD) has been investigated in a large number of studies using varying research approaches with divergent results. In contrast, there is limited information about sex- or subtype-related differences from studies with small sample size. Method: A large sample of 910 individuals (458 males, 452 females) affected with aADHD was recruited at a tertiary referral center. All probands underwent a four-step procedure for diagnosing aADHD, including the Structured Clinical Interview of Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) Axis I disorders to assess comorbidity. This study will provide additional information regarding the co-morbidity of Axis I disorders in the currently largest clinical referral sample. However, the main objective of this study is to gain information about sex- or subtype-related differences. Results: Affected females show higher rates of mood (61% vs. 49%), anxiety (32% vs. 22%), and eating disorders (16% vs. 1%) than affected males, while substance use disorders were more frequent in affected males (45% vs. 29%), which mirrors sex differences in prevalence in the general population. There were hardly any relevant differences in comorbidities between subtypes, with the exception of the inattentive subtype having an especially low prevalence of panic disorder. Comorbidity in general and substance use disorders in particular, but not sex or subtype, were highly predictive of lower psychosocial status. Conclusion: Sex-related differences in the comorbidity of aADHD are more pronounced than subtype-related differences. (J. of Att. Dis. XXXX; XX(X) XX-XX).
    Journal of Attention Disorders 11/2013; · 2.16 Impact Factor
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    ABSTRACT: Alzheimer's disease (AD) is a complex neurodegenerative disorder involving dysregulation of many biological pathways at multiple levels. Classical epigenetic mechanisms, including DNA methylation and histone modifications, and regulation by microRNAs (miRNAs), are among the major regulatory elements that control these pathways at the molecular level, with epigenetic modifications regulating gene expression transcriptionally and miRNAs suppressing gene expression posttranscriptionally. Epigenetic mechanisms and miRNAs have recently been shown to closely interact with each other, thereby creating reciprocal regulatory circuits, which appear to be disrupted in neuronal and glial cells affected by AD. Here, we review those miRNAs implicated in AD that are regulated by promoter DNA methylation and/or chromatin modifications and, which frequently direct the expression of constituents of the epigenetic machinery, concluding with the delineation of a complex epigenetic-miRNA regulatory network and its alterations in AD.
    Neurobiology of aging 10/2013; · 5.94 Impact Factor
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    ABSTRACT: There is recognition that biomedical research into the causes of mental disorders and their treatment needs to adopt new approaches to research. Novel biomedical techniques have advanced our understanding of how the brain develops and is shaped by behaviour and environment. This has led to the advent of stratified medicine, which translates advances in basic research by targeting aetiological mechanisms underlying mental disorder. The resulting increase in diagnostic precision and targeted treatments may provide a window of opportunity to address the large public health burden, and individual suffering associated with mental disorders. While mental health and mental disorders have significant representation in the "health, demographic change and wellbeing" challenge identified in Horizon 2020, the framework programme for research and innovation of the European Commission (2014-2020), and in national funding agencies, clear advice on a potential strategy for mental health research investment is needed. The development of such a strategy is supported by the EC-funded "Roadmap for Mental Health Research" (ROAMER) which will provide recommendations for a European mental health research strategy integrating the areas of biomedicine, psychology, public health well being, research integration and structuring, and stakeholder participation. Leading experts on biomedical research on mental disorders have provided an assessment of the state of the art in core psychopathological domains, including arousal and stress regulation, affect, cognition social processes, comorbidity and pharmacotherapy. They have identified major advances and promising methods and pointed out gaps to be addressed in order to achieve the promise of a stratified medicine for mental disorders.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 10/2013; · 3.68 Impact Factor
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    ABSTRACT: Complex disorders have proved to be elusive in the search for underlying genetic causes. In the presence of large multi-generation pedigrees with multiple affected individuals, heritable familial forms of the disorders can be postulated. Observations of particular chromosomal haplotypes shared among all affected individuals within pedigrees may reveal chromosomal regions, in which the disease-related genes may be located. Hence, the biochemical pathways involved in pathogenesis can be exposed. We have recruited eight large Attention Deficit-Hyperactivity Disorder (ADHD, OMIM: #143465) families of German descent. Densely spaced informative microsatellite markers with high heterozygosity rates were used to fine-map and haplotype chromosomal regions of interest in these families. In three subsets and one full family of the eight ADHD families, haplotypes co-segregating with ADHD-affected individuals were identified at chromosomes 1q25, 5q11-5q13, 9q31-9q32, and 18q11-18q21. Positive LOD scores supported these co-segregations. The existence of haplotypes co-segregating among affected individuals in large ADHD pedigrees suggests the existence of Mendelian forms of the disorder and that ADHD-related genes are located within these haplotypes. In depth sequencing of these haplotype regions can identify causative genetic mechanisms and will allow further insights into the clinico-genetics of this complex disorder. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 09/2013; · 3.23 Impact Factor
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    ABSTRACT: A previous genome-wide screen for copy number variations (CNVs) in attention deficit/hyperactivity disorder (ADHD) revealed a de novo chromosome 3q26.1 deletion in one of the patients. Candidate genes at this locus include the acetylcholine-metabolizing butyrylcholinesterase (BCHE) expressing gene (OMIM #177400), which is of particular interest. The present study investigates the hypothesis that the heterozygous deletion of the BCHE gene is associated with adult ADHD (aADHD). Ina first step, we screened 348 aADHD patients and 352 controls for stretches of loss of heterozygosity (LOH) across the entire BCHE gene to screen for the deletion. Our second aim was to clarify whether BCHE single nucleotide polymorphisms (SNPs) themselves influence the risk towards ADHD. Putative functional consequences of associated SNPs as well as their un-typed proxies were predicted by several bioinformatic tools. 96 individuals displayed entirely homozygous genotype reads in all 12examined SNPs, making them possible candidates to harbor a heterozygous BCHE deletion. DNA from these 96 probands was further analyzed by real-time PCR using a BCHE-specific CNV assay. However, no deletion was found. Of the 12 tag SNPs that passed inclusion criteria, rs4680612 and rs829508were significantly associated with aADHD, as their minor alleles occurred more often in cases than in controls (p = 0.018 and p = 0.039, respectively). The risk variant rs4680612 is located in the transcriptional control region of the gene and predicted to disrupt a binding site for MYT-1, which has previously been associated with mental disorders. However, when examining a second independent adult ADHD sample of 353 cases, the association did not replicate. When looking up the deletion in three genome-wide screens for CNV in ADHD and combining it with the present study, it became apparent that 3 from a total of 1030 ADHD patients, but none of 5787 controls, featured a deletion of the BCHE promoter region including rs4680612 (p = 0.00004). Taken together, there are several lines of evidence suggesting a potential involvement of BCHE in the etiopathology of ADHD, as a rare hemizygous deletion as well as a common SNP in the same region are associated with disease, although with different penetrance. Both variations result in the disruption of the binding site of the transcription factor MYT-1 suggesting epistatic effects of BCHE and MYT-1 in the pathogenesis of ADHD. As we were not able to replicate the SNP association, our findings should be considered preliminary and call for larger studies in extended phenotypes.
    Journal of Psychiatric Research 08/2013; · 4.09 Impact Factor
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    ABSTRACT: Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17–29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn’s disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
    Nature Genetics 08/2013; AOP. · 35.21 Impact Factor

Publication Stats

6k Citations
1,082.11 Total Impact Points

Institutions

  • 2014
    • Maastricht University
      • MHeNS School for Mental Health and Neuroscience
      Maestricht, Limburg, Netherlands
  • 1998–2014
    • University of Wuerzburg
      • • Division of Molecular Psychiatry
      • • Institute for Anatomy and Cell Biology
      • • Department of Psychiatry, Psychosomatics, and Psychotherapy
      • • Department of Psychology
      • • Department of Neurology
      Würzburg, Bavaria, Germany
  • 2013
    • Maastricht Universitair Medisch Centrum
      Maestricht, Limburg, Netherlands
  • 2010–2013
    • University of Tartu
      • Estonian Centre of Behavioural and Health Sciences (consortium)
      Tartu, Tartumaa, Estonia
  • 2008–2013
    • Goethe-Universität Frankfurt am Main
      • Institute of Psychology
      Frankfurt, Hesse, Germany
    • Universität Trier
      • Department of Neurobehavioural Genetics
      Trier, Rheinland-Pfalz, Germany
    • University of Milan
      • Department of Neurological Sciences
      Milano, Lombardy, Italy
  • 2004–2013
    • University of Münster
      • Department of Psychiatry
      Muenster, North Rhine-Westphalia, Germany
  • 2012
    • Autonomous University of Barcelona
      • Departamento de Psiquiatría y Medicina Legal
      Cerdanyola del Vallès, Catalonia, Spain
    • University of Tuebingen
      • Department of Psychiatry and Psychotherapy
      Tübingen, Baden-Wuerttemberg, Germany
  • 2003–2012
    • Technische Universität Dresden
      • • Fachrichtung Psychologie
      • • Institut für Pathologie
      Dresden, Saxony, Germany
  • 2009–2011
    • University Hospital Vall d'Hebron
      • Department of Psychiatry
      Barcelona, Catalonia, Spain
    • Radboud University Nijmegen
      • Department of Human Genetics
      Nijmegen, Provincie Gelderland, Netherlands
  • 2007–2011
    • Stony Brook University
      • Department of Psychology
      Stony Brook, NY, United States
  • 2004–2009
    • National Institute of Mental Health (NIMH)
      • Laboratory of Clinical Science
      Maryland, United States
  • 2001–2008
    • National Institutes of Health
      • • Molecular Neurobiology Research Branch
      • • Laboratory of Clinical and Translational Studies
      • • Section on Molecular Neurobiology
      Bethesda, MD, United States
  • 2006
    • Universität des Saarlandes
      Saarbrücken, Saarland, Germany
  • 2002
    • Indiana University-Purdue University Indianapolis
      • Department of Anatomy and Cell Biology
      Indianapolis, IN, United States
  • 1999
    • Ben-Gurion University of the Negev
      Be'er Sheva`, Southern District, Israel