Phenotypic misclassification (between cases) has been shown to reduce the power to detect association in genetic studies. However, it is conceivable that complex traits are heterogeneous with respect to individual genetic susceptibility and disease pathophysiology, and that the effect of heterogeneity has a larger magnitude than the effect of phenotyping errors. Although an intuitively clear concept, the effect of heterogeneity on genetic studies of common diseases has received little attention. Here we investigate the impact of phenotypic and genetic heterogeneity on the statistical power of genome wide association studies (GWAS). We first performed a study of simulated genotypic and phenotypic data. Next, we analyzed the Wellcome Trust Case-Control Consortium (WTCCC) data for diabetes mellitus (DM) type 1 (T1D) and type 2 (T2D), using varying proportions of each type of diabetes in order to examine the impact of heterogeneity on the strength and statistical significance of association previously found in the WTCCC data. In both simulated and real data, heterogeneity (presence of “non-cases”) reduced the statistical power to detect genetic association and greatly decreased the estimates of risk attributed to genetic variation. This finding was also supported by the analysis of loci validated in subsequent large-scale meta-analyses. For example, heterogeneity of 50% increases the required sample size by approximately three times. These results suggest that accurate phenotype delineation may be more important for detecting true genetic associations than increase in sample size.
There is mounting evidence for the influence of emotional content on working memory performance. This is particularly important in light of the emotion processing that needs to take place when emotional content interferes with executive functions. In this study, we used emotional words of different valence but with similar arousal levels in an n-back task.
We examined the effects on activation in the prefrontal cortex by means of functional near-infrared spectroscopy (fNIRS) and on the late positive potential (LPP). FNIRS and LPP data were examined in 30 healthy subjects.
Behavioral results show an influence of valence on the error rate depending on the difficulty of the task: more errors were made when the valence was negative and the task difficult. Brain activation was dependent both on the difficulty of the task and on the valence: negative valence of a word diminished the increase in activation, whereas positive valence did not influence the increase in activation, while difficulty levels increased. The LPP also differentiated between the different valences, and in addition was influenced by the task difficulty, the more difficult the task, the less differentiation could be observed.
Summarized, this study shows the influence of valence on a verbal working memory task. When a word contained a negative valence, the emotional content seemed to take precedence in contrast to words containing a positive valence. Working memory and emotion processing sites seemed to overlap and compete for resources even when words are carriers of the emotional content.
In chronic PTSD, a preattentive neural alarm system responds rapidly to emotional information, leading to increased prefrontal cortex (PFC) activation at early processing stages (<100 ms). Enhanced PFC responses are followed by a reduction in occipito-temporal activity during later processing stages. However, it remains unknown if this neuronal pattern is a result of a long lasting mental disorder or if it represents changes in brain function as direct consequences of severe trauma.
The present study investigates early fear network activity in acutely traumatized patients with PTSD. It focuses on the question whether dysfunctions previously observed in chronic PTSD patients are already present shortly after trauma exposure. We recorded neuromagnetic activity towards emotional pictures in seven acutely traumatized PTSD patients between one and seven weeks after trauma exposure and compared brain responses to a balanced healthy control sample. Inverse modelling served for mapping sources of differential activation in the brain.
Compared to the control group, acutely traumatized PTSD patients showed an enhanced PFC response to high-arousing pictures between 60 to 80 ms. This rapid prefrontal hypervigilance towards arousing pictorial stimuli was sustained during 120–300 ms, where it was accompanied by a reduced affective modulation of occipito-temporal neural processing.
Our findings indicate that the hypervigilance-avoidance pattern seen in chronic PTSD is not necessarily a product of an endured mental disorder, but arises as an almost immediate result of severe traumatisation. Thus, traumatic experiences can influence emotion processing strongly, leading to long-lasting changes in trauma network activation and expediting a chronic manifestation of maladaptive cognitive and behavioral symptoms.
Whereas German suicide rates had a clear decreasing tendency between 1991 and 2006, they increased from 2007 to 2010. Deeper analyses of suicide data might help to understand better this change. The aim of this study was to analyze 1) whether recent trends can be related to changes in specific suicide methods and diverge by gender and age; 2) whether the decrease of suicide rates before 2007 as well as the increase from 2007 to 2010 are driven by the same suicide method.
Analyses were based on suicide data from the Federal Statistical Office of Germany. For 1998–2010, 136.583 suicide cases of men and women with known age and suicide method could be identified. These data were analyzed by joinpoint regression analysis, allowing identification of the best fitting point in time (“joinpoint”) at which the suicide rate significantly changes in magnitude or direction.
The national downward trend between 1998 and 2007 was mainly due to corresponding changes in self-poisoning by other means than drugs (e.g., pesticides) (annual percentage change (APC) ≤ −4.33), drowning (APC ≤ −2.73), hanging (APC ≤ −2.69) and suicides by firearms (APC ≤ −1.46) in both genders. Regarding the overall increase of age-adjusted suicide rates in Germany 2007–2010, mainly the increase of self-poisoning (e.g., by drugs) and “being overrun” (APC ≥ 1.50) contributed to this trend.
The true suicide rates might have been underestimated because of errors in the official death certificates.
Increase in suicide rates in Germany since 2007 went along with corresponding changes for “being overrun” and “self-poisoning”. Copycat suicides following the railway suicide of the goalkeeper Robert Enke partly contributed to the results. Thus, prevention of Werther effects and limitation of the availability of high pack sizes for drugs are of special relevance for the reversal of this trend.
Early identification of Bipolar Disorder (BD) remains poor despite the high levels of disability associated with the disorder.
We developed and evaluated a new DSM orientated scale for the identification of young people at risk for BD based on the Child Behavior Checklist (CBCL) and compared its performance against the CBCL-Pediatric Bipolar Disorder (CBCL-PBD) and the CBCL-Externalizing Scale, the two most widely used scales.
The new scale, CBCL-Mania Scale (CBCL-MS), comprises 19 CBCL items that directly correspond to operational criteria for mania. We tested the reliability, longitudinal stability and diagnostic accuracy of the CBCL-MS on data from the TRacking Adolescents' Individual Lives Survey (TRAILS), a prospective epidemiological cohort study of 2230 Dutch youths assessed with the CBCL at ages 11, 13 and 16. At age 19 lifetime psychiatric diagnoses were ascertained with the Composite International Diagnostic Interview. We compared the predictive ability of the CBCL-MS against the CBCL-Externalising Scale and the CBCL-PBD in the TRAILS sample.
The CBCL-MS had high internal consistency and satisfactory accuracy (area under the curve = 0.64) in this general population sample. Principal Component Analyses, followed by parallel analyses and confirmatory factor analyses, identified four factors corresponding to distractibility/disinhibition, psychosis, increased libido and disrupted sleep. This factor structure remained stable across all assessment ages. Logistic regression analyses showed that the CBCL-MS had significantly higher predictive ability than both the other scales.
Our data demonstrate that the CBCL-MS is a promising screening instrument for BD. The factor structure of the CBCL-MS showed remarkable temporal stability between late childhood and early adulthood suggesting that it maps on to meaningful developmental dimensions of liability to BD.
People with mood disorders often have disruptions in their circadian rhythms. Recent molecular genetics has linked circadian clock genes to mood disorders. Our objective was to study two core circadian clock genes, CRY1 and CRY2 as well as TTC1 that interacts with CRY2, in relation to depressive and anxiety disorders. Of these three genes, 48 single-nucleotide polymorphisms (SNPs) whose selection was based on the linkage disequilibrium and potential functionality were genotyped in 5910 individuals from a nationwide population-based sample. The diagnoses of major depressive disorder, dysthymia and anxiety disorders were assessed with a structured interview (M-CIDI). In addition, the participants filled in self-report questionnaires on depressive and anxiety symptoms. Logistic and linear regression models were used to analyze the associations of the SNPs with the phenotypes. Four CRY2 genetic variants (rs10838524, rs7121611, rs7945565, rs1401419) associated significantly with dysthymia (false discovery rate q<0.05). This finding together with earlier CRY2 associations with winter depression and with bipolar type 1 disorder supports the view that CRY2 gene has a role in mood disorders.
The CDH13 gene codes for T-cadherin, a GPI-anchored protein with cell adhesion properties that is highly expressed in the brain and cardiovascular system. Previous studies have suggested that CDH13 may be a promising candidate gene for Attention Deficit/Hyperactivity Disorder (ADHD). The aims of this study were to identify, functionally characterize, and estimate the frequency of coding CDH13 variants in adult ADHD patients and controls. We performed sequencing of the CDH13 gene in 169 Norwegian adult ADHD patients and 63 controls and genotyping of the identified variants in 641 patients and 668 controls. Native and green fluorescent protein tagged wild type and variant CDH13 proteins were expressed and studied in CHO and HEK293 cells, respectively. Sequencing identified seven rare missense CDH13 variants, one of which was novel. By genotyping, we found a cumulative frequency of these rare variants of 2.9% in controls and 3.2% in ADHD patients, implying that much larger samples are needed to obtain adequate power to study the genetic association between ADHD and rare CDH13 variants. Protein expression and localization studies in CHO cells and HEK293 cells showed that the wild type and mutant proteins were processed according to the canonical processing of GPI-anchored proteins. Although some of the mutations were predicted to severely affect protein secondary structure and stability, no significant differences were observed between the expression levels and distribution of the wild type and mutant proteins in either HEK293 or CHO cells. This is the first study where the frequency of coding CDH13 variants in patients and controls is reported and also where the functional properties of these variants are examined. Further investigations are needed to conclude whether CDH13 is involved in the pathogenesis of ADHD or other conditions.
Large rare copy number variants (CNVs) have been recognized as significant genetic risk factors for the development of schizophrenia (SCZ). However, due to their low frequency (1∶150 to 1∶1000) among patients, large sample sizes are needed to detect an association between specific CNVs and SCZ. So far, the majority of genome-wide CNV analyses have focused on reporting only CNVs that reached a significant P-value within the study cohort and merely confirmed the frequency of already-established risk-carrying CNVs. As a result, CNVs with a very low frequency that might be relevant for SCZ susceptibility are lost for secondary analyses. In this study, we provide a concise collection of high-quality CNVs in a large German sample consisting of 1,637 patients with SCZ or schizoaffective disorder and 1,627 controls. All individuals were genotyped on Illumina's BeadChips and putative CNVs were identified using QuantiSNP and PennCNV. Only those CNVs that were detected by both programs and spanned ≥30 consecutive SNPs were included in the data collection and downstream analyses (2,366 CNVs, 0.73 CNVs per individual). The genome-wide analysis did not reveal a specific association between a previously unknown CNV and SCZ. However, the group of CNVs previously reported to be associated with SCZ was more frequent in our patients than in the controls. The publication of our dataset will serve as a unique, easily accessible, high-quality CNV data collection for other research groups. The dataset could be useful for the identification of new disease-relevant CNVs that are currently overlooked due to their very low frequency and lack of power for their detection in individual studies.
Although it is well established that cognitive performance in children with attention-deficit/hyperactivity disorder (ADHD) is affected by reward and that key deficits associated with the disorder may thereby be attenuated or even compensated, this phenomenon in adults with ADHD has thus far not been addressed. Therefore, the aim of the present study was to examine the motivating effect of financial reward on task performance in adults with ADHD by focusing on the domains of executive functioning, attention, time perception, and delay aversion.
We examined male and female adults aged 18–40 years with ADHD (n = 38) along with a matched control group (n = 40) using six well-established experimental paradigms.
Impaired performance in the ADHD group was observed for stop-signal omission errors, n-back accuracy, reaction time variability in the continuous performance task, and time reproduction accuracy, and reward normalized time reproduction accuracy. Furthermore, when rewarded, subjects with ADHD exhibited longer reaction times and fewer false positives in the continuous performance task, which suggests the use of strategies to prevent impulsivity errors.
Taken together, our results support the existence of both cognitive and motivational mechanisms for the disorder, which is in line with current models of ADHD. Furthermore, our data suggest cognitive strategies of “stopping and thinking” as a possible underlying mechanism for task improvement that seems to be mediated by reward, which highlights the importance of the interaction between motivation and cognition in adult ADHD.
Little is known about the contribution of impulsivity, inattention and comorbid attention deficit/hyperactivity disorder (ADHD) in the development and maintenance of bulimia nervosa (BN). In particular, their specific contribution to disordered eating symptoms and whether they have additive effects to the general psychopathological burden remains unclear.
Fifty-seven female patients seeking treatment for BN and 40 healthy controls completed diagnostic questionnaires and interviews that investigated: a) ADHD, b) impulsivity, c) eating disorders and d) general psychopathology. Attentional processes and impulsivity were assessed by a comprehensive computer-based neuropsychological battery.
Twenty-one percent of patients with BN met the clinical cut-off for previous childhood ADHD compared to 2.5% of healthy controls. Adult ADHD according to DSM IV was also more prevalent in patients with BN, with an odds ratio of 4.2. Patients with BN and previous childhood ADHD were more impulsive and inattentive than patients with BN alone. These patients also displayed more severely disordered eating patterns and more general psychopathological symptoms compared with those without ADHD. Severity of eating disorder symptoms was better explained by inattentiveness than by either impulsivity or hyperactivity.
Our data suggest an elevated rate of former childhood and current ADHD-symptoms in treatment-seeking patients with BN. Stronger impulsivity and inattention associated with more severe neuropsychological deficits and eating disorder symptoms indicate an additive risk that is clinically relevant for these patients. Thus, clinicians should identify comorbid patients who might profit from additional ADHD-specific treatments.
The Coloboma mouse carries a ∼2 cM deletion encompassing the SNAP25 gene and has a hyperactive phenotype similar to that of ADHD. Such mice are 3 fold more active compared to their control littermates. Genetic association studies support a role for allelic variants of the human SNAP25 gene in predisposing to ADHD.
We performed association analysis across the SNAP25 gene in 1,107 individuals (339 ADHD trios). To assess the functional relevance of the SNAP25-ADHD associated allele, we performed quantitative PCR on post-mortem tissue derived from the inferior frontal gyrus of 89 unaffected adults. Significant associations with the A allele of SNP rs362990 (χ2 = 10, p-corrected = 0.019, OR = 1.5) and three marker haplotypes (rs6108461, rs362990 and rs362998) were observed. Furthermore, a significant additive decrease in the expression of the SNAP25 transcript as a function of the risk allele was also observed. This effect was detected at the haplotype level, where increasing copies of the ADHD-associated haplotype reduced the expression of the transcript.
Our data show that DNA variation at SNAP25 confers risk to ADHD and reduces the expression of the transcript in a region of the brain that is critical for the regulation of attention and inhibition.
There is converging evidence for genetic, biochemical, and neuropsychological factors to increase the risk for anxiety and anxiety disorders. The pathogenesis of anxiety disorders is assumed to be influenced by a complex interaction of these individual risk factors on several levels, affecting intermediate phenotypes of anxiety such as the startle reflex. Thus, in the present double-blind, placebo-controlled study we attempted to paradigmatically investigate a multi-level pathogenetic model of anxiety by testing the effect of 300 mg caffeine citrate as an antagonist at the adenosine A2A receptor vs placebo on the emotion-potentiated (unpleasant, neutral, and pleasant International Affective Picture System pictures) startle reflex in 110 healthy individuals (male=56, female=54) stratified for the adenosine A2A receptor (ADORA2A) 1976T>C polymorphism (rs5751876). In addition to the expected main effect of picture category (highest startle amplitude for unpleasant, lowest for pleasant pictures) groups across all ADORA2A 1976T>C genotype and intervention (caffeine vs placebo) groups, an interaction effect of genotype, intervention, and picture category was discerned: In ADORA2A 1976TT risk genotype carriers, highest startle magnitudes were observed after caffeine administration in response to unpleasant pictures, with this effect arising particularly from the female subgroup. Our data point to a complex, multi-level, and potentially gender-specific pathogenetic model of anxiety, with genetic and biochemical factors interactively increasing the risk of maladaptive emotional processing and thereby possibly also anxiety disorders. The present findings may eventually aid in improving primary and secondary prevention by sharpening the risk profiles of anxiety-prone individuals.
adenosine; caffeine; ADORA2A; panic disorder; emotional processing; startle; mood; anxiety; stress disorders; neurogenetics; neurophysiology; adenosine; caffeine; ADORA2A; panic disorder; emotional processing
Abnormalities of motivation and behavior in the context of reward are a fundamental component of addiction and mood disorders. Here we test the effect of a functional missense mutation in the dopamine 3 receptor (DRD3) gene (ser9gly, rs6280) on reward-associated dopamine (DA) release in the striatum. Twenty-six healthy controls (HCs) and 10 unmedicated subjects with major depressive disorder (MDD) completed two positron emission tomography (PET) scans with [11C]raclopride using the bolus plus constant infusion method. On one occasion subjects completed a sensorimotor task (control condition) and on another occasion subjects completed a gambling task (reward condition). A linear regression analysis controlling for age, sex, diagnosis, and self-reported anhedonia indicated that during receipt of unpredictable monetary reward the glycine allele was associated with a greater reduction in D2/3 receptor binding (i.e., increased reward-related DA release) in the middle (anterior) caudate (p<0.01) and the ventral striatum (p<0.05). The possible functional effect of the ser9gly polymorphism on DA release is consistent with previous work demonstrating that the glycine allele yields D3 autoreceptors that have a higher affinity for DA and display more robust intracellular signaling. Preclinical evidence indicates that chronic stress and aversive stimulation induce activation of the DA system, raising the possibility that the glycine allele, by virtue of its facilitatory effect on striatal DA release, increases susceptibility to hyperdopaminergic responses that have previously been associated with stress, addiction, and psychosis.
The use of clinical features to define subtypes of a disorder may aid in gene identification for complex diseases. In particular, clinical subtypes of mania may distinguish phenotypic subgroups of bipolar subjects that may also differ genetically. To assess this possibility, we performed a genome-wide association study using genotype data from the Bipolar Genome Study (BiGS) and subjects that were categorized as having either irritable or elated mania during their most severe episode. A bipolar case-only analysis in the GAIN bipolar sample identified several genomic regions that differed between irritable and elated subjects, the most significant of which was for 33 SNPs on chromosome 13q31 (peak p = 2×10−7). This broad peak is in a relative gene desert over an unknown EST and between the SLITRK1 and SLITRK6 genes. Evidence for association to this region came predominantly from subjects in the sample that were originally collected as part of a family-based bipolar linkage study, rather than those collected as bipolar singletons. We then genotyped an additional sample of bipolar singleton cases and controls, and the analysis of irritable vs. elated mania in this new sample did not replicate our previous findings. However, this lack of replication is likely due to the presence of significant differences in terms of clinical co-morbity that were identified between these singleton bipolar cases and those that were selected from families segregating the disorder. Despite these clinical differences, analysis of the combined sample provided continued support for 13q31 and other regions from our initial analysis. Though genome-wide significance was not achieved, our results suggest that irritable mania results from a distinct set of genes, including a region on chromosome 13q31.
The serotonin (5-HT) and neuropeptide S (NPS) systems are discussed as important genetic modulators of fear and sustained anxiety contributing to the etiology of anxiety disorders. Sustained anxiety is a crucial characteristic of most anxiety disorders which likely develops through contextual fear conditioning. This study investigated if and how genetic alterations of the 5-HT and the NPS systems as well as their interaction modulate contextual fear conditioning; specifically, function polymorphic variants in the genes coding for the 5-HT transporter (5HTT) and the NPS receptor (NPSR1) were studied. A large group of healthy volunteers was therefore stratified for 5HTTLPR (S+ vs. LL carriers) and NPSR1 rs324981 (T+ vs. AA carriers) polymorphisms resulting in four genotype groups (S+/T+, S+/AA, LL/T+, LL/AA) of 20 participants each. All participants underwent contextual fear conditioning and extinction using a virtual reality (VR) paradigm. During acquisition, one virtual office room (anxiety context, CXT+) was paired with an unpredictable electric stimulus (unconditioned stimulus, US), whereas another virtual office room was not paired with any US (safety context, CXT−). During extinction no US was administered. Anxiety responses were quantified by fear-potentiated startle and ratings. Most importantly, we found a gene × gene interaction on fear-potentiated startle. Only carriers of both risk alleles (S+/T+) exhibited higher startle responses in CXT+ compared to CXT−. In contrast, anxiety ratings were only influenced by the NPSR1 polymorphism with AA carriers showing higher anxiety ratings in CXT+ as compared to CXT−. Our results speak in favor of a two level account of fear conditioning with diverging effects on implicit vs. explicit fear responses. Enhanced contextual fear conditioning as reflected in potentiated startle responses may be an endophenotype for anxiety disorders.
5HTTLPR; NPSR1; gene × gene interaction; contextual fear conditioning; fear-potentiated startle
The nonapeptide oxytocin (OXT) and its receptor (OXTR) have been implicated in social cognition, empathy, emotion and stress regulation in humans. Previous studies reported associations between OXT and OXTR genetic polymorphisms and risk for disorders characterized by impaired socio-emotional functioning, such as schizophrenia and autism. Here we investigate the influence of two single nucleotide polymorphisms (SNPs) within the OXTR gene on a measure of socio-emotional functioning in schizophrenic patients. OXTR SNPs that were previously investigated in other studies were genotyped in 145 patients diagnosed with schizophrenia according to DSM-IV and 145 healthy controls matched for age and gender. The Interpersonal Reactivity Index (IRI) was used to assess cognitive (‘perspective taking’), affective (‘empathic concern’) and self-related (‘personal distress’) dimensions of empathy. No group differences in genotype frequencies were observed. MANCOVA revealed a significant main (F [1,282] = 10.464; p<0.01) and interaction effect (genotype by diagnosis: F [1,282] = 4.329; p<0.05) of OXTR SNP rs2254298(A>GG) with ‘empathic concern’. Within the schizophrenia group, linear regression analysis determined OXTR rs2254298 genotype, PANSS negative and general symptom score, and age of disease onset as being significantly associated with ‘empathic concern’. OXTR rs2254298 significantly impacted PANSS general psychopathology scores. No associations were found for OXTR rs53576, IRI ‘perspective taking’ or ‘personal distress’ ratings. Our preliminary findings support hypotheses about an involvement of OXTR rs2254298 in emotional empathy in schizophrenic and healthy individuals, warranting independent replication.
Although bipolar disorder has high heritability, the onset occurs during several decades of life, suggesting that social and environmental factors may have considerable influence on disease onset. This study examined the association between the age of onset and sunlight at the location of onset.
Data were obtained from 2414 patients with a diagnosis of bipolar I disorder, according to DSM-IV criteria. Data were collected at 24 sites in 13 countries spanning latitudes 6.3 to 63.4 degrees from the equator, including data from both hemispheres. The age of onset and location of onset were obtained retrospectively, from patient records and/or direct interviews. Solar insolation data, or the amount of electromagnetic energy striking the surface of the earth, were obtained from the NASA Surface Meteorology and Solar Energy (SSE) database for each location of onset.
The larger the maximum monthly increase in solar insolation at the location of onset, the younger the age of onset (coefficient= −4.724, 95% CI: −8.124 to −1.323, p = 0.006), controlling for each country’s median age. The maximum monthly increase in solar insolation occurred in springtime. No relationships were found between the age of onset and latitude, yearly total solar insolation, and the maximum monthly decrease in solar insolation. The largest maximum monthly increases in solar insolation occurred in diverse environments, including Norway, arid areas in California, and Chile.
The large maximum monthly increase in sunlight in springtime may have an important influence on the onset of bipolar disorder.
PMID: 22612720 CAMSID: cams2451
age of onset; bipolar disorder; solar insolation; sunlight
The Prevalence and persistence of ADHD have not been described in young Australian adults and few studies have examined how conduct problems (CP) are associated with ADHD for this age group. We estimate lifetime and adult prevalence and persistence rates for three categories of ADHD for 3795 Australian adults, and indicate how career, health and childhood risk factors differ for people with ADHD symptoms and ADHD symptoms plus CP.
Trained interviewers collected participant experience of ADHD, CP, education, employment, childhood experience, relationship and health variables. Three diagnostic definitions of ADHD used were (i) full DSM-IV criteria; (ii) excluding the age 7 onset criterion (no age criterion); (iii) participant experienced difficulties due to ADHD symptoms (problem symptoms).
Prevalence rates in adulthood were 1.1%, 2.3% and 2.7% for each categorization respectively. Persistence of ADHD from childhood averaged across gender was 55.3% for full criteria, 50.3% with no age criterion and 40.2% for problem symptoms. ADHD symptoms were associated with parental conflict, poor health, being sexually assaulted during childhood, lower education, income loss and higher unemployment. The lifetime prevalence of conduct problems for adults with ADHD was 57.8% and 6.9% for adults without ADHD. The greatest disadvantage was experienced by participants with ADHD plus CP.
The persistence of ADHD into adulthood was greatest for participants meeting full diagnostic criteria and inattention was associated with the greatest loss of income and disadvantage. The disadvantage associated with conduct problems differed in severity and was relevant for a high proportion of adults with ADHD. Women but not men with ADHD reported more childhood adversity, possibly indicating varied etiology and treatment needs. The impact and treatment needs of adults with ADHD and CP and the report of sexual assault during childhood by women and men with ADHD also deserve further study.
Several linkage analyses implicated the chromosome 9q22 region in attention deficit/hyperactivity disorder (ADHD), a neurodevelopmental disease with remarkable persistence into adulthood. This locus contains the brain-expressed GTP-binding RAS-like 2 gene (DIRAS2) thought to regulate neurogenesis. As DIRAS2 is a positional and functional ADHD candidate gene, we conducted an association study in 600 patients suffering from adult ADHD (aADHD) and 420 controls. Replication samples consisted of 1035 aADHD patients and 1381 controls, as well as 166 families with a child affected from childhood ADHD. Given the high degree of co-morbidity with ADHD, we also investigated patients suffering from bipolar disorder (BD) (n=336) or personality disorders (PDs) (n=622). Twelve single-nucleotide polymorphisms (SNPs) covering the structural gene and the transcriptional control region of DIRAS2 were analyzed. Four SNPs and two haplotype blocks showed evidence of association with ADHD, with nominal p-values ranging from p=0.006 to p=0.05. In the adult replication samples, we obtained a consistent effect of rs1412005 and of a risk haplotype containing the promoter region (p=0.026). Meta-analysis resulted in a significant common OR of 1.12 (p=0.04) for rs1412005 and confirmed association with the promoter risk haplotype (OR=1.45, p=0.0003). Subsequent analysis in nuclear families with childhood ADHD again showed an association of the promoter haplotype block (p=0.02). rs1412005 also increased risk toward BD (p=0.026) and cluster B PD (p=0.031). Additional SNPs showed association with personality scores (p=0.008–0.048). Converging lines of evidence implicate genetic variance in the promoter region of DIRAS2 in the etiology of ADHD and co-morbid impulsive disorders.
adult ADHD; linkage; genome-wide association; ras pathway; association study; bipolar disorder; biological psychiatry; neurogenetics; depression; unipolar/bipolar; development/developmental disorders; adult ADHD; linkage; genome-wide association study; ras pathway
Serotonergic system participates in a wide range of physiological processes and behaviors, but its role is generally considered as modulatory and noncrucial, especially concerning life-sustaining functions. We recently created a transgenic mouse line in which a functional deficit in serotonin homeostasis due to excessive serotonin autoinhibition was produced by inducing serotonin 1A receptor (Htr1a) overexpression selectively in serotonergic neurons (Htr1a raphe-overexpressing or Htr1aRO mice). Htr1aRO mice exhibit episodes of autonomic dysregulation, cardiovascular crises and death, resembling those of sudden infant death syndrome (SIDS) and revealing a life-supporting role of serotonergic system in autonomic control. Since midbrain serotonergic neurons are chemosensitive and are implicated in arousal we hypothesized that their chemosensitivity might be impaired in Htr1aRO mice.
Loose-seal cell-attached recordings in brainstem slices revealed that serotonergic neurons in dorsal raphe nucleus of Htr1aRO mice have dramatically reduced responses to hypercapnic challenge as compared with control littermates. In control mice, application of 9% CO2 produced an increase in firing rate of serotonergic neurons (0.260±0.041 Hz, n = 20, p = 0.0001) and application of 3% CO2 decreased their firing rate (−0.142±0.025 Hz, n = 17, p = 0.0008). In contrast, in Htr1aRO mice, firing rate of serotonergic neurons was not significantly changed by 9% CO2 (0.021±0.034 Hz, n = 16, p = 0.49) and by 3% CO2 (0.012±0.046 Hz, n = 12, p = 0.97).
Our findings support the hypothesis that chemosensitivity of midbrain serotonergic neurons provides a physiological mechanism for arousal responses to life-threatening episodes of hypercapnia and that functional impairment, such as excessive autoinhibition, of midbrain serotonergic neuron responses to hypercapnia may contribute to sudden death.
Recently, several genome-wide association studies (GWAS) on bipolar disorder (BPD) suggested novel risk genes. However, only few of them were followed up and further, the specificity of these genes is even more elusive. To address these issues, we genotyped SNPs in ANK3, CACNA1C, CMTM8, DGKH, EGFR, and NPAS3, which were significantly associated with BPD in previous GWAS, in a sample of 380 BPD patients. Replicated SNPs were then followed up in patients suffering from unipolar depression (UPD; n=387) or adult attention-deficit/hyperactivity disorder (aADHD; n=535). While we could not confirm an association of ANK3, CACNA1C, and EGFR with BPD, 10 SNPs in DGKH, CMTM8, and NPAS3 were nominally associated with disease, with two DGKH markers surviving correction for multiple testing. When these were followed up in UPD and aADHD, seven DGKH SNPs were also associated with UPD, while one SNP each in NPAS3 and CMTM8 and four in DGKH were linked to aADHD. Furthermore, a DGKH haplotype consisting of rs994856/rs9525580/rs9525584 GAT was associated with all disorders tested, while the complementary AGC haplotype was protective. The corresponding haploblock spans a 27-kb region covering exons coding for amino acids 65–243, and thus might include functional variants yet to be identified. We demonstrate an association of DGKH with BPD, UPD, and aADHD by applying a two-stage design. These disorders share the feature of mood instability, so that this phenotype might be associated with genetic variation in DGKH.
association; bipolar disorder; depression; adult ADHD; NPAS3; CMTM8; depression; unipolar/bipolar; neurogenetics; signal transduction; biological psychiatry; association; adult ADHD; NPAS3; CMTM8; EGFR
The endocannabinoid (eCB) system is implicated in several psychiatric disorders. Investigating emotional–motivational dysfunctions as underlying mechanisms, a study in humans revealed that in the C385A polymorphism of the fatty acid amide hydrolase (FAAH), the degrading enzyme of the eCB anandamide (AEA), A carriers, who are characterized by increased signaling of AEA as compared to C/C carriers, exhibited reduced brain reactivity towards unpleasant faces and enhanced reactivity towards reward. However, the association of eCB system with emotional–motivational reactivity is complex and bidirectional due to upcoming compensatory processes.
Therefore, we further investigated the relationship of the FAAH polymorphism and emotional–motivational reactivity in humans.
We assessed the affect-modulated startle, and ratings of valence and arousal in response to higher arousing pleasant, neutral, and unpleasant pictures in 67 FAAH C385AC/C carriers and 45 A carriers.
Contrarily to the previous functional MRI study, A carriers compared to C/C carriers exhibited an increased startle potentiation and therefore emotional responsiveness towards unpleasant picture stimuli and reduced startle inhibition indicating reduced emotional reactivity in response to pleasant pictures, while both groups did not differ in ratings of arousal and valence.
Our findings emphasize the bidirectionality and thorough examination of the eCB system’s impact on emotional reactivity as a central endophenotype underlying various psychiatric disorders.
Electronic supplementary material
The online version of this article (doi:10.1007/s00213-012-2785-y) contains supplementary material, which is available to authorized users.
FAAH; Genetics; Endocannabinoid; Emotion; Startle reflex
The etiology of emotion-related disorders such as anxiety or affective disorders is considered to be complex with an interaction of biological and environmental factors. Particular evidence has accumulated for alterations in the dopaminergic and noradrenergic system – partly conferred by catechol-O-methyltransferase (COMT) gene variation – for the adenosinergic system as well as for early life trauma to constitute risk factors for those conditions. Applying a multi-level approach, in a sample of 95 healthy adults, we investigated effects of the functional COMT Val158Met polymorphism, caffeine as an adenosine A2A receptor antagonist (300 mg in a placebo-controlled intervention design) and childhood maltreatment (CTQ) as well as their interaction on the affect-modulated startle response as a neurobiologically founded defensive reflex potentially related to fear- and distress-related disorders. COMT val/val genotype significantly increased startle magnitude in response to unpleasant stimuli, while met/met homozygotes showed a blunted startle response to aversive pictures. Furthermore, significant gene-environment interaction of COMT Val158Met genotype with CTQ was discerned with more maltreatment being associated with higher startle potentiation in val/val subjects but not in met carriers. No main effect of or interaction effects with caffeine were observed. Results indicate a main as well as a GxE effect of the COMT Val158Met variant and childhood maltreatment on the affect-modulated startle reflex, supporting a complex pathogenetic model of the affect-modulated startle reflex as a basic neurobiological defensive reflex potentially related to anxiety and affective disorders.
Hyperactivity is one of the core symptoms in attention deficit hyperactivity disorder (ADHD). However, it remains unclear in which way the motor system itself and its development are affected by the disorder. Movement-related potentials (MRP) can separate different stages of movement execution, from the programming of a movement to motor post-processing and memory traces. Pre-movement MRP are absent or positive during early childhood and display a developmental increase of negativity.
We examined the influences of response-speed, an indicator of the level of attention, and stimulant medication on lateralized MRP in 16 children with combined type ADHD compared to 20 matched healthy controls.
We detected a significantly diminished lateralisation of MRP over the pre-motor and primary motor cortex during movement execution (initial motor potential peak, iMP) in patients with ADHD. Fast reactions (indicating increased visuo-motor attention) led to increased lateralized negativity during movement execution only in healthy controls, while in children with ADHD faster reaction times were associated with more positive amplitudes. Even though stimulant medication had some effect on attenuating group differences in lateralized MRP, this effect was insufficient to normalize lateralized iMP amplitudes.
A reduced focal (lateralized) motor cortex activation during the command to muscle contraction points towards an immature motor system and a maturation delay of the (pre-) motor cortex in children with ADHD. A delayed maturation of the neuronal circuitry, which involves primary motor cortex, may contribute to ADHD pathophysiology.