Analysis of serum and plasma identifies differences in molecular coverage, measurement variability, and candidate biomarker selection.

Purpose: To compare the use of serum and plasma in multiplex immunoassay analyses of 190 proteins and small molecules, and associated molecular pathways. We also tested whether differences between these biofluids can influence the identification of potential biomarkers in a preliminary study comparing bipolar disorder patients with controls.

Experimental Design: Using multiplexed immunoassay analyses, we compared the measurement levels and interindividual variation of 190 proteins and small molecules between serum and plasma collected from 21 healthy individuals.

COMT x DRD4 epistasis impacts prefrontal cortex function underlying response control.

The prefrontal cortex plays a major role in cognitive control, but it is unclear how single genes and gene-gene interactions (genetic epistasis) impact neural and behavioral phenotypes. Both dopamine (DA) availability ("inverted U-model") and excitatory versus inhibitory DA receptor stimulation ("dual-state theory") have been linked to important principles of prefrontal processing. Catechol-O-methyltransferase (COMT; Val158Met) and DA D4-receptor (DRD4; 48 bp VNTR) genotypes were analyzed for effects on behavioral and neural correlates of prefrontal response control (NoGo-anteriorization, NGA) using a Go-NoGo task and electroencephalography (114 controls and 181 patients with attention-deficit/hyperactivity disorder).

Impact of sunlight on the age of onset of bipolar disorder.

Objective: 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.

Method: Data were obtained from 2414 patients with a diagnosis of bipolar I disorder, according to DSM-IV criteria.

Expression of monoamine transporters, nitric oxide synthase 3, and neurotrophin genes in antidepressant-stimulated astrocytes.

Background: There is increasing evidence that glial cells play a role in the pathomechanisms of mood disorders and the mode of action of antidepressant drugs.

Methods: To examine whether there is a direct effect on the expression of different genes encoding proteins that have been implicated in the pathophysiology of affective disorders, primary astrocyte cell cultures from rats were treated with two different antidepressant drugs, imipramine and escitalopram, and the RNA expression of brain-derived neurotrophic factor (Bdnf), serotonin transporter (5Htt), dopamine transporter (Dat), and endothelial nitric oxide synthase (Nos3) was examined.

Results: Stimulation of astroglial cell culture with imipramine, a tricyclic antidepressant, led to a significant increase of the Bdnf RNA level whereas treatment with escitalopram did not.

Progranulin gene variability and plasma levels in bipolar disorder and schizophrenia.

Basing on the assumption that frontotemporal lobar degeneration (FTLD), schizophrenia and bipolar disorder (BPD) might share common aetiological mechanisms, we analyzed genetic variation in the FTLD risk gene progranulin (GRN) in a German population of patients with schizophrenia (n = 271) or BPD (n = 237) as compared with 574 age-, gender- and ethnicity-matched controls. Furthermore, we measured plasma progranulin levels in 26 German BPD patients as well as in 61 Italian BPD patients and 29 matched controls.A significantly decreased allelic frequency of the minor versus the wild-type allele was observed for rs2879096 (23.

An association study of sequence variants in the forkhead box P2 (FOXP2) gene and adulthood attention-deficit/hyperactivity disorder in two European samples.

Objectives: Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder manifesting as symptoms of inattention, hyperactivity, and/or impulsivity. Learning disabilities co-occur with ADHD in 20-30% of cases and this high co-occurrence raises the possibility of a common etiological background. Forkhead box P2 (FOXP2) encodes a transcription factor involved in speech and language impairment and in the control of the corticobasal ganglia circuits known to be relevant in ADHD, suggesting a possible role of FOXP2 in ADHD.

Monoamine oxidase A gene DNA hypomethylation - a risk factor for panic disorder?

The monoamine oxidase A (MAOA) gene has been suggested as a prime candidate in the pathogenesis of panic disorder. In the present study, DNA methylation patterns in the MAOA regulatory and exon 1/intron 1 region were investigated for association with panic disorder with particular attention to possible effects of gender and environmental factors. Sixty-five patients with panic disorder (44 females, 21 males) and 65 healthy controls were analysed for DNA methylation status at 42 MAOA CpG sites via direct sequencing of sodium bisulfate treated DNA extracted from blood cells.

Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 15q13.3.

Objective: Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable psychiatric disorder. Because of its multifactorial etiology, however, identifying the genes involved has been difficult. The authors followed up on recent findings suggesting that rare copy number variants (CNVs) may be important for ADHD etiology.

Candidate system analysis in ADHD: evaluation of nine genes involved in dopaminergic neurotransmission identifies association with DRD1.

Objectives: Several pharmacological and genetic studies support the involvement of the dopamine neurotransmitter system in the aetiology of attention-deficit hyperactivity disorder (ADHD). Based on this information we evaluated the contribution to ADHD of nine genes involved in dopaminergic neurotransmission (DRD1, DRD2, DRD3, DRD4, DRD5, DAT1, TH, DBH and COMT).

Methods: We genotyped a total of 61 tagging single nucleotide polymorphisms (SNPs) in a sample of 533 ADHD patients (322 children and 211 adults), 533 sex-matched unrelated controls and additional 196 nuclear ADHD families from Spain.

Neuropeptide S receptor gene (NPSR) and life events: G × E effects on anxiety sensitivity and its subdimensions.

Objectives: The pathogenesis of anxiety is assumed to be interactively influenced by genetic and environmental factors. Thus, a gene-environment interaction (G × E) study of the neuropeptide S receptor gene (NPSR) A/T polymorphism (rs324981) and life events was conducted with respect to anxiety sensitivity (AS) as an intermediate phenotype of anxiety disorders.

Methods: A sample of 475 healthy German subjects was genotyped for NPSR and assessed for AS, childhood maltreatment (CTQ) and recent life events (LTE).

Modification of caffeine effects on the affect-modulated startle by neuropeptide S receptor gene variation.

Rationale/objectives: Both the neuropeptide S (NPS) system and antagonism at the adenosine A2A receptor (e.g., by caffeine) were found to play a crucial role in the mediation of arousal and anxiety/panic in animal and human studies.

Human IgG directed against amphiphysin induces anxiety behavior in a rat model after intrathecal passive transfer.

Stiff person syndrome with auto-antibodies against amphiphysin is characterized by muscular stiffness, spasms, and anxiety which is a less appreciated core symptom. Here, we report that intrathecal application of purified immunoglobulin G-antibodies against amphiphysin from one patient induce anxiety behavior in rats. Immunostaining demonstrated binding of anti-amphiphysin antibodies to brain structures which are associated with anxiety disorders, such as the amygdala.

Behavioral genetics of affective and anxiety disorders.

As shown by clinical genetic studies, affective and anxiety disorders are complex genetic disorders with genetic and environmental factors interactively determining their respective pathomechanism. Advances in molecular genetic techniques including linkage studies, association studies, and genome-wide association studies allow for the detailed dissection of the genetic influence on the development of these disorders. Besides the molecular genetic investigation of categorical entities according to standardized diagnostic criteria, intermediate phenotypes comprising neurobiological or neuropsychological traits (e.

Dopamine transporter (DAT1) and dopamine receptor D4 (DRD4) genotypes differentially impact on electrophysiological correlates of error processing.

Recent studies as well as theoretical models of error processing assign fundamental importance to the brain's dopaminergic system. Research about how the electrophysiological correlates of error processing--the error-related negativity (ERN) and the error positivity (Pe)--are influenced by variations of common dopaminergic genes, however, is still relatively scarce. In the present study, we therefore investigated whether polymorphisms in the DAT1 gene and in the DRD4 gene, respectively, lead to interindividual differences in these error processing correlates.

Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is a common, heritable neuropsychiatric disorder of unknown etiology. We performed a whole-genome copy number variation (CNV) study on 1,013 cases with ADHD and 4,105 healthy children of European ancestry using 550,000 SNPs. We evaluated statistically significant findings in multiple independent cohorts, with a total of 2,493 cases with ADHD and 9,222 controls of European ancestry, using matched platforms.

The genetics of attention deficit/hyperactivity disorder in adults, a review.

The adult form of attention deficit/hyperactivity disorder (aADHD) has a prevalence of up to 5% and is the most severe long-term outcome of this common neurodevelopmental disorder. Family studies in clinical samples suggest an increased familial liability for aADHD compared with childhood ADHD (cADHD), whereas twin studies based on self-rated symptoms in adult population samples show moderate heritability estimates of 30-40%. However, using multiple sources of information, the heritability of clinically diagnosed aADHD and cADHD is very similar.

Reduced prefrontal oxygenation during object and spatial visual working memory in unpolar and bipolar depression.

Altered prefrontal brain activity (e.g. hypofrontality) during cognitive tasks such as working memory is a core neuroimaging marker in unipolar (UNI) and bipolar (BI) depression.

Genome-wide association study in German patients with attention deficit/hyperactivity disorder.

The heritability of attention deficit hyperactivity disorder (ADHD) is approximately 0.8. Despite several larger scale attempts, genome-wide association studies (GWAS) have not led to the identification of significant results.

ADORA2A Gene variation, caffeine, and emotional processing: a multi-level interaction on startle reflex.

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).

Serotonergic modulation in executive functioning: linking genetic variations to working memory performance.

Emerging evidence from studies using, for example, acute tryptophan depletion or investigating genetic variation of genes related to the serotonin signaling pathway suggest a role of serotonin in executive functions such as top-down attention, working memory and inhibitory control. In the current study, we aimed at extending this evidence by using the n-back task to examine working memory performance of 130 participants via behavioral and neurophysiological indices and by focusing on variations within genes encoding key regulators of the serotonergic system: the serotonin transporter gene-linked polymorphic region (5-HTTLPR) and a repeat polymorphism in the transcriptional control region of the monoamine-oxidase gene (MAOA-uVNTR). Because serotonin and norepinephrine systems have been shown to be structurally and functionally highly interrelated, we also examined a novel polymorphism in the promoter region of the norepinephrine transporter gene (NET -3081) in anticipation of epistatic effects.

NOS1 ex1f-VNTR polymorphism affects prefrontal oxygenation during response inhibition tasks.

Impulsivity is a trait shared by many psychiatric disorders and therefore a suitable intermediate phenotype for their underlying biological mechanisms. One of the molecular determinants involved is the NOS1 ex1f-VNTR, whose short variants are associated with a variety of impulsive behaviors. Fifty-six healthy controls were stratified into homozygous long (LL) (30 probands) and short (SS) (26 probands) allele groups.

DIRAS2 is associated with adult ADHD, related traits, and co-morbid disorders.

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.

No evidence for association between a functional promoter variant of the Norepinephrine Transporter gene SLC6A2 and ADHD in a family-based sample.

Noradrenergic neurotransmission influences executive functions, attentional performance, and general alertness, involving neuronal networks affected in attention deficit/hyperactivity disorder (ADHD). The norepinephrine transporter facilitates the reuptake of norepinephrine and dopamine in the prefrontal cortex and represents the main target of atomoxetine, an effective drug in the treatment of ADHD. Due to its influence on catecholaminergic signaling, variants of the coding gene (SLC6A2) have been widely investigated in ADHD.

Serotonin transporter gene and childhood trauma--a G × E effect on anxiety sensitivity.

Background: Genetic factors and environmental factors are assumed to interactively influence the pathogenesis of anxiety disorders. Thus, a gene-environment interaction (G × E) study was conducted with respect to anxiety sensitivity (AS) as a promising intermediate phenotype of anxiety disorders.

Method: Healthy subjects (N = 363) were assessed for AS, childhood maltreatment (Childhood Trauma Questionnaire), and genotyped for functional serotonin transporter gene variants (5-HTTLPR/5-HTT rs25531).