Showing papers in "Molecular Psychiatry in 2010"
TL;DR: Evidence of a preponderance of early onset cases in men, high comorbidity with a wide range of disorders, and reliable associations between disorder severity and key outcomes may have implications for how OCD is classified in DSM-V.
Abstract: Despite significant advances in the study of obsessive-compulsive disorder (OCD), important questions remain about the disorder's public health significance, appropriate diagnostic classification, and clinical heterogeneity. These issues were explored using data from the National Comorbidity Survey Replication (NCS-R), a nationally representative survey of U.S. adults. A subsample of 2073 respondents was assessed for lifetime DSM-IV OCD. More than one-quarter of respondents reported experiencing obsessions or compulsions at some time in their lives. While conditional probability of OCD was strongly associated with the number of obsessions and compulsions reported, only small proportions of respondents met full DSM-IV criteria for lifetime (2.3%) or 12-month (1.2%) OCD. OCD is associated with substantial comorbidity, not only with anxiety and mood disorders but also with impulse-control and substance use disorders. Severity of OCD, assessed by an adapted version of the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), is associated with poor insight, high comorbidity, high role impairment, and high probability of seeking treatment. The high prevalence of subthreshold OCD symptoms may help explain past inconsistencies in prevalence estimates across surveys and suggests that the public health burden of OCD may be greater than its low prevalence implies. Evidence of a preponderance of early-onset cases in males, high comorbidity with a wide range of disorders, and reliable associations between disorder severity and key outcomes may have implications for how OCD is classified in DSM-V.
1,971 citations
TL;DR: Examination of the unique associations between individual disorders and subsequent suicidal behavior using data from the National Comorbidity Survey Replication reveals that depression predicts suicide ideation, but not suicide plans or attempts among those with ideation.
Abstract: Mental disorders, comorbidity and suicidal behavior: Results from the National Comorbidity Survey Replication
953 citations
TL;DR: Combined long-term results of DBS studies show that the procedure can be successfully implemented by dedicated interdisciplinary teams, and support its therapeutic promise, and suggest that neural networks relevant to therapeutic improvement might be modulated more effectively at a more posterior target.
Abstract: Psychiatric neurosurgery teams in the United States and Europe have studied deep brain stimulation (DBS) of the ventral anterior limb of the internal capsule and adjacent ventral striatum (VC/VS) for severe and highly treatment-resistant obsessive-compulsive disorder. Four groups have collaborated most closely, in small-scale studies, over the past 8 years. First to begin was Leuven/Antwerp, followed by Butler Hospital/Brown Medical School, the Cleveland Clinic and most recently the University of Florida. These centers used comparable patient selection criteria and surgical targeting. Targeting, but not selection, evolved during this period. Here, we present combined long-term results of those studies, which reveal clinically significant symptom reductions and functional improvement in about two-thirds of patients. DBS was well tolerated overall and adverse effects were overwhelmingly transient. Results generally improved for patients implanted more recently, suggesting a ‘learning curve’ both within and across centers. This is well known from the development of DBS for movement disorders. The main factor accounting for these gains appears to be the refinement of the implantation site. Initially, an anterior–posterior location based on anterior capsulotomy lesions was used. In an attempt to improve results, more posterior sites were investigated resulting in the current target, at the junction of the anterior capsule, anterior commissure and posterior ventral striatum. Clinical results suggest that neural networks relevant to therapeutic improvement might be modulated more effectively at a more posterior target. Taken together, these data show that the procedure can be successfully implemented by dedicated interdisciplinary teams, and support its therapeutic promise.
736 citations
TL;DR: Peripheral administration of IFN-α activated IDO in concert with central cytokine responses, resulting in increased brain KYN and QUIN, which correlated with depressive symptoms.
Abstract: Cytokine-induced activation of indoleamine 2,3-dioxygenase (IDO) catabolizes L-tryptophan (TRP) into L-kynurenine (KYN), which is metabolized to quinolinic acid (QUIN) and kynurenic acid (KA). QUIN and KA are neuroactive and may contribute to the behavioral changes experienced by some patients during exposure to inflammatory stimuli such as interferon (IFN)-alpha. A relationship between depressive symptoms and peripheral blood TRP, KYN and KA during treatment with IFN-alpha has been described. However, whether peripheral blood changes in these IDO catabolites are manifest in the brain and whether they are related to central nervous system cytokine responses and/or behavior is unknown. Accordingly, TRP, KYN, QUIN and KA were measured in cerebrospinal fluid (CSF) and blood along with CSF concentrations of relevant cytokines, chemokines and soluble cytokine receptors in 27 patients with hepatitis C after approximately 12 weeks of either treatment with IFN-alpha (n=16) or no treatment (n=11). Depressive symptoms were assessed using the Montgomery-Asberg Depression Rating Scale. IFN-alpha significantly increased peripheral blood KYN, which was accompanied by marked increases in CSF KYN. Increased CSF KYN was in turn associated with significant increases in CSF QUIN and KA. Despite significant decreases in peripheral blood TRP, IFN-alpha had no effect on CSF TRP concentrations. Increases in CSF KYN and QUIN were correlated with increased CSF IFN-alpha, soluble tumor necrosis factor-alpha receptor 2 and monocyte chemoattractant protein-1 as well as increased depressive symptoms. In conclusion, peripheral administration of IFN-alpha activated IDO in concert with central cytokine responses, resulting in increased brain KYN and QUIN, which correlated with depressive symptoms.
571 citations
TL;DR: It is shown for general cognitive ability that, to the contrary, genetic influence increases with age, and this finding suggests new ways of thinking about the interface between nature and nurture during the school years.
Abstract: Although common sense suggests that environmental influences increasingly account for individual differences in behavior as experiences accumulate during the course of life, this hypothesis has not previously been tested, in part because of the large sample sizes needed for an adequately powered analysis. Here we show for general cognitive ability that, to the contrary, genetic influence increases with age. The heritability of general cognitive ability increases significantly and linearly from 41% in childhood (9 years) to 55% in adolescence (12 years) and to 66% in young adulthood (17 years) in a sample of 11 000 pairs of twins from four countries, a larger sample than all previous studies combined. In addition to its far-reaching implications for neuroscience and molecular genetics, this finding suggests new ways of thinking about the interface between nature and nurture during the school years. Why, despite life's ‘slings and arrows of outrageous fortune’, do genetically driven differences increasingly account for differences in general cognitive ability? We suggest that the answer lies with genotype–environment correlation: as children grow up, they increasingly select, modify and even create their own experiences in part based on their genetic propensities.
545 citations
King's College London1, French Alternative Energies and Atomic Energy Commission2, University of Cambridge3, Charité4, Trinity College, Dublin5, German National Metrology Institute6, French Institute of Health and Medical Research7, University of Nottingham8, University of Toronto9, Montreal Neurological Institute and Hospital10, Dresden University of Technology11, University of Sussex12
TL;DR: The strategies the IMAGEN consortium used to meet the challenges posed by large-scale multicentre imaging–genomics investigations are described, including standardization of the clinical, psychometric and neuroimaging-acquisition protocols, development of a central database for efficient analyses of large multimodal data sets and new analytic approaches to large- scale genetic neuroim imaging analyses.
Abstract: The IMAGEN study: reinforcement-related behaviour in normal brain function and psychopathology
490 citations
TL;DR: It is suggested that rare inherited structural variations play an important role in ADHD development and a set of putative candidate genes for further study in the etiology of ADHD are indicated.
Abstract: Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable disorder, but specific genetic factors underlying risk remain elusive. To assess the role of structural variation in ADHD, we identified 222 inherited copy number variations (CNVs) within 335 ADHD patients and their parents that were not detected in 2026 unrelated healthy individuals. Although no excess CNVs, either deletions or duplications, were found in the ADHD cohort relative to controls, the inherited rare CNV-associated gene set was significantly enriched for genes reported as candidates in studies of autism, schizophrenia and Tourette syndrome, including A2BP1, AUTS2, CNTNAP2 and IMMP2L. The ADHD CNV gene set was also significantly enriched for genes known to be important for psychological and neurological functions, including learning, behavior, synaptic transmission and central nervous system development. Four independent deletions were located within the protein tyrosine phosphatase gene, PTPRD, recently implicated as a candidate gene for restless legs syndrome, which frequently presents with ADHD. A deletion within the glutamate receptor gene, GRM5, was found in an affected parent and all three affected offspring whose ADHD phenotypes closely resembled those of the GRM5 null mouse. Together, these results suggest that rare inherited structural variations play an important role in ADHD development and indicate a set of putative candidate genes for further study in the etiology of ADHD.
472 citations
TL;DR: A meta-analysis of all available neuroimaging studies of rs4680 shows significant association between the COMT genotype and prefrontal activation, and meta-analytical evidence for a neural substrate for the pleiotropic behavioral effects of COMT genetic variation is found.
Abstract: Genetic variation in catechol-O-methyltransferase (COMT), encoding an enzyme critical for prefrontal dopamine flux, has been studied extensively using both behavioral and neuroimaging methods. In behavior, pleiotropic action of a functional Val(158)Met (rs4680) polymorphism on executive cognition and emotional stability has been described and proposed to be of evolutionary significance (the 'warrior/worrier' hypothesis). We conducted a meta-analysis of all available neuroimaging studies of rs4680 to investigate the evidence for a neural substrate of this behavioral pleiotropy. We show significant association between the COMT genotype and prefrontal activation, with large (d=0.73) effect size without evidence for publication bias. Strong and opposing effects were found for executive cognition paradigms (favoring Met allele carriers) and emotional paradigms (favoring Val), providing meta-analytical evidence for a neural substrate for the pleiotropic behavioral effects of COMT genetic variation and validating the use of intermediate phenotypes as a method to bridge between genes and behavior.
458 citations
TL;DR: It is suggested that the BDNF Val66Met polymorphism is of greater importance in the development of MDD in men than in women, and future research into gender issues will be of interest.
Abstract: Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that has antidepressant-like effects in animals and may be implicated in the etiology of mood-related phenotypes. However, genetic association studies of the BDNF Val66Met polymorphism (single nucleotide polymorphism rs6265) in major depressive disorder (MDD) have produced inconsistent results. We conducted a meta-analysis of studies comparing the frequency of the BDNF Val66Met-coding variant in depressed cases (MDD) and nondepressed controls. A total of 14 studies involving 2812 cases with DSM-III or -IV defined MDD and 10 843 nondepressed controls met the inclusion criteria. Analyses were stratified either by gender or ethnicity (Asian and Caucasian) because MDD is more prevalent in women and in Caucasians and because BDNF allele frequencies differ by ethnicity. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were provided for allelic analyses (Met versus Val), as well as for genotypic analyses (Met/Met and Val/Met versus Val/Val). In the total sample, the BDNF Val66Met polymorphism was not significantly associated with depression. However, the gender stratified analyses revealed significant effects in both the allelic and genotypic analyses in men (OR(MET), 95% CI; 1.27 (1.10-1.47); OR(MET/MET), 95% CI; 1.67 (1.19-2.36)). Stratification according to ethnicity did not show significant effects of the Val66Met polymorphism on MDD. Our results suggest that the BDNF Val66Met polymorphism is of greater importance in the development of MDD in men than in women. Future research into gender issues will be of interest.
446 citations
TL;DR: The findings are evidence of some degree of overlap in the biological underpinnings of susceptibility to mental illness across the clinical spectrum of mood and psychotic disorders, and show that at least some loci can have a relatively general effect on susceptibility to diagnostic categories, as currently defined.
Abstract: Molecular genetic analysis offers opportunities to advance our understanding of the nosological relationship between psychiatric diagnostic categories in general, and the mood and psychotic disorders in particular. Strong evidence (P=7.0 × 10−7) of association at the polymorphism rs1006737 (within CACNA1C, the gene encoding the α-1C subunit of the L-type voltage-gated calcium channel) with the risk of bipolar disorder (BD) has recently been reported in a meta-analysis of three genome-wide association studies of BD, including our BD sample (N=1868) studied within the Wellcome Trust Case Control Consortium. Here, we have used our UK case samples of recurrent major depression (N=1196) and schizophrenia (N=479) and UK non-psychiatric comparison groups (N=15316) to examine the spectrum of phenotypic effect of the bipolar risk allele at rs1006737. We found that the risk allele conferred increased risk for schizophrenia (P=0.034) and recurrent major depression (P=0.013) with similar effect sizes to those previously observed in BD (allelic odds ratio ~1.15). Our findings are evidence of some degree of overlap in the biological underpinnings of susceptibility to mental illness across the clinical spectrum of mood and psychotic disorders, and show that at least some loci can have a relatively general effect on susceptibility to diagnostic categories, as currently defined. Our findings will contribute to a better understanding of the pathogenesis of major psychiatric illness, and such knowledge should be useful in providing an etiological rationale for shaping psychiatric nosology, which is currently reliant entirely on descriptive clinical data.
443 citations
TL;DR: An updated review of 34 human observational studies indicates that the length polymorphism of the serotonin transporter gene moderates the effect of environmental adversity in the development of depression.
Abstract: An updated review of 34 human observational studies indicates that the length polymorphism of the serotonin transporter gene moderates the effect of environmental adversity in the development of depression. This finding depends on the use of contextual or objective methods to assess environmental adversity and is attenuated when self-report instruments are used. Inconsistent findings in male adolescents suggest a developmental stage and sex-specific protective mechanism. These systematic relationships between method and results should be followed up to specify causal mechanisms leading to depression.
TL;DR: The finding suggests that 5-HTTLPR, STin2, H TR1A, HTR2A, TPH1 and BDNF may modulate antidepressant response.
Abstract: This systematic review summarizes pharmacogenetic studies on antidepressant response and side effects. Out of the 17 genes we reviewed, 8 genes were entered into the meta-analysis (SLC6A4, HTR1A, HTR2A, TPH1, gene encoding the β-3 subunit, brain-derived neurotrophic factor (BDNF), HTR3A and HTR3B). TPH1 218C/C genotype (7 studies, 754 subjects) was significantly associated with a better response (odds ratio, OR=1.62; P=0.005) with no heterogeneity between ethnicities. A better response was also observed in subjects with the Met variant within the BDNF 66Val/Met polymorphism (4 studies, 490 subjects; OR=1.63, P=0.02). Variable number of tandem repeats polymorphism within intron 2 (STin2) 12/12 genotype showed a trend toward a better response in Asians (STin2: 5 studies, 686 subjects; OR=3.89, P=0.03). As for side effects, pooled ORs of serotonin transporter gene promoter polymorphism (5-HTTLPR) l (9 studies, 2642 subjects) and HTR2A −1438G/G (7 studies, 801 subjects) were associated with a significant risk modulation (OR=0.64, P=0.0005) and (OR=1.91, P=0.0006), respectively. Interestingly, this significance became more robust when analyzed with side effect induced by selective serotonin reuptake inhibitors only (5-HTTLPR: P=0.0001, HTR2A: P<0.0001). No significant result could be observed for the other variants. These results were not corrected for multiple testing in each variant, phenotype and subcategory. This would have required a Bonferroni significance level of P<0.0023. Although some heterogeneity was present across studies, our finding suggests that 5-HTTLPR, STin2, HTR1A, HTR2A, TPH1 and BDNF may modulate antidepressant response.
TL;DR: It is found that a specific BDNF knockdown in the ventral subiculum induces anhedonic-like behavior and the specific effect of BDNF reduction on neuronal differentiation has broader implications for the study of neurodevelopment and neurodegenerative diseases.
Abstract: Depression has been associated with reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. In addition, animal studies suggest an association between reduced hippocampal neurogenesis and depressive-like behavior. These associations were predominantly established based on responses to antidepressant drugs and alterations in BDNF levels and neurogenesis in depressive patients or animal models for depressive behavior. Nevertheless, there is no direct evidence that the actual reduction of the BDNF protein in specific brain sites can induce depressive-like behaviors or affect neurogenesis in vivo. Using BDNF knockdown by RNA interference and lentiviral vectors injected into specific subregions of the hippocampus we show that a reduction in BDNF expression in the dentate gyrus, but not the CA3, reduces neurogenesis and affects behaviors associated with depression. Moreover, we show that BDNF has a critical function in neuronal differentiation, but not proliferation in vivo. Finally, we found that a specific BDNF knockdown in the ventral subiculum induces anhedonic-like behavior. These findings provide substantial support for the neurotrophic hypothesis of depression and specify anatomical and neurochemical targets for potential antidepressant interventions. Moreover, the specific effect of BDNF reduction on neuronal differentiation has broader implications for the study of neurodevelopment and neurodegenerative diseases.
TL;DR: This study provides the first experimental evidence that chronic stress impairs cortical glial function and provides further validation of hypothesis that glial dysfunction and disrupted amino-acid neurotransmission contribute to the pathophysiology of depression and that modulation of glutamate metabolism, uptake and/or release represent viable targets for antidepressant drug development.
Abstract: Growing evidence indicates that glia pathology and amino-acid neurotransmitter system abnormalities contribute to the pathophysiology and possibly the pathogenesis of major depressive disorder. This study investigates changes in glial function occurring in the rat prefrontal cortex (PFC) after chronic unpredictable stress (CUS), a rodent model of depression. Furthermore, we analyzed the effects of riluzole, a Food and Drug Administration-approved drug for the treatment of amyotrophic laterosclerosis, known to modulate glutamate release and facilate glutamate uptake, on CUS-induced glial dysfunction and depressive-like behaviors. We provide the first experimental evidence that chronic stress impairs cortical glial function. Animals exposed to CUS and showing behavioral deficits in sucrose preference and active avoidance exhibited significant decreases in 13C-acetate metabolism reflecting glial cell metabolism, and glial fibrillary associated protein (GFAP) mRNA expression in the PFC. The cellular, metabolic and behavioral alterations induced by CUS were reversed and/or blocked by chronic treatment with the glutamate-modulating drug riluzole. The beneficial effects of riluzole on CUS-induced anhedonia and helplessness demonstrate the antidepressant action of riluzole in rodents. Riluzole treatment also reversed CUS-induced reductions in glial metabolism and GFAP mRNA expression. Our results are consistent with recent open-label clinical trials showing the drug's effect in mood and anxiety disorders. This study provides further validation of hypothesis that glial dysfunction and disrupted amino-acid neurotransmission contribute to the pathophysiology of depression and that modulation of glutamate metabolism, uptake and/or release represent viable targets for antidepressant drug development.
TL;DR: Data show the presence of excitotoxicity and neuroinflammation in BD frontal cortex, with particular activation of the IL-R cascade, which may account for reported evidence of disease progression in BD and be a target for future therapy.
Abstract: Reports of cognitive decline, symptom worsening and brain atrophy in bipolar disorder (BD) suggest that the disease progresses over time. The worsening neuropathology may involve excitotoxicity and neuroinflammation. We determined protein and mRNA levels of excitotoxicity and neuroinflammatory markers in postmortem frontal cortex from 10 BD patients and 10 age-matched controls. The brain tissue was matched for age, postmortem interval and pH. The results indicated statistically significant lower protein and mRNA levels of the N-methyl-D-aspartate receptors, NR-1 and NR-3A, but significantly higher protein and mRNA levels of interleukin (IL)-1beta, the IL-1 receptor (IL-1R), myeloid differentiation factor 88, nuclear factor-kappa B subunits, and astroglial and microglial markers (glial fibrillary acidic protein, inducible nitric oxide synthase, c-fos and CD11b) in postmortem frontal cortex from BD compared with control subjects. There was no significant difference in mRNA levels of tumor necrosis factor alpha or neuronal nitric oxide synthase in the same region. These data show the presence of excitotoxicity and neuroinflammation in BD frontal cortex, with particular activation of the IL-R cascade. The changes may account for reported evidence of disease progression in BD and be a target for future therapy.
TL;DR: A significant schizophrenia-associated increase in global microRNA expression was associated with an elevation of primary microRNA processing and corresponded with an increase in the microprocessor component DGCR8.
Abstract: MicroRNA expression profiling and quantitative reverse transcription-PCR analysis of the superior temporal gyrus and the dorsolateral prefrontal cortex revealed a significant schizophrenia-associated increase in global microRNA expression. This change was associated with an elevation of primary microRNA processing and corresponded with an increase in the microprocessor component DGCR8. The biological implications for this extensive increase in gene silencing are profound, and were exemplified by members of the miR-15 family and other related microRNA, which were significantly upregulated in both brain regions. This functionally convergent influence is overrepresented in pathways involved in synaptic plasticity and includes many genes and pathways associated with schizophrenia, some of which were substantiated in vitro by reporter gene assay. Given the magnitude of microRNA changes and their wide sphere of influence, this phenomenon could represent an important dimension in the pathogenesis of schizophrenia.
TL;DR: The endophenotype (EP) construct has important potential lessons for etiological research in PDs that can be optimized by considering it as a special case of a broader set of multivariate genetic models, which can be fitted using currently available methodology.
Abstract: This paper provides a conceptual analysis of the endophenotype (EP) construct that is having an increasing role in genetic strategies for unraveling the etiology of psychiatric disorders (PDs). We make six major points illustrated through the method of path analysis. First, it is important to distinguish between mediational and liability-index (or ‘risk indicator’) models for EP, as only the former requires genetic risk for PD to pass through EP. Second, the relative reliability of EP and PD can have a critical role in the interpretation of results. Ignoring them can lead to substantial errors of inference. Third, we need to consider bidirectional relationships between an EP and a PD, and the possibility that genetic effects on PD are only partially mediated by EP. Fourth, EP models typically assume that all genetic effects that have an impact on EP also alter risk for PD. However, among the genetic influences on EP and PD, it is also plausible that some will influence only EP, some only PD and some both. Fifth, we should also consider models incorporating multiple EPs and PDs, which can be well captured by multivariate genetic methods. Sixth, EPs may also reflect the impact of the environment on risk for PDs. The EP concept has important potential lessons for etiological research in PDs that can be optimized by considering it as a special case of a broader set of multivariate genetic models, which can be fitted using currently available methodology.
TL;DR: It is shown that the receptor for corticotropin-releasing factor (CRF), the neuropeptide that orchestrates the stress response, signals and is trafficked differently in female rats in a manner that could result in a greater response and decreased adaptation to stressors.
Abstract: Sex differences in corticotropin-releasing factor receptor signaling and trafficking: potential role in female vulnerability to stress-related psychopathology
TL;DR: A concatenation of findings from preclinical and clinical studies support a preeminent function for the corticotropin-releasing factor (CRF) system in mediating the physiological response to external stressors and in the pathophysiology of anxiety and depression.
Abstract: A concatenation of findings from preclinical and clinical studies support a preeminent function for the corticotropin-releasing factor (CRF) system in mediating the physiological response to external stressors and in the pathophysiology of anxiety and depression. Recently, human genetic studies have provided considerable support to several long-standing hypotheses of mood and anxiety disorders, including the CRF hypothesis. These data, reviewed in this report, are congruent with the hypothesis that this system is of paramount importance in mediating stress-related psychopathology. More specifically, variants in the gene encoding the CRF1 receptor interact with adverse environmental factors to predict risk for stress-related psychiatric disorders. In-depth characterization of these variants will likely be important in furthering our understanding of the long-term consequences of adverse experience.
TL;DR: Living in an enriched environment is highly effective in extinguishing submissive behavioral traits developed during chronic social stress, and these effects are critically dependent on adult neurogenesis, indicating that beneficial behavioral adaptations are dependent on intact adult neuroGenesis.
Abstract: The subgranular zone of the adult hippocampal dentate gyrus contains a pool of neural stem cells that continuously divide and differentiate into functional granule cells. It has been shown that production of new hippocampal neurons is necessary for amelioration of stress-induced behavioral changes by antidepressants in animal models of depression. The survival of newly born hippocampal neurons is decreased by chronic psychosocial stress and increased by exposure to enriched environments. These observations suggest the existence of a link between hippocampal neurogenesis, stress-induced behavioral changes, and the beneficial effects of enriched environment. To show causality, we subjected transgenic mice with conditionally suppressed neurogenesis to psychosocial stress followed by environmental enrichment. First, we showed that repeated social defeat coupled with chronic exposure to an aggressor produces robust and quantifiable indices of submissive and depressive-like behaviors; second, subsequent exposure to an enriched environment led to extinction of the submissive phenotype, while animals exposed to an impoverished environment retained the submissive phenotype; and third, enrichment was not effective in reversing the submissive and depressive-like behaviors in transgenic mice lacking neurogenesis. Our data show two main findings. First, living in an enriched environment is highly effective in extinguishing submissive behavioral traits developed during chronic social stress, and second, these effects are critically dependent on adult neurogenesis, indicating that beneficial behavioral adaptations are dependent on intact adult neurogenesis.
TL;DR: It is inferred that a large number of loci may influence personality traits and disorders, requiring larger sample sizes for the GWA approach to confidently identify associated genetic variants.
Abstract: Personality traits are summarized by five broad dimensions with pervasive influences on major life outcomes, strong links to psychiatric disorders and clear heritable components. To identify genetic variants associated with each of the five dimensions of personality we performed a genome-wide association (GWA) scan of 3972 individuals from a genetically isolated population within Sardinia, Italy. On the basis of the analyses of 362 129 single-nucleotide polymorphisms we found several strong signals within or near genes previously implicated in psychiatric disorders. They include the association of neuroticism with SNAP25 (rs362584, P=5 × 10−5), extraversion with BDNF and two cadherin genes (CDH13 and CDH23; Ps<5 × 10−5), openness with CNTNAP2 (rs10251794, P=3 × 10−5), agreeableness with CLOCK (rs6832769, P=9 × 10−6) and conscientiousness with DYRK1A (rs2835731, P=3 × 10−5). Effect sizes were small (less than 1% of variance), and most failed to replicate in the follow-up independent samples (N up to 3903), though the association between agreeableness and CLOCK was supported in two of three replication samples (overall P=2 × 10−5). We infer that a large number of loci may influence personality traits and disorders, requiring larger sample sizes for the GWA approach to confidently identify associated genetic variants.
TL;DR: The results from this study suggest that SNPs with substantial odds ratio are unlikely to exist for MDD, at least in the authors' datasets and among the relatively common SNPs genotyped or tagged by the half-million-loci arrays.
Abstract: Major depressive disorder (MDD) is a highly prevalent disorder with substantial heritability. Heritability has been shown to be substantial and higher in the variant of MDD characterized by recurrent episodes of depression. Genetic studies have thus far failed to identify clear and consistent evidence of genetic risk factors for MDD. We conducted a genome-wide association study (GWAS) in two independent datasets. The first GWAS was performed on 1022 recurrent MDD patients and 1000 controls genotyped on the Illumina 550 platform. The second was conducted on 492 recurrent MDD patients and 1052 controls selected from a population-based collection, genotyped on the Affymetrix 5.0 platform. Neither GWAS identified any SNP that achieved GWAS significance. We obtained imputed genotypes at the Illumina loci for the individuals genotyped on the Affymetrix platform, and performed a meta-analysis of the two GWASs for this common set of approximately half a million SNPs. The meta-analysis did not yield genome-wide significant results either. The results from our study suggest that SNPs with substantial odds ratio are unlikely to exist for MDD, at least in our datasets and among the relatively common SNPs genotyped or tagged by the half-million-loci arrays. Meta-analysis of larger datasets is warranted to identify SNPs with smaller effects or with rarer allele frequencies that contribute to the risk of MDD.
TL;DR: Lithium and rosiglitazone, possibly by the activation of the Wnt signaling pathway, reduce various AD neuropathological markers and may be considered as potential therapeutic agents against the disease.
Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, accumulation of the amyloid-beta-peptide (Abeta) and synaptic alterations. Treatment with lithium has been shown to provide neuroprotection against several insults, including protection against Abeta neurotoxicity in vitro. Rosiglitazone, a peroxisome proliferator activated receptor-gamma agonist, has been shown to attenuate Abeta-peptide neurotoxic effects, including the inflammatory response of microglia and astrocytes. Both types of drugs activate Wnt signaling, a pathway that has been shown to be related to AD. In this study, a double transgenic mouse model, which coexpresses APPswe and the exon 9 deletion of the presenilin 1 (PSEN1) gene, was used to examine, in vivo, the effect of lithium and rosiglitazone on Abeta neurotoxicity. Mice were tested for spatial memory, and their brain samples were used for histochemical and biochemical analysis. In this study, we report that both drugs significantly reduced (1) spatial memory impairment induced by amyloid burden; (2) Abeta aggregates and Abeta oligomers; and (3) astrocytic and microglia activation. They also prevented changes in presynaptic and postsynaptic marker proteins. Finally, both drugs activate Wnt signaling shown by the increase in beta-catenin and by the inhibition of the glycogen synthase kinase-3beta. We conclude that lithium and rosiglitazone, possibly by the activation of the Wnt signaling pathway, reduce various AD neuropathological markers and may be considered as potential therapeutic agents against the disease.
National Institutes of Health1, University of Antioquia2, Children's Hospital of Philadelphia3, University of Bergen4, University of Barcelona5, Autonomous University of Barcelona6, Virginia Commonwealth University7, State University of New York Upstate Medical University8, Saarland University9, University of Trier10, University of Würzburg11, University of California, Irvine12, New York University13
TL;DR: Functional studies revealed that LPHN3 variants are expressed in key brain regions related to attention and activity, affect metabolism in neural circuits implicated in ADHD, and are associated with response to stimulant medication.
Abstract: Attention-Deficit/Hyperactivity Disorder (ADHD) has a very high heritability (0.8), suggesting that about 80% of phenotypic variance is due to genetic factors. We used the integration of statistical and functional approaches to discover a novel gene that contributes to ADHD. For our statistical approach, we started with a linkage study based on large multigenerational families in a population isolate, followed by fine mapping of targeted regions using a family-based design. Family- and population-based association studies in five samples from disparate regions of the world were used for replication. Brain imaging studies were performed to evaluate gene function. The linkage study discovered a genome region harbored in the Latrophilin 3 gene (LPHN3). In the world-wide samples (total n=6360, with 2627 ADHD cases and 2531 controls) statistical association of LPHN3 and ADHD was confirmed. Functional studies revealed that LPHN3 variants are expressed in key brain regions related to attention and activity, affect metabolism in neural circuits implicated in ADHD, and are associated with response to stimulant medication. Linkage and replicated association of ADHD with a novel non-candidate gene (LPHN3) provide new insights into the genetics, neurobiology, and treatment of ADHD.
TL;DR: There is considerable BDNF allele and haplotype diversity among global populations and evidence for positive selection at the BDNF locus, which can have a profound impact on the detection of disease susceptibility genes.
Abstract: Genetic variants in the brain-derived neurotrophic factor (BDNF) gene, predominantly the functional Val66Met polymorphism, have been associated with risk of bipolar disorder and other psychiatric disorders. However, not all studies support these findings, and overall the evidence for the association of BDNF with disease risk is weak. As differences in population genetic structure between patient samples could cause discrepant or spurious association results, we investigated this possibility by carrying out population genetic analyses of the BDNF genomic region. Substantial variation was detected in BDNF coding region single-nucleotide polymorphism (SNP) allele and haplotype frequencies between 58 global populations, with the derived Met allele of Val66Met ranging in frequency from 0 to 72% across populations. F(ST) analyses to assess diversity in the HapMap populations determined that the Val66Met F(ST) value was at the 99.8th percentile among all SNPs in the genome. As the BDNF population genetic differences may be due to local selection, we performed the long-range haplotype test for selection using 68 SNPs spanning the BDNF genomic region in 12 European-derived pedigrees. Evidence for positive selection was found for a high-frequency Val-carrying haplotype, with a relative extended haplotype homozygosity value above the 99 th percentile compared with HapMap data (P=4.6 x 10(-4)). In conclusion, we observed considerable BDNF allele and haplotype diversity among global populations and evidence for positive selection at the BDNF locus. These phenomena can have a profound impact on the detection of disease susceptibility genes and must be considered in gene association studies of BDNF.
TL;DR: Converging lines of evidences demonstrate actions of tianeptine on the glutamatergic system, which could provide a key pathway for its antidepressant action, and therefore offer new insights into how tianptine may be useful in the treatment of depressive disorders.
Abstract: Tianeptine is a clinically used antidepressant that has drawn much attention, because this compound challenges traditional monoaminergic hypotheses of depression. It is now acknowledged that the antidepressant actions of tianeptine, together with its remarkable clinical tolerance, can be attributed to its particular neurobiological properties. The involvement of glutamate in the mechanism of action of the antidepressant tianeptine is consistent with a well-developed preclinical literature demonstrating the key function of glutamate in the mechanism of altered neuroplasticity that underlies the symptoms of depression. This article reviews the latest evidence on tianeptine's mechanism of action with a focus on the glutamatergic system, which could provide a key pathway for its antidepressant action. Converging lines of evidences demonstrate actions of tianeptine on the glutamatergic system, and therefore offer new insights into how tianeptine may be useful in the treatment of depressive disorders.
TL;DR: Higher doses of SSRIs are associated with greater efficacy in the treatment of OCD, and this SSRI efficacy pattern stands in contrast to other psychiatric disorders like Major Depressive Disorder.
Abstract: We sought to determine differences in efficacy and tolerability between different doses of selective serotonin reuptake inhibitors in the treatment of obsessive-compulsive disorder (OCD) using meta-analysis. We identified 9 studies involving 2268 subjects that were randomized, double-blind placebo-controlled clinical trials that compared multiple, fixed-doses of selective serotonin reuptake inhibitors (SSRIs) to each other and to placebo in the treatment of adults with OCD. Change in Y-BOCS score, proportion of treatment responders, and dropouts (all-cause and due to side-effects) were determined for each included study. Weighted mean difference was used to examine mean change in Y-BOCS score. Pooled absolute risk difference was used to examine dichotomous outcomes. Meta-analysis was performed using a fixed effects model in RevMan 4.2.8. We found that compared with either low or medium doses, higher doses of SSRIs were associated with improved treatment efficacy, using either Y-BOCS score or proportion of treatment responders as an outcome. Dose of SSRIs was not associated with the number of all-cause dropouts. Higher doses of SSRIs were associated with significantly higher proportion of dropouts due to side-effects. These results suggests that higher doses of SSRIs are associated with greater efficacy in the treatment of OCD. This SSRI efficacy pattern stands in contrast to other psychiatric disorders like Major Depressive Disorder. This greater treatment efficacy is somewhat counterbalanced by the greater side-effect burden with higher doses of SSRIs. At present, there are insufficient data to generalize these findings to children or adolescents with OCD.
TL;DR: This study replicates the original reported association of ZNF804A with schizophrenia and suggests that there is a consistent link between the A allele of rs1344706, increased expression of Z NF804A and risk for schizophrenia.
Abstract: Replication of association between schizophrenia and ZNF804A in the Irish Case–Control Study of Schizophrenia sample
TL;DR: This review covers a number of proposed factors and the evidences for and against these factors that may account for gender differences in depression, including the possible role of estrogens at puberty, differences in exposure to childhood trauma, Differences in stress perception between men and women and the biological differences in stress response.
Abstract: Although few studies dispute that there are gender differences in depression, the etiology is still unknown. In this review, we cover a number of proposed factors and the evidences for and against these factors that may account for gender differences in depression. These include the possible role of estrogens at puberty, differences in exposure to childhood trauma, differences in stress perception between men and women and the biological differences in stress response. None of these factors seem to explain gender differences in depression. Finally, we do know that when depressed, women show greater hypothalamic-pituitary-adrenal (HPA) axis activation than men and that menopause with loss of estrogens show the greatest HPA axis dysregulation. It may be the constantly changing steroid milieu that contributes to these phenomena and vulnerability to depression.
TL;DR: Excessive Ca2+ levels are responsible for boosting AGC activity, mitochondrial metabolism and, to a more variable degree, oxidative stress in autistic brains, and their modulation could provide new preventive and therapeutic strategies.
Abstract: Autism is a severe developmental disorder, whose pathogenetic underpinnings are still largely unknown. Temporocortical gray matter from six matched patient-control pairs was used to perform post-mortem biochemical and genetic studies of the mitochondrial aspartate/glutamate carrier (AGC), which participates in the aspartate/malate reduced nicotinamide adenine dinucleotide shuttle and is physiologically activated by calcium (Ca(2+)). AGC transport rates were significantly higher in tissue homogenates from all six patients, including those with no history of seizures and with normal electroencephalograms prior to death. This increase was consistently blunted by the Ca(2+) chelator ethylene glycol tetraacetic acid; neocortical Ca(2+) levels were significantly higher in all six patients; no difference in AGC transport rates was found in isolated mitochondria from patients and controls following removal of the Ca(2+)-containing postmitochondrial supernatant. Expression of AGC1, the predominant AGC isoform in brain, and cytochrome c oxidase activity were both increased in autistic patients, indicating an activation of mitochondrial metabolism. Furthermore, oxidized mitochondrial proteins were markedly increased in four of the six patients. Variants of the AGC1-encoding SLC25A12 gene were neither correlated with AGC activation nor associated with autism-spectrum disorders in 309 simplex and 17 multiplex families, whereas some unaffected siblings may carry a protective gene variant. Therefore, excessive Ca(2+) levels are responsible for boosting AGC activity, mitochondrial metabolism and, to a more variable degree, oxidative stress in autistic brains. AGC and altered Ca(2+) homeostasis play a key interactive role in the cascade of signaling events leading to autism: their modulation could provide new preventive and therapeutic strategies.