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The Neuronal Transporter Gene SLC6A15 Confers Risk to Major Depression
Abstract
Major depression (MD) is one of the most prevalent psychiatric disorders and a leading cause of loss in work productivity. A combination of genetic and environmental risk factors probably contributes to MD. We present data from a genome-wide association study revealing a neuron-specific neutral amino acid transporter (SLC6A15) as a susceptibility gene for MD. Risk allele carrier status in humans and chronic stress in mice were associated with a downregulation of the expression of this gene in the hippocampus, a brain region implicated in the pathophysiology of MD. The same polymorphisms also showed associations with alterations in hippocampal volume and neuronal integrity. Thus, decreased SLC6A15 expression, due to genetic or environmental factors, might alter neuronal circuits related to the susceptibility for MD. Our convergent data from human genetics, expression studies, brain imaging, and animal models suggest a pathophysiological mechanism for MD that may be accessible to drug targeting.
... The SLC6A15 gene is based on a novel candidate gene responsible for MDD, but it remains unclear how the SLC6A15 genes alter the brain functional activities of the MDD patients. The SLC6A15 gene encoding a sodium-dependent branched amino acid transporter is the nearest annotated gene with a distance of about 287 Kb to the region of association [48]. In the present study we investigate the impact of polymorphism of SLC615 gene rs1545843 found no significant association between case and control samples. ...
... In the present study we investigate the impact of polymorphism of SLC615 gene rs1545843 found no significant association between case and control samples. Recently, SLC6A15 was found to be associated with MDD, especially in a genome-wide association analysis, SNP rs1545843 documented with significant results [48]. Another study found the impact of rs1545843 in MDD patients on adrenocorticotropic hormone (ACTH) and cortisol levels was also shown and an associating of polymorphism with cognitive functions, like memories and continued attention, was already documented in these patients [49]. ...
... Another study found the impact of rs1545843 in MDD patients on adrenocorticotropic hormone (ACTH) and cortisol levels was also shown and an associating of polymorphism with cognitive functions, like memories and continued attention, was already documented in these patients [49]. Although the proposed significance of these genes in the stress susceptibility documented in animal model research and potential links with MDD predisposition was recently investigated by GWAS [48]. The exact neurobiological role of this genetic polymorphism in the pathophysiologic phase of MDD and association of structural changes in specific brain regions in not clearly explained. ...
People around the world are currently affected by Major Depressive Disorder (MDD). Despite its many aspects, symptoms, manifestations and impacts, efforts have been made to identify the root causes of the disorder. In particular, genetic studies have concentrated on identifying candidate genes for MDD and exploring associations between these genes and some specific group of individuals. The aim of this research was to find out the association between single nucleotide polymorphisms in 6 candidate genes linked to the neurobiology of major depressive disorder in the North-Western population of Pakistan. We performed a case-control analysis, with 400 MDD and 232 controls. A trained psychiatrist or clinical psychologists evaluated the patients. Six polymorphisms were genotyped and tested for allele and genotype association with MDD. There were no statistical variations between MDD patients and healthy controls for genotypic and allelic distribution of all the polymorphisms observed. Thus, our analysis does not support the major role of these polymorphisms in contributing to MDD susceptibility, although it does not preclude minor impact. The statistically significant correlation between six polymorphisms and major depressive disorder in the studied population was not observed. There are inconsistencies in investigations around the world. Future research, including GWAS and association analysis on larger scale should be addressed for further validation and replication of the present findings.
... SLC6A15 gene is founded a novel candidate gene responsible for MDD still it is unknown how SLC6A15 genes alter brain functional activities of MDD patients. The SLC6A15 coding for a sodium dependent branched amino acid transporter is the nearest annotated gene with a distance of approximately 287kb to the region of association [40]. In the present study we investigate the impact of polymorphism of SLC615 gene rs1545843 found no significant association between . ...
... ; case and control samples. Recently SLC6A15 has been found to be MDD associated particularly in a genome wide association analysis, SNP rs1545843 documented with significant result [40]. Another study found an effect of rs1545843 in MDD patients on adrenocorticotropic hormone (ACTH) and cortisol levels and documented an association in these patients between his polymorphism and cognitive functions such as memory and sustained attention [41]. ...
... Another study found an effect of rs1545843 in MDD patients on adrenocorticotropic hormone (ACTH) and cortisol levels and documented an association in these patients between his polymorphism and cognitive functions such as memory and sustained attention [41]. Although a recent GWAS investigated the proposed role of this genes in the stress susceptibility documented in animal model studies and potential associations with a predisposition to MDD [40]. The exact neurobiological role of this genetic polymorphism in the pathophysiologic phase of MDD and association of structural changes in specific brain regions in not clearly explained. ...
People around the world are currently affected by Major Depressive Disorder (MDD). Despite its many aspects, symptoms, manifestations and impacts, efforts have been made to identify the root causes of the disorder. In particular, genetic studies have concentrated on identifying candidate genes for MDD and exploring associations between these genes and some specific group of individuals. The aim of this research was to find out the association between single nucleotide polymorphisms in 6 candidate genes linked to the neurobiology of major depressive disorder in the North-Western population of Pakistan. We performed a case-control analysis, with 400 MDD and 232 controls. A trained psychiatrist or clinical psychologists evaluated the patients. Six polymorphisms were genotyped and tested for allele and genotype association with MDD. There were no statistical variations between MDD patients and healthy controls for genotypic and allelic distribution of all the polymorphisms observed. Thus, our analysis does not support the major role of these polymorphisms in contributing to MDD susceptibility, although it does not preclude minor impact. The statistically significant correlation between six polymorphisms and major depressive disorder in the studied population was not observed. There are inconsistencies in investigations around the world. Future research, including GWAS and association analysis on larger scale should be addressed for further validation and replication of the present findings.
... The research proves the relation between chronic stress in mice and down-regulation of the Slc6a15 in the hippocampus. Potentially, these changes lead directly to alterations in the hippocampal volume and the integrity of neurons [90]. It has been showed, that the decreased Slc6a15 expression, due to genetic or environmental factors, might alter neuronal circuits related to the susceptibility for major depression [90]. ...
... Potentially, these changes lead directly to alterations in the hippocampal volume and the integrity of neurons [90]. It has been showed, that the decreased Slc6a15 expression, due to genetic or environmental factors, might alter neuronal circuits related to the susceptibility for major depression [90]. The lower Slc6a15 expression, especially in the hippocampus, could increase stress susceptibility, also by altering excitatory neurotransmission in the brain. ...
... The studies show that the Slc6a15 plays a role in modulating emotional behaviour, possibly mediated by its impact on glutamatergic neurotransmission [91]. A decreased expression of this gene may lead to disturbances around the neuronal conduction, thus, the Slc6a15 protein may be the grip point for drugs which affect its function [90]. A decreased expression of Slc6a15 was noted in the cerebral cortex of mice receiving only istradefylline, Mg 2+ , Zn 2+ and simultaneously istradefylline with Mg 2+ . ...
The purpose of the study was to investigate whether the co-administration of Mg2+ and Zn2+ with selective A1 and A2A receptor antagonists might be an interesting antidepressant strategy. Forced swim, tail suspension, and spontaneous locomotor motility tests in mice were performed. Further, biochemical and molecular studies were conducted. The obtained results indicate the interaction of DPCPX and istradefylline with Mg2+ and Zn2+ manifested in an antidepressant-like effect. The reduction of the BDNF serum level after co-administration of DPCPX and istradefylline with Mg2+ and Zn2+ was noted. Additionally, Mg2+ or Zn2+, both alone and in combination with DPCPX or istradefylline, causes changes in Adora1 expression, DPCPX or istradefylline co-administered with Zn2+ increases Slc6a15 expression as compared to a single-drug treatment, co-administration of tested agents does not have a more favourable effect on Comt expression. Moreover, the changes obtained in Ogg1, MsrA, Nrf2 expression show that DPCPX-Mg2+, DPCPX-Zn2+, istradefylline-Mg2+ and istradefylline-Zn2+ co-treatment may have greater antioxidant capacity benefits than administration of DPCPX and istradefylline alone. It seems plausible that a combination of selective A1 as well as an A2A receptor antagonist and magnesium or zinc may be a new antidepressant therapeutic strategy.
... In the vast wake of genome-wide association studies (GWAS) and meta-analysis studies trying to pinpoint genetic risk factors for psychiatric disorders, SLC6A15 has recently gained attention due to several publications implicating the gene in the etiology of MDD. Single nucleotide polymorphisms (SNPs) near SLC6A15 correlated with MDD prevalence and stress vulnerability (Kohli et al., 2011), and hypothalamus-pituitary-adrenal (HPA) axis regulation and memory (Schuhmacher et al., 2013). Recently, another SNP in close proximity to SLC6A15 reached genome-wide significance in a joint study that associated 15 genetic loci with the risk of MDD (Hyde et al., 2016). ...
... p*** < .001, bars represent mean ± SEM increased risk of MDD and difficulties in regulating the HPA axis (Kohli et al., 2011;Schuhmacher et al., 2013). In addition, animal studies indicate that this neutral amino acid transporter affects stress resilience phenotypes (Chandra et al., 2017;Santarelli et al., 2016). ...
... As previous reports on SLC6A15 already speculated that glutamatergic signalling might be affected by this transporter (Kohli et al., 2011) and especially glutamate tissue concentration was found to be reduced in the hippocampus of SLC6A15 KO mice (Santarelli et al., 2015), we hypothesized that neuronal activity might directly be affected. Indeed, our results demonstrate that the spontaneous release probability of excitatory neurons is significantly reduced in SLC6A15 KO cells. ...
Major depressive disorder (MDD) is one of the most severe global health problems with millions of people affected, however, the mechanisms underlying this disorder is still poorly understood. Genome‐wide association studies have highlighted a link between the neutral amino acid transporter SLC6A15 and MDD. Additionally, a number of preclinical studies support the function of this transporter in modulating levels of brain neurotransmitters, stress system regulation and behavioural phenotypes related to MDD. However, the molecular and functional mechanisms involved in this interaction are still unresolved. Therefore, to investigate the effects of the SLC6A15 transporter, we used hippocampal tissue from Slc6a15‐KO and wild‐type mice, together with several in‐vitro assays in primary hippocampal neurons. Utilizing a proteomics approach we identified differentially regulated proteins that formed a regulatory network and pathway analysis indicated significantly affected cellular domains, including metabolic, mitochondrial and structural functions. Furthermore, we observed reduced release probability at glutamatergic synapses, increased mitochondrial function, higher GSH/GSSG redox ratio and an improved neurite outgrowth in primary neurons lacking SLC6A15. In summary, we hypothesize that by controlling the intracellular concentrations of neutral amino acids, SLC6A15 affects mitochondrial activity, which could lead to alterations in neuronal structure and activity. These data provide further indication that a pharmacological or genetic reduction of SLC6A15 activity may indeed be a promising approach for antidepressant therapy.
... Whereas atypical antipsychotics lead to an increase of social behavior (Corbett et al., 1993). Concerning the serotonergic system, acutely 3,4methylenedioxymethamphetamine (MDMA) seems to have prosocial effects, both in humans and rodents (see for review (Kamilar-Britt and Bedi, 2017)). MDMA initially leads to an increase in the extracellular availability of 5-HT (Nichols et al., 1982), coinciding with its acute effects. ...
... Not only manipulation of the dopamine system can alter social behavior in distant species, substances affecting serotine pathways show similar evolutionary conservatism. As stated before, MDMA has prosocial effects, in humans and rodents (see for review (Kamilar-Britt and Bedi, 2017). ...
Social withdrawal is found across neuropsychiatric disorders and in animal species under various conditions. It has substantial impact on the quality of life in patients suffering from neuropsychiatric disorders. Often it occurs prodromal to the disease, suggesting that it is either an early biomarker or central to its etiology. Healthy social functioning is supported by the social brain of which the building blocks go back millions of years, showing overlap between humans, rodents and insects. Thus, to elucidate social withdrawal, we have to approach its environmental triggers and its neural and molecular genetic determinants in an evolutionary context. Pathological social withdrawal may originate from a faulty regulation of specific neural circuits. As there is a considerable heritability in social disorders, the genetic building blocks of the social decision making network might be our most relevant targets to obtain an understanding of the transition of normal social interaction into social withdrawal.
... To gain new insight into the mechanism of lung adenocarcinoma, we analyzed the existing information on the four genes forming the top two gene pairs. CHRM2 has been associated with nicotine dependence [38], while SLC6A15 has been associated with depression disorders [39]. Furthermore, SUGP1 has been recently linked to lung cancer [40], and PSD2 has been linked to neurological diseases according to GeneCards. ...
Cancer arises from the complex interplay of various factors. Traditionally, the identification of driver genes focuses primarily on the analysis of somatic mutations. We describe a new method for the detection of driver gene pairs based on an epistasis analysis that considers both germline and somatic variations. Specifically, the identification of significantly mutated gene pairs entails the calculation of a contingency table, wherein one of the co-mutated genes can exhibit a germline variant. By adopting this approach, it is possible to select gene pairs in which the individual genes do not exhibit significant associations with cancer. Finally, a survival analysis is used to select clinically relevant gene pairs. To test the efficacy of the new algorithm, we analyzed the colon adenocarcinoma (COAD) and lung adenocarcinoma (LUAD) samples available at The Cancer Genome Atlas (TCGA). In the analysis of the COAD and LUAD samples, we identify epistatic gene pairs significantly mutated in tumor tissue with respect to normal tissue. We believe that further analysis of the gene pairs detected by our method will unveil new biological insights, enhancing a better description of the cancer mechanism.
... This is a novel finding since in recent genome-wide association studies no strong signal was observed for solute carrier transporters. Interestingly, SLC6A4 and SLC6A15 gene variants have been associated with age at depression onset [29,30]. Despite this lack of specific data on SLC22A2 variants on the risk of depressive disorders, gene-diseases association biobanks suggest they may have the second highest association strength (after SLC6A4) [31]. ...
Neuropsychiatric symptoms have been reported in patients receiving dolutegravir, a known inhibitor of the renal and neuronal-expressed organic anion transporter 2 (encoded by SLC22A2 gene). The effect of the genetic variant SLC22A2 808C>A on dolutegravir discontinuation was assessed and analyzed by real-time PCR. We enrolled 627 participants: CA/AA carriers showed a higher prevalence of pre-existing psychiatric comorbidities and use of antidepressants. After 27.9 months, 108 participants discontinued dolutegravir, 64 for neuropsychiatric symptoms. Patients with pre-existing psychiatric comorbidities were at higher risk of dolutegravir discontinuation, while patients carrying the SLC22A2 CA/AA genotype were not. Combining the two variables, an opposite effect of SLC22A2 variants according to pre-existing psychiatric disorders was observed. Using multivariate Cox models, the combined variable pre-existing psychiatric comorbidities/SLC22A2 variants and the use of non-tenofovir alafenamide containing antiretroviral regimens were predictors of dolutegravir discontinuation for neuropsychiatric symptoms. Within 30 days, the majority of participants had a complete resolution of symptoms (61.8%), while 32.7% and 5.5% had partial or no change after dolutegravir discontinuation, respectively. Discontinuation of dolutegravir for neuropsychiatric symptoms was not uncommon and more frequent in participants with pre-existing psychiatric disorders. We described an interaction between SLC22A2 genetic variant and psychiatric comorbidities. In 38.2% of patients, a complete neuropsychiatric symptoms resolution was not observed after dolutegravir discontinuation suggesting the involvement of additional factors.
... However, we found that two genes, SLC6A15 and KCNQ5, exhibit unidirectional regulation in the mouse models of NP and IP, respectively. SLC6A15 encodes neuronal amino acid transport and was previously reported as a depression gene [77]. ...
The mechanisms of chronic pain are complex, and genetic factors play an essential role in the development of chronic pain. Neuropathic pain (NP) and inflammatory pain (IP) are two primary components of chronic pain. Previous studies have uncovered some common biological processes in NP and IP. However, the shared genetic mechanisms remained poorly studied. We utilized multi-omics systematic analyses to investigate the shared genetic mechanisms of NP and IP. First, by integrating several genome-wide association studies (GWASs) with multi-omics data, we revealed the significant overlap of the gene co-expression modules in NP and IP. Further, we uncovered the shared biological pathways, including the previously reported mitochondrial electron transport and ATP metabolism, and stressed the role of genetic factors in chronic pain with neurodegenerative diseases. Second, we identified 24 conservative key drivers (KDs) contributing to NP and IP, containing two well-established pain genes, IL1B and OPRM1, and some novel potential pain genes, such as C5AR1 and SERPINE1. The subnetwork of those KDs highlighted the processes involving the immune system. Finally, gene expression analysis of the KDs in mouse models underlined two of the KDs, SLC6A15 and KCNQ5, with unidirectional regulatory functions in NP and IP. Our study provides strong evidence to support the current understanding of the shared genetic regulatory networks underlying NP and IP and potentially benefit the future common therapeutic avenues for chronic pain.
... SLC6A15 plays a role in modulating emotional behavior, possibly mediated by its effects on glutamatergic neurotransmission [56]. It has been shown that the reduced expression of SLC6A15 in the brain can increase susceptibility to stress by altering the neural integrity of the excitatory neurotransmission [86]. Our study showed a very significant increase in the expression of Slc6a15 in the brains of mice subjected to combined Se and DPCPX therapy, both compared to the control group and to groups receiving the tested drugs alone. ...
The main goal of this study was to determine the antidepressant-like potential of the co-administration of sodium selenite (Se) and the selective adenosine A1 and A2A antagonists DPCPX and istradefylline (IST), respectively, in mice despair tests. Biochemical studies were performed to elucidate the action mechanisms of the investigated treatment strategies. The results confirmed that, when administered by itself, Se exerts an antidepressant-like effect in the FST and TST and that this activity is dose-dependent. Further experiments demonstrated that Se (0.25 mg/kg) significantly enhanced the activity of mice in both tests when co-administered with DPCPX (1 mg/kg) and IST (0.5 mg/kg) at doses which would be ineffective if administered individually. Our research revealed that neither DPCPX, IST, nor Se or combinations of the tested substances induced significant changes in the brain-derived neurotrophic factor (BDNF) levels in mice serum vs. the NaCl-treated group. However, we observed a decrease in the mRNA level of antioxidant defense enzymes. Molecular studies also showed changes in the expression of the Slc6a15, Comt, and Adora1 genes, particularly after exposure to the combination of Se and DPCPX, which indicates a beneficial effect and may help to explain the key mechanism of the antidepressant effect. The combination of Se with substances attenuating adenosine neurotransmission may become a new therapeutic strategy for patients with depression.
... 45 Studies have shown that neuronal transporter gene SLC6A15 in particular sites of the brain is responsible for emotional regulation but when altered becomes vulnerable to stress and depression. 46 The initial goal of this survey was to correlate psychological stress with academic performance, a burden to success, post-graduation map out's, enormous workload and expectations from family. Thus, these all concerns may cause a spike increase in stress score. ...
Restricted information regarding the protective effect of quercetin against stress-effectuated depression, anxiety and hypertension in students has been evaluated. Quercetin, king of flavonoids offers a great promise to reduce depression that negatively affects human mental and physical health which ultimately proliferates cardiovascular risks. This study aimed to enlighten the propitious effect of oral consumption of quercetin at a dose of 200 mg/day for 30 days on healthy college students prone to academic stress to explore its beneficial effects on body composition, blood pressure, oxidative stress and inflammatory markers in a randomised, double-blinded, placebo-controlled cross-over trial (n=100). In contrast to placebo, quercetin-rich supplementation significantly reduced (p‹0.05) psychological stress scale, body fat ratio (BFR), pulse rate, systolic pressure (SP) and tumour necrosis factor-alpha (TNFα) from their baseline values. Furthermore, a significant increase (p‹0.05) in oxidative and (anti) inflammatory marker i.e., superoxide dismutase (SOD) and interleukin 10 (IL10) were observed but did not affect catalase (CAT) and reduced glutathione (GSH) when compared with placebo. Thus, daily quercetin-rich supplementation supervenes antidepressant effects by attenuating inflammatory response, rehabilitating the activity of antioxidant enzymes, declining oxidative stress markers and hence improving alterations of the HPA axis which ultimately reduces blood pressure. These data are the first to our knowledge to show that quercetin supplementation could be a supportive therapy for improving stress and physical fitness in depressed subjects. This indicates the effectiveness of the flavonoid as a nutraceutical compound against the expansion of behavioural perturbation induced by psychological stress in a cost-effective, biofriendly manner. We explored a non-pharmacological but decent supra nutritional dose of quercetin since these data should provide a rational basis for the development of functional foods. The interminable effectiveness of quercetin supplementation for better improvement of stress remains to be investigated.
... The SLC6A15 transporter is almost exclusively expressed in the CNS and has been functionally characterized as a Na + -coupled amino acid transporter [78]. Previous research provided supportive roles for SLC6A15 in modulating anxiety and depressive-like behavior [79]. CPLX3 regulates synaptic vesicle fusion speed and Ca 2+ sensitivity and is necessary for the maintenance of synaptic structures in the retina; indeed, its loss caused vision deficits [80]. ...
Aquaculture environments frequently experience hypoxia and subsequent reoxygenation conditions, which have significant effects on hypoxia-sensitive fish populations. In this study, hepatic biochemical activity indices in serum and the content of major neurotransmitters in the brain were altered markedly after acute hypoxia and reoxygenation exposure in silver carp (Hypophthalmichthys molitrix). Proteomics analysis of the liver showed that a number of immune-related and cytoskeletal organization-related proteins were downregulated, the ferroptosis pathway was activated, and several antioxidant molecules and detoxifying enzymes were upregulated. Proteomics analysis of the brain showed that somatostatin-1A (SST1A) was upregulated, dopamine-degrading enzyme catechol O methyltransferase (COMT) and ferritin, heavy subunit (FerH) were downregulated, and the levels of proteins involved in the nervous system were changed in different ways. In conclusion, these findings highlight that hypoxia–reoxygenation has potential adverse effects on growth, locomotion, immunity, and reproduction of silver carp, and represents a serious threat to liver and brain function, possibly via ferroptosis, oxidative stress, and cytoskeleton destruction in the liver, and abnormal expression of susceptibility genes for neurodegenerative disorders in the brain. Our present findings provide clues to the mechanisms of hypoxia and reoxygenation damage in the brain and liver of hypoxia-sensitive fish. They could also be used to develop methods to reduce hypoxia or reoxygenation injury to fish.
... There seems to be a relationship between specific genes and the vulnerability to depression. Indeed, it was observed that people with altered levels of neuronal transporter gene SLC6A15 in specific brain regions involved in emotional regulation are more vulnerable to depression or other stressrelated emotional issues [79]. ...
Depressive-like behavior is a highly prevalent worldwide neuropsychiatric disorder that owns a complex pathophysiologic mechanism. The available pharmacotherapy is ineffective for most patients and shown several adverse effects. Therefore, it is important to find efficacy and safe antidepressive compounds. Some phytochemicals compounds regulate the same genes and pathways targeted by drugs; therefore, diets rich in fruits and vegetables could be considered novel treatment approaches. Currently, the functional properties of quercetin acquired great interest, due to its beneficial effects on health. Quercetin is a flavonoid ubiquitously present in vegetables and fruits, interestingly for its strong antioxidant properties. The purpose of this review is to summarize the preclinical studies present in the literature, in the last ten years, aimed at illustrating the effects of quercetin pre-treatment in depressive-like behaviors. Quercetin resulted in antidepressant-like actions due to its antioxidant, anti-inflammatory, and neuroprotective effects. This pointed out the usefulness of this flavonoid as a nutraceutical compound against the development of psychological stress-induced behavioral perturbation. Therefore, quercetin or a diet containing it may become a prospective supplementation or an efficient adjuvant therapy for preventing stress-mediated depressive-like behavior.
... Val allele was suggested to be associated in Caucasian populations (Frazier et al., 2014) whereas findings in Han Chinese population showed Met allele to be associated with BD (Wang et al., 2012;Xu et al., 2010). The recent GWAS studies in European population could not confirm association of BDNF with BD (Cichon et al., 2011;Kohli et al., 2011;McMahon et al., 2010;Mühleisen et al., 2014;Sklar et al., 2011). While some meta-analyses on the European population have shown the Val allele to be associated with BD, there have been mixed results in other populations (González-Castro et al., 2015;Li et al., 2016;Rai et al., 2019). ...
Background
The association of the Val66Met (rs6265) polymorphism in the brain-derived neurotrophic factor ( BDNF) gene with bipolar disorder (BD) and response to lithium treatment has been suggested, though inconsistently. The considerable diversity of allele frequency across different populations contributes to this. There is no data from South Asia till date. Hence, we examined the association of this polymorphism in BD cases from India, and its association with lithium treatment response.
Methods
BD patients ( N = 301) were recruited from the clinical services of National Institute of Mental Health and Neurosciences (NIMHANS), India. Lithium treatment response for 190 BD subjects was assessed using Alda scale by NIMH life charts. Patients with total score ⩾7 were defined as lithium responders ( N = 115) and patients with score <7 were defined as lithium non-responders ( N = 75). Healthy controls ( N = 484) with no lifetime history of neuropsychiatric illness or a family history of mental illness were recruited as control set. Genotyping was performed by TaqMan genotyping assay.
Results
Genotype and allele frequency of BDNF Val66Met SNP was significantly different (χ2 = 7.78, p = 0.02) in cases compared to controls, and the Val(G) allele was more frequent (χ2 = 7.08, p = 0.008) in BD patients. However, no significant difference is noted in genotype or allele frequencies of this polymorphism between the lithium responders and non-responders.
Conclusions
The Val(G) allele of BDNF Val66Met polymorphism is associated with risk of BD in this sample, but it is not related to response to lithium.
... Containing 1 (CRYBG1), which does not have an established function in brain to date, but was found to be in close proximity to a new locus associated with systemic inflammation in adulthood (Shin et al., 2019). One of these highly hypermethylated probes was moreover annotated to Solute Carrier Family 6 Member 15 (SLC6A15), [135] which was found to be involved in glutamatergic transmission (Santarelli et al., 2016) and confer risk to major depression (Kohli et al., 2011). ...
Prenatal stress is a known risk factor for alterations in brain structure, cognition and behavior associated with neurodevelopmental psychiatric disorders. However, underlying molecular mechanisms are not fully understood and have never been investigated in live human embryonic neuronal cells. This study aimed at examining the potential molecular effects of prenatal stress on the developing brain by modelling embryonic neurogenesis in human stem cells and inducing glucocorticoid receptor-dependent epigenetic changes. Embryonic stem cells and induced pluripotent stem cells were differentiated into ventricular zone-like neuronal progenitors and migrating neurons. Glucocorticoid receptor expression and translocation to the nucleus upon stimulation with dexamethasone were traced across neuronal development and epigenomic changes assessed by alterations in methylation profile and differential gene expression. The results support an intrinsic role of the glucocorticoid receptor during early neurogenesis and suggest that exposure to external glucocorticoids has little effect on neurulating cells up until the start of radial migration towards outer cortical layers. In migrating neurons however, glucocorticoid receptor activation led to hypermethylation of genes with well-established implications in psychiatric disorders, forebrain development, migration, axon development, and Wnt signaling. These effects were mirrored on the transcriptome level in that the number of genes significantly regulated by dexamethasone exposure increased in parallel with glucocorticoid receptor expression and translocation to the nucleus over neural differentiation. An understanding of the molecular mechanisms linking prenatal stress to psychiatric disorders may both help promote awareness of its impact and the development of targeted interventions.
... The first GWAS of depression ( Sullivan et al., 2009 ), involving ˜3,500 individuals of European ancestry, reported no genome-wide significant SNPs. Additional GWAS were unsuccessful in identifying variants reaching the stringent threshold of genome-wide significance, until Kohli et al. (2011) found one genome-wide significant SNP around the gene SLC6A15 (solute carrier family 6 protein). Although this SNP has not been successfully replicated in subsequent GWAS, a number of follow-up studies in animals and humans examining this candidate gene have identified plausible biological links between SLC6A15 and depression. ...
Depression is the world's leading cause of disability. Greater understanding of the neurobiological basis of depression is necessary for developing novel treatments with improved efficacy and acceptance. Recently, major advances have been made in the search for genetic variants associated with depression which may help to elucidate etiological mechanisms. The present review has two major objectives. First, we offer a brief review of two major biological systems with strong evidence for involvement in depression pathology: neurotransmitter systems and the stress response. Secondly, we provide a synthesis of the functions of the 269 genes implicated by the most recent genome-wide meta-analysis, supporting the importance of these systems in depression and providing insights into other possible mechanisms involving neurodevelopment, neurogenesis, and neurodegeneration. Our goal is to undertake a broad, preliminary stock-taking of the most recent hypothesis-free findings and examine the weight of the evidence supporting these existing theories and highlighting novel directions. This qualitative review and accompanying gene function table provides a valuable resource and guide for basic and translational researchers, with suggestions for future mechanistic research, leveraging genetics to prioritize studies on the neurobiological processes involved in depression etiology and treatment.
... Containing 1 (CRYBG1), which does not have an established function in brain to date, but was found to be in close proximity to a new locus associated with systemic inflammation in adulthood (Shin et al., 2019). One of these highly hypermethylated probes was moreover annotated to Solute Carrier Family 6 Member 15 (SLC6A15), [135] which was found to be involved in glutamatergic transmission (Santarelli et al., 2016) and confer risk to major depression (Kohli et al., 2011). ...
Prenatal stress is a known risk factor for alterations in brain structure, cognition and behavior associated with neurodevelopmental psychiatric disorders. However, underlying molecular mechanisms are not fully understood and have never been investigated in live human embryonic neuronal cells. This study aimed at examining the potential molecular effects of prenatal stress on the developing brain by modelling embryonic neurogenesis in human stem cells and inducing glucocorticoid receptor-dependent epigenetic changes. Embryonic stem cells and induced pluripotent stem cells were differentiated into ventricular zone-like neuronal progenitors and migrating neurons. Glucocorticoid receptor expression and translocation to the nucleus upon stimulation with dexamethasone were traced across neuronal development and epigenomic changes assessed by alterations in methylation profile and differential gene expression. The results support an intrinsic role of the glucocorticoid receptor during early neurogenesis and suggest that exposure to external glucocorticoids has little effect on neurulating cells up until the start of radial migration towards outer cortical layers. In migrating neurons however, glucocorticoid receptor activation led to hypermethylation of genes with well-established implications in psychiatric disorders, forebrain development, migration, axon development, and Wnt signaling. These effects were mirrored on the transcriptome level in that the number of genes significantly regulated by dexamethasone exposure increased in parallel with glucocorticoid receptor expression and translocation to the nucleus over neural differentiation. An understanding of the molecular mechanisms linking prenatal stress to psychiatric disorders may both help promote awareness of its impact and the development of targeted interventions.
... The function of SLCs is essential for the homeostasis of the brain, since they participate in energy and glutamate metabolism, neurotransmitter release, blood-brain barrier, etc. (54). Notably, both mice and human studies emphasized the importance of SLC6A15/v7-3 in the development of depression, of which the mechanism is associated with a neuronal circuits alteration that raises susceptibility to depression (55,56). ...
Suicide is the most severe consequence of depression which has become a leading cause of disability and a global disease burden. Recent evidence indicates a central role of small molecules in the pathogenesis of depression and associated suicidal behaviors. However, there lacks a systemic exploration of small molecules in the development of depression-associated suicide, and it remains unclear how they affect an individual’s behavior. In order to compare the metabonomic profiles between drug-naïve patients with depression-associated suicidal behaviors and healthy individuals, we conducted a systemic database search for studies of metabolic characteristics in depression-associated suicidal behavior. Manual data curation and statistical analysis and integration were performed in Excel. We further performed an enrichment analysis of signaling pathway prediction using the Reactome Pathway Analysis tool. We have identified 17 metabolites that expressed differently between drug-naïve patients with depression-associated suicidal behaviors and healthy controls. We have integrated these metabolites into biological signaling pathways and provided a visualized signaling network in depressed suicidal patients. We have revealed that “transport of small molecules”, “disease”, “metabolism” and “metabolism of proteins” were the most relevant signaling sections, among which “transport of inorganic cations/anions and amino acids/oligopeptides”, “SLC-mediated transmembrane transport”, and “metabolism of amino acids and derivatives” should be further studied to elucidate their potential pathogenic mechanism in the development of depression and associated suicidal behavior. In conclusion, our findings of these 17 metabolites and associated signaling pathways could provide an insight into the molecular pathogenesis of depression-associated suicidal behavior and potential targets for new drug inventions.
... In the present study, we investigated genetic heterogeneity in major depression by conducting genetic analyses on individual symptoms of MDD in 148,752 participants from the UK Biobank. We identified nine genomic risk loci across the nine MDD symptoms and sum-score phenotypes, all have not been associated with major depression in previous GWASs Direk et al., 2017;Hall et al., 2017;Hek et al., 2013;Hyde et al., 2016;Kohli et al., 2011;Li et al., 2018;Power et al., 2017;. Our results revealed substantial genetic heterogeneity in depression symptoms with no overlap in significant loci across PHQ items. ...
... One locus (locus 3, tagged by lead SNP rs143756010) was identified in a recent GWAS of depression (Howard et al., 2019). The other eight loci have not been associated with depression in previous GWASs (Kohli et al., 2011;Hek et al., 2013;Cai et al., 2015;Hyde et al., 2016;Okbay et al., 2016;Direk et al., 2017;Power et al., 2017;Hall et al., 2018;Howard et al., 2018;Li et al., 2018;Wray et al., 2018;Howard et al., 2019), illustrating the importance of exploring genetic associations for specific symptoms. Our results revealed genetic heterogeneity in depressive symptoms with no overlap in significant loci across PHQ items. ...
Background
Depression is a clinically heterogeneous disorder. Previous large-scale genetic studies of depression have explored genetic risk factors of depression case–control status or aggregated sums of depressive symptoms, ignoring possible clinical or genetic heterogeneity.
Methods
We analyse data from 148 752 subjects of white British ancestry in the UK Biobank who completed nine items of a self-rated measure of current depressive symptoms: the Patient Health Questionnaire (PHQ-9). Genome-Wide Association analyses were conducted for nine symptoms and two composite measures. LD Score Regression was used to calculate SNP-based heritability ( h²SNP ) and genetic correlations ( rg ) across symptoms and to investigate genetic correlations with 25 external phenotypes. Genomic structural equation modelling was used to test the genetic factor structure across the nine symptoms.
Results
We identified nine genome-wide significant genomic loci (8 novel), with no overlap in loci across symptoms. h²SNP ranged from 6% (concentration problems) to 9% (appetite changes). Genetic correlations ranged from 0.54 to 0.96 (all p < 1.39 × 10 ⁻³ ) with 30 of 36 correlations being significantly smaller than one. A two-factor model provided the best fit to the genetic covariance matrix, with factors representing ‘psychological’ and ‘somatic’ symptoms. The genetic correlations with external phenotypes showed large variation across the nine symptoms.
Conclusions
Patterns of SNP associations and genetic correlations differ across the nine symptoms, suggesting that current depressive symptoms are genetically heterogeneous. Our study highlights the value of symptom-level analyses in understanding the genetic architecture of a psychiatric trait. Future studies should investigate whether genetic heterogeneity is recapitulated in clinical symptoms of major depression.
Echocardiography, a rapid and cost-effective imaging technique, assesses cardiac function and structure. Despite its popularity in cardiovascular medicine and clinical research, image-derived phenotypic measurements are manually performed, requiring expert knowledge and training. Notwithstanding great progress in deep-learning applications in small animal echocardiography, the focus has so far only been on images of anesthetized rodents. We present here a new algorithm specifically designed for echocardiograms acquired in conscious mice called Echo2Pheno, an automatic statistical learning workflow for analyzing and interpreting high-throughput non-anesthetized transthoracic murine echocardiographic images in the presence of genetic knockouts. Echo2Pheno comprises a neural network module for echocardiographic image analysis and phenotypic measurements, including a statistical hypothesis-testing framework for assessing phenotypic differences between populations. Using 2159 images of 16 different knockout mouse strains of the German Mouse Clinic, Echo2Pheno accurately confirms known cardiovascular genotype–phenotype relationships (e.g., Dystrophin) and discovers novel genes (e.g., CCR4-NOT transcription complex subunit 6-like, Cnot6l, and synaptotagmin-like protein 4, Sytl4), which cause altered cardiovascular phenotypes, as verified by H&E-stained histological images. Echo2Pheno provides an important step toward automatic end-to-end learning for linking echocardiographic readouts to cardiovascular phenotypes of interest in conscious mice.
Graphical abstract
Our research fills a critical gap in the depression literature by utilizing a life course perspective to examine gender–gene interactions in association with depression trajectories over time. Using data from the Health and Retirement Study, we estimated multi-level negative binomial and logistic mixed models to analyze gender-specific trajectories of depressive symptoms (CESD-8) and potential clinical depression risk from middle to late adulthood in relation to gender-by-polygenic-risk (PRS) interactions. We found increasingly greater female-male gaps in the CESD-8 scale and a higher probability of clinical depression risk with increasing polygenic risk scores. Furthermore, females’ higher genetic vulnerabilities to depressive conditions than males vary from ages 51 to 90 years, with most salient larger differences at oldest old ages at 76–85 (e.g. 0.28 higher CESD-8 scale for females at ages 76–85 years than for similar-aged males; higher 3.44% probability of depression risk for females at ages 81–85 compared to similar-aged males) followed by old ages at 61–70 years (e.g. about 2.40% higher probability of depression risk for females at ages 61–70 years than for similar-aged males) in comparison to younger ages during middle adulthood. This study contributes to new knowledge of how gender-by-polygenic-risk interactions are associated with depression trajectories across the life course.
(Full-text access: https://www.tandfonline.com/eprint/EP5RT7MBXGNVHSQVXPUA/full?target=10.1080/19485565.2023.2196710 )
Background:
Genome-wide association studies have discovered blocks of common variants-likely transcriptional-regulatory-associated with major depressive disorder (MDD), though the functional subset and their biological impacts remain unknown. Likewise, why depression occurs in females more frequently than males is unclear. We therefore tested the hypothesis that risk-associated functional variants interact with sex and produce greater impact in female brains.
Methods:
We developed techniques to directly measure regulatory variant activity and sex interactions using massively parallel reporter assays (MPRAs) in the mouse brain in vivo, in a cell type-specific manner, and applied these approaches to measure activity of >1,000 variants from >30 MDD loci.
Results:
We identified extensive sex-by-allele effects in mature hippocampal neurons, suggesting sex-differentiated impacts of genetic risk may underlie sex bias in disease. Unbiased informatics approaches indicated that functional MDD variants recurrently disrupt a number of transcription factor binding motifs, including those of sex hormone receptors. We confirmed a role for the latter by performing MPRAs in neonatal mice on the day of birth (during a sex-differentiating hormone surge) and hormonally-quiescent juveniles.
Conclusions:
Our study provides novel insights into the influence of age, biological sex, and cell type on regulatory variant function, and provides a framework for in vivo parallel assays to functionally define interactions between organismal variables like sex and regulatory variation. Moreover, we experimentally demonstrate that a portion the sex differences seen in MDD occurrence may be a product of sex-differentiated effects at associated regulatory variants.
The genetic dissection of major depressive disorder (MDD) ranks as one of the success stories of psychiatric genetics, with genome-wide association studies (GWAS) identifying 178 genetic risk loci and proposing more than 200 candidate genes. However, the GWAS results derive from the analysis of cohorts in which most cases are diagnosed by minimal phenotyping, a method that has low specificity. I review data indicating that there is a large genetic component unique to MDD that remains inaccessible to minimal phenotyping strategies and that the majority of genetic risk loci identified with minimal phenotyping approaches are unlikely to be MDD risk loci. I show that inventive uses of biobank data, novel imputation methods, combined with more interviewer diagnosed cases, can identify loci that contribute to the episodic severe shifts of mood, and neurovegetative and cognitive changes that are central to MDD. Furthermore, new theories about the nature and causes of MDD, drawing upon advances in neuroscience and psychology, can provide handles on how best to interpret and exploit genetic mapping results.
The second volume of Behavioral Genetics of the Mouse provides a comprehensive overview of the major genetically modified mouse lines used to model human neurobehavioral disorders; from disorders of perception, of autonomous and motor functions to social and cognitive syndromes, drug abuse and dependence as well as neurodegenerative pathologies. Mouse models obtained with different types of genetic manipulations (i.e. transgenic, knockout/in mice) are described in their pathological phenotypes, with a special emphasis on behavioral abnormalities. The major results obtained with many of the existing models are discussed in depth highlighting their strengths and limitations. A lasting reference, the thorough reviews offer an easy entrance into the extensive literature in this field, and will prove invaluable to students and specialists alike.
The second volume of Behavioral Genetics of the Mouse provides a comprehensive overview of the major genetically modified mouse lines used to model human neurobehavioral disorders; from disorders of perception, of autonomous and motor functions to social and cognitive syndromes, drug abuse and dependence as well as neurodegenerative pathologies. Mouse models obtained with different types of genetic manipulations (i.e. transgenic, knockout/in mice) are described in their pathological phenotypes, with a special emphasis on behavioral abnormalities. The major results obtained with many of the existing models are discussed in depth highlighting their strengths and limitations. A lasting reference, the thorough reviews offer an easy entrance into the extensive literature in this field, and will prove invaluable to students and specialists alike.
The second volume of Behavioral Genetics of the Mouse provides a comprehensive overview of the major genetically modified mouse lines used to model human neurobehavioral disorders; from disorders of perception, of autonomous and motor functions to social and cognitive syndromes, drug abuse and dependence as well as neurodegenerative pathologies. Mouse models obtained with different types of genetic manipulations (i.e. transgenic, knockout/in mice) are described in their pathological phenotypes, with a special emphasis on behavioral abnormalities. The major results obtained with many of the existing models are discussed in depth highlighting their strengths and limitations. A lasting reference, the thorough reviews offer an easy entrance into the extensive literature in this field, and will prove invaluable to students and specialists alike.
The second volume of Behavioral Genetics of the Mouse provides a comprehensive overview of the major genetically modified mouse lines used to model human neurobehavioral disorders; from disorders of perception, of autonomous and motor functions to social and cognitive syndromes, drug abuse and dependence as well as neurodegenerative pathologies. Mouse models obtained with different types of genetic manipulations (i.e. transgenic, knockout/in mice) are described in their pathological phenotypes, with a special emphasis on behavioral abnormalities. The major results obtained with many of the existing models are discussed in depth highlighting their strengths and limitations. A lasting reference, the thorough reviews offer an easy entrance into the extensive literature in this field, and will prove invaluable to students and specialists alike.
The second volume of Behavioral Genetics of the Mouse provides a comprehensive overview of the major genetically modified mouse lines used to model human neurobehavioral disorders; from disorders of perception, of autonomous and motor functions to social and cognitive syndromes, drug abuse and dependence as well as neurodegenerative pathologies. Mouse models obtained with different types of genetic manipulations (i.e. transgenic, knockout/in mice) are described in their pathological phenotypes, with a special emphasis on behavioral abnormalities. The major results obtained with many of the existing models are discussed in depth highlighting their strengths and limitations. A lasting reference, the thorough reviews offer an easy entrance into the extensive literature in this field, and will prove invaluable to students and specialists alike.
The second volume of Behavioral Genetics of the Mouse provides a comprehensive overview of the major genetically modified mouse lines used to model human neurobehavioral disorders; from disorders of perception, of autonomous and motor functions to social and cognitive syndromes, drug abuse and dependence as well as neurodegenerative pathologies. Mouse models obtained with different types of genetic manipulations (i.e. transgenic, knockout/in mice) are described in their pathological phenotypes, with a special emphasis on behavioral abnormalities. The major results obtained with many of the existing models are discussed in depth highlighting their strengths and limitations. A lasting reference, the thorough reviews offer an easy entrance into the extensive literature in this field, and will prove invaluable to students and specialists alike.
The second volume of Behavioral Genetics of the Mouse provides a comprehensive overview of the major genetically modified mouse lines used to model human neurobehavioral disorders; from disorders of perception, of autonomous and motor functions to social and cognitive syndromes, drug abuse and dependence as well as neurodegenerative pathologies. Mouse models obtained with different types of genetic manipulations (i.e. transgenic, knockout/in mice) are described in their pathological phenotypes, with a special emphasis on behavioral abnormalities. The major results obtained with many of the existing models are discussed in depth highlighting their strengths and limitations. A lasting reference, the thorough reviews offer an easy entrance into the extensive literature in this field, and will prove invaluable to students and specialists alike.
The second volume of Behavioral Genetics of the Mouse provides a comprehensive overview of the major genetically modified mouse lines used to model human neurobehavioral disorders; from disorders of perception, of autonomous and motor functions to social and cognitive syndromes, drug abuse and dependence as well as neurodegenerative pathologies. Mouse models obtained with different types of genetic manipulations (i.e. transgenic, knockout/in mice) are described in their pathological phenotypes, with a special emphasis on behavioral abnormalities. The major results obtained with many of the existing models are discussed in depth highlighting their strengths and limitations. A lasting reference, the thorough reviews offer an easy entrance into the extensive literature in this field, and will prove invaluable to students and specialists alike.
Background:
A huge body of evidence has signaled a correlation between adult depression and energy metabolism. The key links are the energy supply and substrates for brain energy metabolism and the crucial signaling molecule lactate. Nevertheless, the association between lactate metabolism and depression remains elusive.
Objective:
The primary objective of this study was to explore the difference in serum LDH levels between patients with major depressive disorder (MDD) and the normal population and to determine whether LDH can be employed as a predictor of suicide attempt (SA) in MDD patients.
Methods:
Serum LDH levels were measured in 232 patients with MDD and 110 healthy controls. Depressive symptoms were assessed using the 24-item Hamilton Depression Scale (HAMD-24). The data were collected and analyzed with SPSS 22.0.
Results:
The serum LDH level of the control group was (196.50 ± 34.40) U/L, while that of the MDD group was (177.94 ± 25.89) U/L (P < 0.001). Notably, the LDH level [(169.96 ± 25.31) U/L] in the SA group was significantly lower than that in the control and non-SA groups [(181.25 ± 25.47) U/L] (P < 0.01); There was no significant correlation with HAMD-24 score (P > 0.05). Collectively, this study demonstrated that a decrease in serum LDH levels is an independent risk factor for SA in MDD patients.
Conclusion:
Our results imply that a decrease in LDH levels may be associated with MDD and suicidal behaviors. Early identification of suicide risk and evaluation of the prognosis of depression is critical.
This chapter reviews the epidemiology and neurobiology of major depressive disorder and suicide. Depression and suicide rates in different countries around the world have changed over the years partly because the onset of major depression is earlier in individuals who are born more recently and partly because of major social changes influencing suicide risk such as per capita alcohol consumption and levels of treatment of major depression. Data are reviewed on gene–environment interactions explaining environmental effects on depression and suicide rates and their neurobiology. The biological basis of resilience is reviewed in an effort to understand how it differs from the diathesis or tendency to depression and suicide. The neurobiology of depression and suicide is described in terms of brain circuits involved and at the cellular and molecular level. Therapeutic approaches are linked to known pathogenesis, and future directions for research and treatment are proposed.
Research in genetics can not fully explain causality or the major contribution to stress-related psychiatric disorders such as posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). Epigenetic alterations are proven to have a crucial role between genetics and environmental effects. Epigenetic mechanisms, unlike genetic factors, are substantially dynamic and alterable, taking into account that they do not cause any change on the genetic material itself, rather, they change the expressions of genes. Thus the field of epigenetics also paves way for a therapeutic potential through mediating gene expression and regulating gene functions. The current chapter focuses on the role of epigenetic alterations in the etiology of these stress-related disorders. Yet, while the reported associations between epigenetics and stress-related disorders are not strong enough to predict a causal relationship, and research on epigenetics is relatively incipient, further studies are clearly needed.
Depression is strongly associated with obesity among other chronic physical diseases. The latest mega- and meta-analysis of genome-wide association studies have identified multiple risk loci robustly associated with depression. In this study, we aimed to investigate whether a genetic-risk score (GRS) combining multiple depression risk single nucleotide polymorphisms (SNPs) might have utility in the prediction of this disorder in individuals with obesity. A total of 30 depression-associated SNPs were included in a GRS to predict the risk of depression in a large case-control sample from the Spanish PredictD-CCRT study, a national multicentre, randomized controlled trial, which included 104 cases of depression and 1546 controls. An unweighted GRS was calculated as a summation of the number of risk alleles for depression and incorporated into several logistic regression models with depression status as the main outcome. Constructed models were trained and evaluated in the whole recruited sample. Non-genetic-risk factors were combined with the GRS in several ways across the five predictive models in order to improve predictive ability. An enrichment functional analysis was finally conducted with the aim of providing a general understanding of the biological pathways mapped by analyzed SNPs. We found that an unweighted GRS based on 30 risk loci was significantly associated with a higher risk of depression. Although the GRS itself explained a small amount of variance of depression, we found a significant improvement in the prediction of depression after including some non-genetic-risk factors into the models. The highest predictive ability for depression was achieved when the model included an interaction term between the GRS and the body mass index (BMI), apart from the inclusion of classical demographic information as marginal terms (AUC = 0.71, 95% CI = [0.65, 0.76]). Functional analyses on the 30 SNPs composing the GRS revealed an over-representation of the mapped genes in signaling pathways involved in processes such as extracellular remodeling, proinflammatory regulatory mechanisms, and circadian rhythm alterations. Although the GRS on its own explained a small amount of variance of depression, a significant novel feature of this study is that including non-genetic-risk factors such as BMI together with a GRS came close to the conventional threshold for clinical utility used in ROC analysis and improves the prediction of depression. In this study, the highest predictive ability was achieved by the model combining the GRS and the BMI under an interaction term. Particularly, BMI was identified as a trigger-like risk factor for depression acting in a concerted way with the GRS component. This is an interesting finding since it suggests the existence of a risk overlap between both diseases, and the need for individual depression genetics-risk evaluation in subjects with obesity. This research has therefore potential clinical implications and set the basis for future research directions in exploring the link between depression and obesity-associated disorders. While it is likely that future genome-wide studies with large samples will detect novel genetic variants associated with depression, it seems clear that a combination of genetics and non-genetic information (such is the case of obesity status and other depression comorbidities) will still be needed for the optimization prediction of depression in high-susceptibility individuals.
The identification of single-nucleotide polymorphisms (SNPs) in genes putatively related to pathophysiological processes in major depressive disorder (MDD) might improve both diagnosis and personalized treatment strategies eventually leading to more effective interventions. Considering the important role of the glucocorticoid receptor and the related FK506 binding protein 51 (FKBP51) in the pathophysiology of MDD, we aimed to investigate putative associations between variants of FKBP5, the coding gene of FKBP51, with antidepressant treatment resistance and MDD susceptibility.
Nine common SNPs of the FKBP5 gene prioritized based on location and, putative or known functions were genotyped in Han Chinese population, including MDD patients with or without antidepressant-treatment resistance and healthy controls. Associations of FKBP5 SNPs with MDD susceptibility and treatment response were examined in the whole group of MDD patients, as well as in subgroups stratified by antidepressant treatment resistance, compared with healthy controls.
In total, 181 Han Chinese patients with MDD and 80 healthy controls were recruited. No significant SNP or haplotype associations were observed in the whole patient group. There were nominal significant differences both for the haplotype block with SNPs in strong LD (r² > 0.8, P = .040) and haplotype block with SNPs in moderate LD (r² > 0.1, P = .017) between the haplotype distributions of patients with antidepressant treatment resistance (n = 81) and healthy controls, but both significances did not survive multiple testing correction. Furthermore, no specific haplotype could be observed causing a significant difference in any combination between all comparisons.
No associations were observed of FKBP5 variants with MDD or antidepressant treatment response. The lack of associations might be due to the relatively small sample size of this study (power ranged from 0.100 to 0.752). A follow-up study will need larger, better phenotyped, and more homogeneous samples to draw a definitive conclusion regarding the involvement of this gene in MDD.
Background
Several studies have evaluated the possible association between polymorphisms or variants in Corticotropin-releasing hormone 1 receptor gene (CRHR1) with depression; however, results remain contradictory and heterogeneous.Objective
To our knowledge, we conducted the first comprehensive systematic review and meta-analysis evaluating the association of the CRHR1 gene and the risk of depression.MethodsA search online was conducted in databases for any CRHR1 genetic association studies in depression. Data were extracted for evaluation of pooled estimates using meta-analytic techniques. Statistical analyses were performed using the Comprehensive Meta-analysis, v2.0 software.ResultA total of 1403 cases and 2353 mentally healthy controls were included in this study. We found a significant association of rs242941, rs1876828 and rs242939 variants of the CRHR1 gene with depression. No association of CRHR1 rs110402 and depression was observed.Conclusion
Our meta-analysis shows that some variants of the CRHR1 gene (rs242941, rs1876828 and rs242939) might confer susceptibility to depression. Further studies with larger sample sizes need to be conducted.
Major depressive disorder is connected with high rates of functional disability and mortality. About a third of the patients are at risk of therapy failure. Several pharmacogenetic markers especially located in CYP450 genes such as CYP2D6 or CYP2C19 are of relevance for therapy outcome prediction in major depressive disorder but a further optimization of predictive tools is warranted. The article summarizes the current knowledge on pharmacogenetic variants, therapy effects and side effects of important antidepressive therapeutics, and sheds light on new methodological approaches for therapy response estimation based on genetic markers with relevance for pharmacokinetics, pharmacodynamics and disease pathology identified in genome-wide association study analyses, highlighting polygenic risk score analysis as a tool for further optimization of individualized therapy outcome prediction.
The research of depression genetics has been occupied by historical candidate genes which were tested by candidate gene association studies. However, these studies were mostly not replicable. Thus, genetics of depression have remained elusive for a long time. As research moves from candidate gene association studies to GWAS, the hypothesis-free non-candidate gene association studies in genome-wide level, this trend will likely change. Despite the fact that the earlier GWAS of depression were not successful, the recent GWAS suggest robust findings for depression genetics. These altogether will catalyze a new wave of multidisciplinary research to pin down the neurobiology of depression.
Solute Carrier Family 6 Member 15 (SLC6A15), a sodium‐dependent neutral amino acid transporter, has been found with dysregulated expression in several kinds of cancers. However, the expression pattern and the biological functions of SLC6A15 in papillary thyroid cancer (PTC) remain unknown. In this study, we found that SLC6A15 was downregulated in PTC, which was related to N classification. Ectopic overexpression of SLC6A15 impaired migratory and invasive abilities of PTC cell in vitro. In addition, we identified intercellular adhesion molecule‐1, a vital oncogene in thyroid cancer progression, was involved in the effects of SLC6A15 on PTC cell. These results indicate that SLC6A15 acts as a tumor suppressor and might be a potential therapeutic target in the treatment of PTC.
Major depressive disorder (MDD) is a common, debilitating, phenotypically heterogeneous disorder with heritability ranges from 30% to 50%. Compared to other psychiatric disorders, its high prevalence, moderate heritability, and strong polygenicity have posed major challenges for gene-mapping in MDD. Studies of common genetic variation in MDD, driven by large international collaborations such as the Psychiatric Genomics Consortium, have confirmed the highly polygenic nature of the disorder and implicated over 100 genetic risk loci to date. Rare copy number variants associated with MDD risk were also recently identified. The goal of this review is to present a broad picture of our current understanding of the epidemiology, genetic epidemiology, molecular genetics, and gene–environment interplay in MDD. Insights into the impact of genetic factors on the aetiology of this complex disorder hold great promise for improving clinical care.
Neurotransmitters, such as γ-aminobutyric acid, glutamate, acetyl choline, glycine and the monoamines, facilitate the crosstalk within the central nervous system. The designated neurotransmitter transporters (NTTs) both release and take up neurotransmitters to and from the synaptic cleft. NTT dysfunction can lead to severe pathophysiological consequences, e.g. epilepsy, intellectual disability, or Parkinson's disease. Genetic point mutations in NTTs have recently been associated with the onset of various neurological disorders. Some of these mutations trigger folding defects in the NTT proteins. Correct folding is a prerequisite for the export of NTTs from the endoplasmic reticulum (ER) and the subsequent trafficking to their pertinent site of action, typically at the plasma membrane. Recent studies have uncovered some of the key features in the molecular machinery responsible for transporter protein folding, e.g., the role of heat shock proteins in fine-tuning the ER quality control mechanisms in cells. The therapeutic significance of understanding these events is apparent from the rising number of reports, which directly link different pathological conditions to NTT misfolding. For instance, folding-deficient variants of the human transporters for dopamine or GABA lead to infantile parkinsonism/dystonia and epilepsy, respectively. From a therapeutic point of view, some folding-deficient NTTs are amenable to functional rescue by small molecules, known as chemical and pharmacological chaperones.
The association between distress caused by tinnitus and psychological factors such as depression and anxiety has been examined and reported. However, prognostic factors remain poorly understood because there are only a few reports on genetic associations. We theorized there might be an association between the grade of tinnitus distress and the genetic background related to psychological factors which might lead us to identify prognostic markers. We enrolled 138 patients who had suffered from tinnitus for over 3 months. Using Tinnitus Handicap Inventory (THI) scores, we examined the association between tinnitus distress and a genetic background related to depression or anxiety. A significant association between single nucleotide polymorphism rs131702 of the Breakpoint Cluster Region (BCR) gene and the severe THI score was identified. In addition, there was an association with the severity of the State-Trait Anxiety Inventory, an index of state anxiety severity. No association was found with the Self-Rating Depression Scale, an index of depression severity. It is reported that rs131702 of BCR in Japanese patients are related to bipolar II depression characterized by fluctuation between abnormal mood states of mania and depression. Our results indicate that rs131702 of BCR is independent of depression in this study and is, therefore, a prognostic factor unique to tinnitus. We conclude that the severity of tinnitus is associated with genes related to depression.
Central nervous system (CNS) diseases are emerging as a major issue in an aging society. Although extensive research has focused on the development of CNS drugs, the limited transport of therapeutic agents across the blood-brain barrier (BBB) remains a major challenge. Conventional two-dimensional culture dishes do not recapitulate in vivo physiology and real-time observations of molecular transport are not possible in animal models. Recent advances in engineering techniques have enabled the generation of more physiologically relevant in vitro BBB models, and their applications have expanded from fundamental biological research to practical applications in the pharmaceutical industry. In this article, we provide an overview of recent advances in the development of in vitro BBB models, with a particular focus on the recapitulation of BBB function. The development of biomimetic BBB models is postulated to revolutionize not only fundamental biological studies but also drug screening.
The Chinese Imaging Genetics (CHIMGEN) study establishes the largest Chinese neuroimaging genetics cohort and aims to identify genetic and environmental factors and their interactions that are associated with neuroimaging and behavioral phenotypes. This study prospectively collected genomic, neuroimaging, environmental, and behavioral data from more than 7000 healthy Chinese Han participants aged 18–30 years. As a pioneer of large-sample neuroimaging genetics cohorts of non-Caucasian populations, this cohort can provide new insights into ethnic differences in genetic-neuroimaging associations by being compared with Caucasian cohorts. In addition to micro-environmental measurements, this study also collects hundreds of quantitative macro-environmental measurements from remote sensing and national survey databases based on the locations of each participant from birth to present, which will facilitate discoveries of new environmental factors associated with neuroimaging phenotypes. With lifespan environmental measurements, this study can also provide insights on the macro-environmental exposures that affect the human brain as well as their timing and mechanisms of action.
Psychiatric disorders such as addiction (substance use and addictive disorders), depression, eating disorders, schizophrenia, and post-traumatic stress disorder (PTSD) are severe, complex, multifactorial mental disorders that carry a high social impact, enormous public health costs, and various comorbidities as well as premature morbidity. Their neurobiological foundation is still not clear. Therefore, it is difficult to uncover new set of genes and possible genetic markers of these disorders since the understanding of the molecular imbalance leading to these disorders is not complete. The integrative approach is needed which will combine genomics and epigenomics; evaluate epigenetic influence on genes and their influence on neuropeptides, neurotransmitters, and hormones; examine gene × gene and gene × environment interplay; and identify abnormalities contributing to development of these disorders. Therefore, novel genetic approaches based on systems biology focused on improvement of the identification of the biological underpinnings might offer genetic markers of addiction, depression, eating disorders, schizophrenia, and PTSD. These markers might be used for early prediction, detection of the risk to develop these disorders, novel subtypes of the diseases and tailored, personalized approach to therapy.
To identify genetic risk loci for major depressive disorder (MDD), two broad study design approaches have been applied: (1) to maximize sample size by combining data from different phenotype assessment modalities (e.g. clinical interview, self-report questionnaires) and (2) to reduce phenotypic heterogeneity through selecting more homogenous MDD subtypes. The value of these strategies has been debated. In this review, we summarize the most recent findings of large genomic studies that applied these approaches, and we highlight the merits and pitfalls of both approaches with particular attention to methodological and psychometric issues. We also discuss the results of analyses that investigated the heterogeneity of MDD. We conclude that both study designs are essential for further research. So far, increasing sample size has led to the identification of a relatively high number of genomic loci linked to depression. However, part of the identified variants may be related to a phenotype common to internalizing disorders and related traits. As such, samples containing detailed clinical information are needed to dissect depression heterogeneity and enable the potential identification of variants specific to a more restricted MDD phenotype. A balanced portfolio reconciling both study design approaches is the optimal approach to progress further in unraveling the genetic architecture of depression.
Over the past decade, genome-wide association studies (GWAS) have evolved into a powerful tool to investigate genetic risk factors for human diseases via a hypothesis-free scan of the genome. The success of GWAS for psychiatric disorders and behavioral traits have been somewhat mixed, partly owing to the complexity and heterogeneity of these traits. Significant progress has been made in the last few years in the development and implementation of complex statistical methods and algorithms incorporating GWAS. Such advanced statistical methods applied to GWAS hits in combination with incorporation of different layers of genomics data have catapulted the search for novel genes for behavioral traits and improved our understanding of the complex polygenic architecture of these traits.
The initial Global Burden of Disease study found that depression was the fourth leading cause of disease burden, accounting for 3.7% of total disability adjusted life years (DALYs) in the world in 1990.
To present the new estimates of depression burden for the year 2000.
DALYs for depressive disorders in each world region were calculated, based on new estimates of mortality, prevalence, incidence, average age at onset, duration and disability severity.
Depression is the fourth leading cause of disease burden, accounting for 4.4% of total DALYs in the year 2000, and it causes the largest amount of non-fatal burden, accounting for almost 12% of all total years lived with disability worldwide.
These data on the burden of depression worldwide represent a major public health problem that affects patients and society.
Several studies have found reduced hippocampal volume in patients with unipolar depression, but discrepancies exist. The authors performed a systematic review and meta-analysis of volumetric studies of the hippocampus in patients with mood disorders.
Studies of hippocampal volume in unipolar and bipolar patients were identified. A meta-analysis of the 12 studies of unipolar depression fulfilling specific criteria was performed. The sample comprised 351 patients and 279 healthy subjects.
The studies were highly heterogeneous regarding age and gender distribution, age at onset of the disorder, average number of episodes, and responsiveness to treatment, but the pooled effect size of depression was significant in both hemispheres for the unipolar patients. The weighted average showed a reduction of hippocampal volume of 8% on the left side and 10% on the right side. The causes of the heterogeneity were analyzed, and a meta-regression showed that the total number of depressive episodes was significantly correlated to right but not left hippocampal volume reduction.
Hippocampal volume is reduced in patients with unipolar depression, maybe as a consequence of repeated periods of major depressive disorder. Bipolar patients did not seem to show a reduction in hippocampal volume, but this has been much less investigated.
Major depressive disorder (MDD) is a common complex disorder with a partly genetic etiology. We conducted a genome-wide association study of the MDD2000+ sample (2431 cases, 3673 screened controls and >1 M imputed single-nucleotide polymorphisms (SNPs)). No SNPs achieved genome-wide significance either in the MDD2000+ study, or in meta-analysis with two other studies totaling 5763 cases and 6901 controls. These results imply that common variants of intermediate or large effect do not have main effects in the genetic architecture of MDD. Suggestive but notable results were (a) gene-based tests suggesting roles for adenylate cyclase 3 (ADCY3, 2p23.3) and galanin (GAL, 11q13.3); published functional evidence relates both of these to MDD and serotonergic signaling; (b) support for the bipolar disorder risk variant SNP rs1006737 in CACNA1C (P=0.020, odds ratio=1.10); and (c) lack of support for rs2251219, a SNP identified in a meta-analysis of affective disorder studies (P=0.51). We estimate that sample sizes 1.8- to 2.4-fold greater are needed for association studies of MDD compared with those for schizophrenia to detect variants that explain the same proportion of total variance in liability. Larger study cohorts characterized for genetic and environmental risk factors accumulated prospectively are likely to be needed to dissect more fully the etiology of MDD.
Studies of major depression in twins and families have shown moderate to high heritability, but extensive molecular studies have failed to identify susceptibility genes convincingly. To detect genetic variants contributing to major depression, the authors performed a genome-wide association study using 1,636 cases of depression ascertained in the U.K. and 1,594 comparison subjects screened negative for psychiatric disorders.
Cases were collected from 1) a case-control study of recurrent depression (the Depression Case Control [DeCC] study; N=1346), 2) an affected sibling pair linkage study of recurrent depression (probands from the Depression Network [DeNT] study; N=332), and 3) a pharmacogenetic study (the Genome-Based Therapeutic Drugs for Depression [GENDEP] study; N=88). Depression cases and comparison subjects were genotyped at Centre National de Génotypage on the Illumina Human610-Quad BeadChip. After applying stringent quality control criteria for missing genotypes, departure from Hardy-Weinberg equilibrium, and low minor allele frequency, the authors tested for association to depression using logistic regression, correcting for population ancestry.
Single nucleotide polymorphisms (SNPs) in BICC1 achieved suggestive evidence for association, which strengthened after imputation of ungenotyped markers, and in analysis of female depression cases. A meta-analysis of U.K. data with previously published results from studies in Munich and Lausanne showed some evidence for association near neuroligin 1 (NLGN1) on chromosome 3, but did not support findings at BICC1.
This study identifies several signals for association worthy of further investigation but, as in previous genome-wide studies, suggests that individual gene contributions to depression are likely to have only minor effects, and very large pooled analyses will be required to identify them.
A genome-wide association study was carried out in 1020 case subjects with recurrent early-onset major depressive disorder (MDD) (onset before age 31) and 1636 control subjects screened to exclude lifetime MDD. Subjects were genotyped with the Affymetrix 6.0 platform. After extensive quality control procedures, 671 424 autosomal single nucleotide polymorphisms (SNPs) and 25 068 X chromosome SNPs with minor allele frequency greater than 1% were available for analysis. An additional 1 892 186 HapMap II SNPs were analyzed based on imputed genotypic data. Single-SNP logistic regression trend tests were computed, with correction for ancestry-informative principal component scores. No genome-wide significant evidence for association was observed, assuming that nominal P<5 × 10(-8) approximates a 5% genome-wide significance threshold. The strongest evidence for association was observed on chromosome 18q22.1 (rs17077540, P=1.83 × 10(-7)) in a region that has produced some evidence for linkage to bipolar-I or -II disorder in several studies, within an mRNA detected in human brain tissue (BC053410) and approximately 75 kb upstream of DSEL. Comparing these results with those of a meta-analysis of three MDD GWAS data sets reported in a companion article, we note that among the strongest signals observed in the GenRED sample, the meta-analysis provided the greatest support (although not at a genome-wide significant level) for association of MDD to SNPs within SP4, a brain-specific transcription factor. Larger samples will be required to confirm the hypothesis of association between MDD (and particularly the recurrent early-onset subtype) and common SNPs.
The efficacy of antidepressant drug treatment in depression is unsatisfactory; 1 in 3 patients does not fully recover even after several treatment trials. Genetic factors and clinical characteristics contribute to the failure of a favorable treatment outcome.
To identify genetic and clinical determinants of antidepressant drug treatment outcome in depression.
Genomewide pharmacogenetic association study with 2 independent replication samples.
We performed a genomewide association study in patients from the Munich Antidepressant Response Signature (MARS) project and in pooled DNA from an independent German replication sample. A set of 328 single-nucleotide polymorphisms highly related to outcome in both genomewide association studies was genotyped in a sample of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study.
A total of 339 inpatients with a depressive episode (MARS sample), a further 361 inpatients with depression (German replication sample), and 832 outpatients with major depression (STAR*D sample).
We generated a multilocus genetic variable that described the individual number of alleles of the selected single nucleotide polymorphisms associated with beneficial treatment outcome in the MARS sample ("response" alleles) to evaluate additive genetic effects on antidepressant drug treatment outcome.
Multilocus analysis revealed a significant contribution of a binary variable that categorized patients as carriers of a high vs low number of response alleles in the prediction of antidepressant drug treatment outcome in both samples (MARS and STAR*D). In addition, we observed that patients with a comorbid anxiety disorder combined with a low number of response alleles showed the least favorable outcome.
These results demonstrate the importance of multiple genetic factors combined with clinical features in the prediction of antidepressant drug treatment outcome, which underscores the multifactorial nature of this trait.
The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in close to a 1,000 research articles and reports (see www.epib.nl/rotterdamstudy). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods.
The exploration of quantitative variation in human populations has become one of the major priorities for medical genetics. The successful identification of variants that contribute to complex traits is highly dependent on reliable assays and genetic maps. We have performed a genome-wide quantitative trait analysis of 630 genes in 60 unrelated Utah residents with ancestry from Northern and Western Europe using the publicly available phase I data of the International HapMap project. The genes are located in regions of the human genome with elevated functional annotation and disease interest including the ENCODE regions spanning 1% of the genome, Chromosome 21 and Chromosome 20q12-13.2. We apply three different methods of multiple test correction, including Bonferroni, false discovery rate, and permutations. For the 374 expressed genes, we find many regions with statistically significant association of single nucleotide polymorphisms (SNPs) with expression variation in lymphoblastoid cell lines after correcting for multiple tests. Based on our analyses, the signal proximal (cis-) to the genes of interest is more abundant and more stable than distal and trans across statistical methodologies. Our results suggest that regulatory polymorphism is widespread in the human genome and show that the 5-kb (phase I) HapMap has sufficient density to enable linkage disequilibrium mapping in humans. Such studies will significantly enhance our ability to annotate the non-coding part of the genome and interpret functional variation. In addition, we demonstrate that the HapMap cell lines themselves may serve as a useful resource for quantitative measurements at the cellular level.
Author Summary
Although humans have a relatively small complement of genes, the proteins encoded by those genes and their biologic function are far more complex. The increased complexity is achieved in part through processes that create different messages from the same gene sequence (alternative splicing) and that regulate the expression of those messages in a tissue-specific fashion. These processes expand the functional capacity of the human genome, but also can create predisposition to disease when these processes go awry. In this study, we investigated how single nucleotide polymorphisms influence both overall gene expression and alternative splicing in two important cell types (brain and blood) highly relevant to human disease. Extensive and tissue-specific regulation of gene expression and alternative splicing were observed in the two tissue types, and some of these polymorphisms were shown to be connected to other polymorphsims that have been recently implicated in human diseases through genome-wide association studies. Most of these connections appeared to relate to alternative splicing as opposed to overall expression changes, suggesting that changes in splicing patterns may be more consequential for disease than those affecting only expression. These data emphasize the importance of comprehensive studies into genetic regulation of gene expression in all human tissue types in order to help understand how genetic variation influences risk of common diseases.
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.
Major depressive disorder (MDD) is a common complex trait with enormous public health significance. As part of the Genetic Association Information Network initiative of the US Foundation for the National Institutes of Health, we conducted a genome-wide association study of 435 291 single nucleotide polymorphisms (SNPs) genotyped in 1738 MDD cases and 1802 controls selected to be at low liability for MDD. Of the top 200, 11 signals localized to a 167 kb region overlapping the gene piccolo (PCLO, whose protein product localizes to the cytomatrix of the presynaptic active zone and is important in monoaminergic neurotransmission in the brain) with P-values of 7.7 x 10(-7) for rs2715148 and 1.2 x 10(-6) for rs2522833. We undertook replication of SNPs in this region in five independent samples (6079 MDD independent cases and 5893 controls) but no SNP exceeded the replication significance threshold when all replication samples were analyzed together. However, there was heterogeneity in the replication samples, and secondary analysis of the original sample with the sample of greatest similarity yielded P=6.4 x 10(-8) for the nonsynonymous SNP rs2522833 that gives rise to a serine to alanine substitution near a C2 calcium-binding domain of the PCLO protein. With the integrated replication effort, we present a specific hypothesis for further studies.
Depression is common in old age. Nevertheless, few incidence studies have established how often depression occurs in elderly persons with and without a history of depression.
To determine the incidence and recurrence rates of depression in an elderly population.
A cohort study of community-dwelling elderly persons aged 56 years or older residing in Rotterdam, the Netherlands, performed between September 1993 and October 2005 and encompassing baseline and 2 follow-up examinations as well as continuous procedures. The study population consisted of 5653 participants free of dementia. Depression was identified through standardized psychiatric examinations, monitoring of medical records, registration of antidepressant use, and self-reported histories of depression. We categorized the depression as depressive syndromes, including DSM-IV-defined major depression, or clinically relevant depressive symptoms.
Incidence and recurrence rates for depressive syndromes as well as for depressive syndromes and symptoms combined. In addition to overall rates, sex- and age-specific rates were calculated.
During the follow-up period of 8 years on average, 566 depressive syndromes and 1073 episodes of clinically relevant depressive symptoms occurred. For depressive syndromes, the incidence rate was 7.0 (95% confidence interval, 6.0-8.3) per 1000 person-years and the recurrence rate was 27.5 (95% confidence interval, 23.7-32.1) per 1000 person-years. The incidence and recurrence rates more than doubled when episodes of depressive symptoms were included. The recurrence rate of depressive syndromes was equal for women and men, but all other rates were almost twice as high for women compared with men. No rates seemed to change with age.
The incidence rate of depression in the elderly population is low except when episodes of clinically relevant depressive symptoms are accounted for. Most late-life depression occurs in persons with a history of depression. Moreover, the recurrence rate of depressive syndromes does not differ between men and women.
Stress-induced structural remodeling in the adult hippocampus, involving debranching and shortening of dendrites and suppression of neurogenesis, provides a cellular basis for understanding the impairment of neural plasticity in the human hippocampus in depressive illness. Accordingly, reversal of structural remodeling may be a desirable goal for antidepressant therapy. The present study investigated the effect of tianeptine, a modified tricyclic antidepressant, in the chronic psychosocial stress model of adult male tree shrews (Tupaia belangeri), a model with high validity for research on the pathophysiology of major depression. Animals were subjected to a 7-day period of psychosocial stress to elicit stress-induced endocrine and central nervous alterations before the onset of daily oral administration of tianeptine (50 mg/kg). The psychosocial stress continued throughout the treatment period of 28 days. Brain metabolite concentrations were determined in vivo by proton magnetic resonance spectroscopy, cell proliferation in the dentate gyrus was quantified by using BrdUrd immunohistochemistry, and hippocampal volume was measured post mortem. Chronic psychosocial stress significantly decreased in vivo concentrations of N-acetyl-aspartate (-13%), creatine and phosphocreatine (-15%), and choline-containing compounds (-13%). The proliferation rate of the granule precursor cells in the dentate gyrus was reduced (-33%). These stress effects were prevented by the simultaneous administration of tianeptine yielding normal values. In stressed animals treated with tianeptine, hippocampal volume increased above the small decrease produced by stress alone. These findings provide a cellular and neurochemical basis for evaluating antidepressant treatments with regard to possible reversal of structural changes in brain that have been reported in depressive disorders.
Many common human diseases have a genetic component as measured by familial studies. Metabolic disorders such as diabetes, cardiovascular diseases such as high blood pressure, psychiatric disorders such as schizophrenia, and neurodegenerative diseases such as Alzheimer’s disease all are thought to have a hereditary component. In some diseases the genetic control is through a single gene, while in others, multiple genes interact in complex ways with environmental factors to produce the disease (1–5).
Haplotype-based methods offer a powerful approach to disease gene mapping, based on the association between causal mutations
and the ancestral haplotypes on which they arose. As part of The SNP Consortium Allele Frequency Projects, we characterized
haplotype patterns across 51 autosomal regions (spanning 13 megabases of the human genome) in samples from Africa, Europe,
and Asia. We show that the human genome can be parsed objectively into haplotype blocks: sizable regions over which there
is little evidence for historical recombination and within which only a few common haplotypes are observed. The boundaries
of blocks and specific haplotypes they contain are highly correlated across populations. We demonstrate that such haplotype
frameworks provide substantial statistical power in association studies of common genetic variation across each region. Our
results provide a foundation for the construction of a haplotype map of the human genome, facilitating comprehensive genetic
association studies of human disease.
Previous work suggests that patients with unipolar depression may have structural as well as functional abnormalities in limbic-thalamic-cortical networks, which are hypothesized to modulate human mood states. A core area in these networks is the hippocampus. In the present study, differences in volumes of hippocampal gray and white matter between patients with a first episode of major depression and healthy comparison subjects were examined.
Thirty patients with a first episode of major depression and 30 healthy comparison subjects who were matched for age, gender, handedness, and education were examined with high-resolution magnetic resonance imaging.
Male patients with a first episode of major depression had significantly smaller hippocampal total and gray matter volumes than healthy male comparison subjects. Both male and female patients showed significant alterations of left-right asymmetry and significant reductions of left and right hippocampal white matter fibers in relation to healthy comparison subjects. Hippocampal measurements were not significantly correlated with clinical variables, such as age at onset of illness, illness duration, or severity of depression.
These results are consistent with findings of structural abnormalities of the hippocampal formation in patients with major depression that were more pronounced in male patients. The authors' findings support the hypothesis that the hippocampus and its connections within limbic-cortical networks may play a crucial role in the pathogenesis of major depression.
A website for performing power calculations for the design of linkage and association genetic mapping studies of complex traits.
Availability: The package is made available athttp://statgen.iop.kcl.ac.uk/gpc/
Contact: s.purcell@iop.kcl.ac.uk
*To whom correspondence should be addressed
Uncertainties exist about prevalence and correlates of major depressive disorder (MDD).
To present nationally representative data on prevalence and correlates of MDD by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, and on study patterns and correlates of treatment and treatment adequacy from the recently completed National Comorbidity Survey Replication (NCS-R).
Face-to-face household survey conducted from February 2001 to December 2002.
The 48 contiguous United States.
Household residents ages 18 years or older (N = 9090) who responded to the NCS-R survey.
Prevalence and correlates of MDD using the World Health Organization's (WHO) Composite International Diagnostic Interview (CIDI), 12-month severity with the Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR), the Sheehan Disability Scale (SDS), and the WHO disability assessment scale (WHO-DAS). Clinical reinterviews used the Structured Clinical Interview for DSM-IV.
The prevalence of CIDI MDD for lifetime was 16.2% (95% confidence interval [CI], 15.1-17.3) (32.6-35.1 million US adults) and for 12-month was 6.6% (95% CI, 5.9-7.3) (13.1-14.2 million US adults). Virtually all CIDI 12-month cases were independently classified as clinically significant using the QIDS-SR, with 10.4% mild, 38.6% moderate, 38.0% severe, and 12.9% very severe. Mean episode duration was 16 weeks (95% CI, 15.1-17.3). Role impairment as measured by SDS was substantial as indicated by 59.3% of 12-month cases with severe or very severe role impairment. Most lifetime (72.1%) and 12-month (78.5%) cases had comorbid CIDI/DSM-IV disorders, with MDD only rarely primary. Although 51.6% (95% CI, 46.1-57.2) of 12-month cases received health care treatment for MDD, treatment was adequate in only 41.9% (95% CI, 35.9-47.9) of these cases, resulting in 21.7% (95% CI, 18.1-25.2) of 12-month MDD being adequately treated. Sociodemographic correlates of treatment were far less numerous than those of prevalence.
Major depressive disorder is a common disorder, widely distributed in the population, and usually associated with substantial symptom severity and role impairment. While the recent increase in treatment is encouraging, inadequate treatment is a serious concern. Emphasis on screening and expansion of treatment needs to be accompanied by a parallel emphasis on treatment quality improvement.
The design and feasibility of genetic studies of complex diseases are critically dependent on the extent and distribution of linkage disequilibrium (LD) across the genome and between different populations. We have examined genomewide and region-specific LD in a young genetically isolated population identified in the Netherlands by genotyping approximately 800 Short Tandem Repeat markers distributed genomewide across 58 individuals. Several regions were analyzed further using a denser marker map. The permutation-corrected measure of LD was used for analysis. A significant (P<0.0004) relation between LD and genetic distance on a genomewide scale was found. Distance explained 4% of the total LD variation. For fine-mapping data, distance accounted for a larger proportion of LD variation (up to 39%). A notable similarity in the genomewide distribution of LD was revealed between this population and other young genetically isolated populations from Micronesia and Costa Rica. Our study population and experiment was simulated in silico to confirm our knowledge of the history of the population. High agreement was observed between results of analysis of simulated and empirical data. We conclude that our population shows a high level of LD similar to that demonstrated previously in other young genetic isolates. In Europe, there may be a large number of young genetically isolated populations that are similar in history to ours. In these populations, a similar degree of LD is expected and thus they may be effectively used for linkage or LD mapping.
The National Center for Biotechnology Information (NCBI) Reference Sequence (RefSeq) database (http://www.ncbi.nlm.nih.gov/RefSeq/) provides a non-redundant collection of sequences representing genomic data, transcripts and proteins. Although the goal
is to provide a comprehensive dataset representing the complete sequence information for any given species, the database pragmatically
includes sequence data that are currently publicly available in the archival databases. The database incorporates data from
over 2400 organisms and includes over one million proteins representing significant taxonomic diversity spanning prokaryotes,
eukaryotes and viruses. Nucleotide and protein sequences are explicitly linked, and the sequences are linked to other resources
including the NCBI Map Viewer and Gene. Sequences are annotated to include coding regions, conserved domains, variation, references,
names, database cross-references, and other features using a combined approach of collaboration and other input from the scientific
community, automated annotation, propagation from GenBank and curation by NCBI staff.
This prospective study aimed to assess the suitability of the 21-item Beck Depression Inventory (BDI-21) as a screening method for current episodes of major depressive disorder in different phases of the disease. In a sample of treatment-seeking outpatients (n=125), a structured interview method (SCID) was used twice with a 2-year interval to screen whether the patient had a current episode of major depressive disorder. The validity of the BDI-21 was also analysed by means of receiver operating characteristic (ROC) curves. The results showed that with a cut-off point of 14/15 the BDI-21 can be used to indicate the presence of a major depressive episode regardless of the phase of the major depressive disorder. The sensitivity and specificity were quite satisfactory with this cut-off point. The areas under the ROC curves were large (0.81 at baseline and 0.93 at follow-up). The same BDI-21 cut-off point is suitable for screening major depression among outpatients in any phase of the disease.
Major depression is a prevalent mental disorder in the general population, with a multi-factorial etiology. However, work stress as a risk factor for major depression has not been well studied.
Using a longitudinal study design, this analysis investigated the association between the levels of work stress and major depressive episode(s) in the Canadian working population, aged 18 to 64 years. Data from the longitudinal cohort of the Canadian National Population Health Survey (NPHS) were used (n = 6663). The NPHS participants who did not have major depressive episodes (MDE) at baseline (1994-1995 NPHS) were classified into four groups by the quartile values of the baseline work stress scores. The proportion of MDE of each group was calculated using the 1996-1997 NPHS data.
The first three quartile groups had a similar risk of MDE. Those who had a work stress score above the 75th percentile had an elevated risk of MDE (7.1%). Using the 75th percentile as a cut-off, work stress was significantly associated with the risk of MDE in multivariate analysis (odds ratio = 2.35, 95% confidence interval 1.54-3.77). Other factors associated with MDE in multivariate analysis included educational level, number of chronic medical illnesses and child and adulthood traumatic events. There was no evidence of effect modification between work stress and selected sociodemographic, clinical and psychosocial variables.
Work stress is an independent risk factor for the development of MDE in the working population. Strategies to improve working environment are needed to keep workers mentally healthy and productive.
The difficulties inherent in obtaining consistent and adequate diagnoses for the purposes of research and therapy have been pointed out by a number of authors. Pasamanick12 in a recent article viewed the low interclinician agreement on diagnosis as an indictment of the present state of psychiatry and called for "the development of objective, measurable and verifiable criteria of classification based not on personal or parochial considerations, but on behavioral and other objectively measurable manifestations."Attempts by other investigators to subject clinical observations and judgments to objective measurement have resulted in a wide variety of psychiatric rating scales.4,15 These have been well summarized in a review article by Lorr11 on "Rating Scales and Check Lists for the Evaluation of Psychopathology." In the area of psychological testing, a variety of paper-and-pencil tests have been devised for the purpose of measuring specific
The CES-D scale is a short self-report scale designed to measure depressive symptomatology in the general population. The items of the scale are symptoms associated with depression which have been used in previously validated longer scales. The new scale was tested in household interview surveys and in psychiatric settings. It was found to have very high internal consistency and adequate test- retest repeatability. Validity was established by pat terns of correlations with other self-report measures, by correlations with clinical ratings of depression, and by relationships with other variables which support its construct validity. Reliability, validity, and factor structure were similar across a wide variety of demographic characteristics in the general population samples tested. The scale should be a useful tool for epidemiologic studies of de pression.
ABSTRACT– A self-assessment scale has been developed and found to be a reliable instrument for detecting states of depression and anxiety in the setting of an hospital medical outpatient clinic. The anxiety and depressive subscales are also valid measures of severity of the emotional disorder. It is suggested that the introduction of the scales into general hospital practice would facilitate the large task of detection and management of emotional disorder in patients under investigation and treatment in medical and surgical departments.
During the past decade, mutations affecting liability to human disease have been discovered at a phenomenal rate, and that rate is increasing. For the most part, however, those diseases have a relatively simple genetic basis. For diseases with a complex genetic and environmental basis, new approaches are needed to pave the way for more rapid discovery of genes affecting liability. One such approach exploits large, population-based samples and large-scale genotyping to evaluate disease/gene associations. A substantial drawback to such samples is the fact that population heterogeneity can induce spurious associations between genes and disease. We describe a method called genomic control (GC), which obviates many of the concerns about population substructure by using the features of the genomes present in the sample to correct for stratification. Two such approaches are now available. The GC approach exploits the fact that population substructure generate “overdispersion” of statistics used to assess association. By testing multiple polymorphisms throughout the genome, only some of which are pertinent to the disease of interest, the degree of overdispersion generated by population substructure can be estimated and taken into account. The other approach, called Structured Association (SA), assumes that the sampled population, while heterogeneous, is composed of subpopulations that are themselves homogeneous. By using multiple polymorphisms throughout the genome, SA probabilistically assigns sampled individuals to these latent subpopulations. We review in detail the overdispersion GC. In addition to outlining the published ideas on this method, we describe several extensions: quantitative trait studies and case–control studies with haplotypes and multiallelic markers. For each study design our goal is to achieve control similar to that obtained for a family-based study, but with the convenience found in a population-based design.
Genome-wide association studies are a powerful tool for unravelling the genetic background of complex disorders such as major depression.|We conducted a genome-wide association study of 604 patients with major depression and 1364 population based control subjects. The top hundred findings were followed up in a replication sample of 409 patients and 541 control subjects.|Two SNPs showed nominally significant association in both the genome-wide association study and the replication samples: 1) rs9943849 (p(combined) = 3.24E-6) located upstream of the carboxypeptidase M (CPM) gene and 2) rs7713917 (p(combined) = 1.48E-6), located in a putative regulatory region of HOMER1. Further evidence for HOMER1 was obtained through gene-wide analysis while conditioning on the genotypes of rs7713917 (p(combined) = 4.12E-3). Homer1 knockout mice display behavioral traits that are paradigmatic of depression, and transcriptional variants of Homer1 result in the dysregulation of cortical-limbic circuitry. This is consiste
The management of acute postoperative pain poses a significant challenge in surgical specialities. Despite the prevalence and impact of acute postoperative pain, there is a paucity of published data regarding its occurrence and sensory qualities after joint replacement.
That a proportion of patients would experience severe acute postoperative pain at rest after total hip replacement (THR) and total knee replacement (TKR).
Pain was assessed preoperatively, and then five times daily for the first three postoperative days in 105 THR and TKR patients. Pain severity was assessed using a pain Visual Analogue Scale and the sensory qualities of pain were assessed using the pain descriptors from the Short-Form McGill Pain Questionnaire.
Median acute pain scores peaked on the first postoperative day, with 58% of TKR patients and 47% of THR patients reporting moderate-severe pain. Preoperative pain was most frequently described as aching, stabbing and sharp, whereas acute postoperative pain was described as aching, heavy and tender. Night pain disturbed between 44-57% of TKR patients and 21-52% of THR patients on postoperative nights 1-3.
These findings demonstrate that acute postoperative pain at rest after joint replacement, particularly TKR, is poorly managed, although it does not reach the severity of preoperative pain.
Level IV (observational cohort study).
Genome-wide association studies are a powerful tool for unravelling the genetic background of complex disorders such as major depression.
We conducted a genome-wide association study of 604 patients with major depression and 1364 population based control subjects. The top hundred findings were followed up in a replication sample of 409 patients and 541 control subjects.
Two SNPs showed nominally significant association in both the genome-wide association study and the replication samples: 1) rs9943849 (p(combined) = 3.24E-6) located upstream of the carboxypeptidase M (CPM) gene and 2) rs7713917 (p(combined) = 1.48E-6), located in a putative regulatory region of HOMER1. Further evidence for HOMER1 was obtained through gene-wide analysis while conditioning on the genotypes of rs7713917 (p(combined) = 4.12E-3). Homer1 knockout mice display behavioral traits that are paradigmatic of depression, and transcriptional variants of Homer1 result in the dysregulation of cortical-limbic circuitry. This is consistent with the findings of our subsequent human imaging genetics study, which revealed that variation in single nucleotide polymorphism rs7713917 had a significant influence on prefrontal activity during executive cognition and anticipation of reward.
Our findings, combined with evidence from preclinical and animal studies, suggest that HOMER1 plays a role in the etiology of major depression and that the genetic variation affects depression via the dysregulation of cognitive and motivational processes.
Chronic stress is a key risk factor for a variety of diseases, including depression. There is a large degree of individual variation in the ability to recover successfully from a chronic stress exposure, but the determinants of this individual stress susceptibility are still poorly understood. We recently developed a novel mouse paradigm for chronic social stress during adolescence, which closely mimics the human condition of chronic social stress in respect to construct, face and predictive validity. By applying this chronic stress model to a large number of animals we aimed at identifying individuals that are either resilient or vulnerable to the persistent effects of chronic social stress exposure. Animals showing markedly elevated basal corticosterone levels 5 weeks following the end of the stress paradigm were considered "vulnerable", whereas individuals recovering quickly and being indistinguishable from controls were classified as "resilient". Stress vulnerability was associated with an increased level of corticotropin-releasing hormone in the paraventricular nucleus, decreased hippocampal mineralocorticoid receptor expression as well as increased anxiety- and depression-like behavior compared to resilient and control animals. In summary, we show that by using a large cohort of animals it is possible to select individuals that are vulnerable or resilient to the lasting effects of chronic social stress. The vulnerable phenotype mimics many aspects of stress-related human affective disorders and this may be used as a novel approach to study depression in an animal model, ultimately contributing to a better understanding and treatment of stress-related disorders.
We present methods for imputing data for ungenotyped markers and for inferring haplotype phase in large data sets of unrelated individuals and parent-offspring trios. Our methods make use of known haplotype phase when it is available, and our methods are computationally efficient so that the full information in large reference panels with thousands of individuals is utilized. We demonstrate that substantial gains in imputation accuracy accrue with increasingly large reference panel sizes, particularly when imputing low-frequency variants, and that unphased reference panels can provide highly accurate genotype imputation. We place our methodology in a unified framework that enables the simultaneous use of unphased and phased data from trios and unrelated individuals in a single analysis. For unrelated individuals, our imputation methods produce well-calibrated posterior genotype probabilities and highly accurate allele-frequency estimates. For trios, our haplotype-inference method is four orders of magnitude faster than the gold-standard PHASE program and has excellent accuracy. Our methods enable genotype imputation to be performed with unphased trio or unrelated reference panels, thus accounting for haplotype-phase uncertainty in the reference panel. We present a useful measure of imputation accuracy, allelic R(2), and show that this measure can be estimated accurately from posterior genotype probabilities. Our methods are implemented in version 3.0 of the BEAGLE software package.
Both obesity and lean mass have been correlated with symptoms of depression.
To investigate the contribution of genetic and environmental factors in the co-occurrence of obesity and lean mass with symptoms of depression.
Individuals were 2383 participants of the Erasmus Rucphen Family study. Symptoms of depression were assessed using the Center for Epidemiologic Studies Depression Scale and the Hospital Anxiety and Depression Scale. Anthropometric and dual-energy X-ray absorptiometry total body scans were obtained for the assessment of body composition. The role of shared genetic and shared environmental factors was quantified by estimating genetic an