Association of ATP6V1B2 rs1106634 with lifetime risk of depression and hippocampal neurocognitive deficits: possible novel mechanisms in the etiopathology of depression

Current understanding and treatment of depression is limited to the monoaminergic theory with little knowledge of the involvement of other cellular processes. Genome-wide association studies, however, implicate several novel single-nucleotide polymorphisms with weak but replicable effects and unclarified mechanisms. We investigated the effect of rs1106634 of the ATPV1B2 gene encoding the vacuolar H+ATPase on lifetime and current depression and the possible mediating role of neuroticism by logistic and linear regression in a white European general sample of 2226 subjects. Association of rs1106634 with performance on frontal (Stockings of Cambridge (SOC)) and hippocampal-dependent (paired associates learning (PAL)) cognitive tasks was investigated in multivariate general linear models in a smaller subsample. The ATP6V1B2 rs1106634 A allele had a significant effect on lifetime but not on current depression. The effect of the A allele on lifetime depression was not mediated by neuroticism. The A allele influenced performance on the PAL but not on the SOC test. We conclude that the effects of variation in the vacuolar ATPase may point to a new molecular mechanism that influences the long-term development of depression. This mechanism may involve dysfunction specifically in hippocampal circuitry and cognitive impairment that characterizes recurrent and chronic depression

Multi-locus genome-wide association analysis supports the role of glutamatergic synaptic transmission in the etiology of major depressive disorder

Major depressive disorder (MDD) is a common psychiatric illness characterized by low mood and loss of interest in pleasurable activities. Despite years of effort, recent genome-wide association studies (GWAS) have identified few susceptibility variants or genes that are robustly associated with MDD. Standard single-SNP (single nucleotide polymorphism)-based GWAS analysis typically has limited power to deal with the extensive heterogeneity and substantial polygenic contribution of individually weak genetic effects underlying the pathogenesis of MDD. Here, we report an alternative, gene-set-based association analysis of MDD in an effort to identify groups of biologically related genetic variants that are involved in the same molecular function or cellular processes and exhibit a significant level of aggregated association with MDD. In particular, we used a text-mining-based data analysis to prioritize candidate gene sets implicated in MDD and conducted a multi-locus association analysis to look for enriched signals of nominally associated MDD susceptibility loci within each of the gene sets. Our primary analysis is based on the meta-analysis of three large MDD GWAS data sets (total N = 4346 cases and 4430 controls). After correction for multiple testing, we found that genes involved in glutamatergic synaptic neurotransmission were significantly associated with MDD (set-based association P = 6.9 X 10(-4)). This result is consistent with previous studies that support a role of the glutamatergic system in synaptic plasticity and MDD and support the potential utility of targeting glutamatergic neurotransmission in the treatment of MDD

Genome-Wide DNA Methylation Scan in Major Depressive Disorder

While genome-wide association studies are ongoing to identify sequence variation influencing susceptibility to major depressive disorder (MDD), epigenetic marks, such as DNA methylation, which can be influenced by environment, might also play a role. Here we present the first genome-wide DNA methylation (DNAm) scan in MDD. We compared 39 postmortem frontal cortex MDD samples to 26 controls. DNA was hybridized to our Comprehensive High-throughput Arrays for Relative Methylation (CHARM) platform, covering 3.5 million CpGs. CHARM identified 224 candidate regions with DNAm differences >10%. These regions are highly enriched for neuronal growth and development genes. Ten of 17 regions for which validation was attempted showed true DNAm differences; the greatest were in PRIMA1, with 12–15% increased DNAm in MDD (p = 0.0002–0.0003), and a concomitant decrease in gene expression. These results must be considered pilot data, however, as we could only test replication in a small number of additional brain samples (n = 16), which showed no significant difference in PRIMA1. Because PRIMA1 anchors acetylcholinesterase in neuronal membranes, decreased expression could result in decreased enzyme function and increased cholinergic transmission, consistent with a role in MDD. We observed decreased immunoreactivity for acetylcholinesterase in MDD brain with increased PRIMA1 DNAm, non-significant at p = 0.08

Considering Trauma Exposure in the Context of Genetics Studies of Posttraumatic Stress Disorder: A Systematic Review

Background: Posttraumatic stress disorder (PTSD) is a debilitating anxiety disorder. Surveys of the general population suggest that while 50-85% of Americans will experience a traumatic event in their lifetime, only 2-50% will develop PTSD. Why some individuals develop PTSD following trauma exposure while others remain resilient is a central question in the field of trauma research. For more than half a century, the role of genetic influences on PTSD has been considered as a potential vulnerability factor. However, despite the exponential growth of molecular genetic studies over the past decade, limited progress has been made in identifying true genetic variants for PTSD. Methods: In an attempt to aid future genome wide association studies (GWAS), this paper presents a systematic review of 28 genetic association studies of PTSD. Inclusion criteria required that 1) all participants were exposed to Criterion A traumatic events, 2) polymorphisms of relevant genes were genotyped and assessed in relation to participants’ PTSD status, 3) quantitative methods were used, and 4) articles were published in English and in peer-reviewed journals. In the examination of these 28 studies, particular attention was given to variables related to trauma exposure (e.g. number of traumas, type of trauma). Results: Results indicated that most articles did not report on the GxE interaction in the context of PTSD or present data on the main effects of E despite having data available. Furthermore, some studies that did consider the GxE interaction had significant findings, underscoring the importance of examining how genotypes can modify the effect of trauma on PTSD. Additionally, results indicated that only a small number of genes continue to be studied and that there were marked differences in methodologies across studies, which subsequently limited robust conclusions. Conclusions: As trauma exposure is a necessary condition for the PTSD diagnosis, this paper identifies gaps in the current literature as well as provides recommendations for how future GWAS studies can most effectively incorporate trauma exposure data in both the design and analysis phases of studies

A Fine-Mapping Study of 7 Top Scoring Genes from a GWAS for Major Depressive Disorder

Major depressive disorder (MDD) is a psychiatric disorder that is characterized -amongst others- by persistent depressed mood, loss of interest and pleasure and psychomotor retardation. Environmental circumstances have proven to influence the aetiology of the disease, but MDD also has an estimated 40% heritability, probably with a polygenic background. In 2009, a genome wide association study (GWAS) was performed on the Dutch GAIN-MDD cohort. A non-synonymous coding single nucleotide polymorphism (SNP) rs2522833 in the PCLO gene became only nominally significant after post-hoc analysis with an Australian cohort which used similar ascertainment. The absence of genome-wide significance may be caused by low SNP coverage of genes. To increase SNP coverage to 100% for common variants (m.a.f.>0.1, r2>0.8), we selected seven genes from the GAIN-MDD GWAS: PCLO, GZMK, ANPEP, AFAP1L1, ST3GAL6, FGF14 and PTK2B. We genotyped 349 SNPs and obtained the lowest P-value for rs2715147 in PCLO at P = 6.8E−7. We imputed, filling in missing genotypes, after which rs2715147 and rs2715148 showed the lowest P-value at P = 1.2E−6. When we created a haplotype of these SNPs together with the non-synonymous coding SNP rs2522833, the P-value decreased to P = 9.9E−7 but was not genome wide significant. Although our study did not identify a more strongly associated variant, the results for PCLO suggest that the causal variant is in high LD with rs2715147, rs2715148 and rs2522833

Piccolo genotype modulates neural correlates of emotion processing but not executive functioning

Major depressive disorder (MDD) is characterized by affective symptoms and cognitive impairments, which have been associated with changes in limbic and prefrontal activity as well as with monoaminergic neurotransmission. A genome-wide association study implicated the polymorphism rs2522833 in the piccolo (PCLO) gene—involved in monoaminergic neurotransmission—as a risk factor for MDD. However, the role of the PCLO risk allele in emotion processing and executive function or its effect on their neural substrate has never been studied. We used functional magnetic resonance imaging (fMRI) to investigate PCLO risk allele carriers vs noncarriers during an emotional face processing task and a visuospatial planning task in 159 current MDD patients and healthy controls. In PCLO risk allele carriers, we found increased activity in the left amygdala during processing of angry and sad faces compared with noncarriers, independent of psychopathological status. During processing of fearful faces, the PCLO risk allele was associated with increased amygdala activation in MDD patients only. During the visuospatial planning task, we found no genotype effect on performance or on BOLD signal in our predefined areas as a function of increasing task load. The PCLO risk allele was found to be specifically associated with altered emotion processing, but not with executive dysfunction. Moreover, the PCLO risk allele appears to modulate amygdala function during fearful facial processing in MDD and may constitute a possible link between genotype and susceptibility for depression via altered processing of fearful stimuli. The current results may therefore aid in better understanding underlying neurobiological mechanisms in MDD

Genome-wide association for major depression through age at onset stratification

BACKGROUND: Major depressive disorder (MDD) is a disabling mood disorder, and despite a known heritable component, a large meta-analysis of genome-wide association studies revealed no replicable genetic risk variants. Given prior evidence of heterogeneity by age at onset in MDD, we tested whether genome-wide significant risk variants for MDD could be identified in cases subdivided by age at onset. METHODS: Discovery case-control genome-wide association studies were performed where cases were stratified using increasing/decreasing age-at-onset cutoffs; significant single nucleotide polymorphisms were tested in nine independent replication samples, giving a total sample of 22,158 cases and 133,749 control subjects for subsetting. Polygenic score analysis was used to examine whether differences in shared genetic risk exists between earlier and adult-onset MDD with commonly comorbid disorders of schizophrenia, bipolar disorder, Alzheimer’s disease, and coronary artery disease. RESULTS: We identified one replicated genome-wide significant locus associated with adult-onset (>27 years) MDD (rs7647854, odds ratio: 1.16, 95% confidence interval: 1.11–1.21, p = 5.2 × 10-11). Using polygenic score analyses, we show that earlier-onset MDD is genetically more similar to schizophrenia and bipolar disorder than adult-onset MDD. CONCLUSIONS: We demonstrate that using additional phenotype data previously collected by genetic studies to tackle phenotypic heterogeneity in MDD can successfully lead to the discovery of genetic risk factor despite reduced sample size. Furthermore, our results suggest that the genetic susceptibility to MDD differs between adult- and earlier-onset MDD, with earlier-onset cases having a greater genetic overlap with schizophrenia and bipolar disorder

Genetic effects influencing risk for major depressive disorder in China and Europe

Major depressive disorder (MDD) is a common, complex psychiatric disorder and a leading cause of disability worldwide. Despite twin studies indicating its modest heritability (similar to 30-40%), extensive heterogeneity and a complex genetic architecture have complicated efforts to detect associated genetic risk variants. We combined single-nucleotide polymorphism (SNP) summary statistics from the CONVERGE and PGC studies of MDD, representing 10 502 Chinese (5282 cases and 5220 controls) and 18 663 European (9447 cases and 9215 controls) subjects. We determined the fraction of SNPs displaying consistent directions of effect, assessed the significance of polygenic risk scores and estimated the genetic correlation of MDD across ancestries. Subsequent trans-ancestry meta-analyses combined SNP-level evidence of association. Sign tests and polygenic score profiling weakly support an overlap of SNP effects between East Asian and European populations. We estimated the trans-ancestry genetic correlation of lifetime MDD as 0.33; female-only and recurrent MDD yielded estimates of 0.40 and 0.41, respectively. Common variants downstream of GPHN achieved genome-wide significance by Bayesian trans-ancestry meta-analysis (rs9323497; log10 Bayes Factor = 8.08) but failed to replicate in an independent European sample (P= 0.911). Gene-set enrichment analyses indicate enrichment of genes involved in neuronal development and axonal trafficking. We successfully demonstrate a partially shared polygenic basis of MDD in East Asian and European populations. Taken together, these findings support a complex etiology for MDD and possible population differences in predisposing genetic factors, with important implications for future genetic studies

Evaluating genetic markers and neurobiochemical analytes for fluoxetine response using a panel of mouse inbred strains

RationaleIdentification of biomarkers that establish diagnosis or treatment response is critical to the advancement of research and management of patients with depression.ObjectiveOur goal was to identify biomarkers that can potentially assess fluoxetine response and risk to poor treatment outcome.MethodsWe measured behavior, gene expression, and the levels of 36 neurobiochemical analytes across a panel of genetically diverse mouse inbred lines after chronic treatment with water or fluoxetine.ResultsGlyoxylase 1 (GLO1) and guanine nucleotide-binding protein 1 (GNB1) mostly account for baseline anxiety-like and depressive-like behavior, indicating a common biological link between depression and anxiety. Fluoxetine-induced biochemical alterations discriminated positive responders, while baseline neurobiochemical differences differentiated negative responders (p < 0.006). Results show that glial fibrillary acidic protein, S100 beta protein, GLO1, and histone deacetylase 5 contributed most to fluoxetine response. These proteins are linked within a cellular growth/proliferation pathway, suggesting the involvement of cellular genesis in fluoxetine response. Furthermore, a candidate genetic locus that associates with baseline depressive-like behavior contains a gene that encodes for cellular proliferation/adhesion molecule (Cadm1), supporting a genetic basis for the role of neuro/gliogenesis in depression.ConclusionWe provided a comprehensive analysis of behavioral, neurobiochemical, and transcriptome data across 30 mouse inbred strains that has not been accomplished before. We identified biomarkers that influence fluoxetine response, which, altogether, implicate the importance of cellular genesis in fluoxetine treatment. More broadly, this approach can be used to assess a wide range of drug response phenotypes that are challenging to address in human samples.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-011-2574-z) contains supplementary material, which is available to authorized users

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders