Treatment response classes in major depressive disorder identified by model-based clustering and validated by clinical prediction models

The identification of generalizable treatment response classes (TRC[s]) in major depressive disorder (MDD) would facilitate comparisons across studies and the development of treatment prediction algorithms. Here, we investigated whether such stable TRCs can be identified and predicted by clinical baseline items. We analyzed data from an observational MDD cohort (Munich Antidepressant Response Signature [MARS] study, N = 1017), treated individually by psychopharmacological and psychotherapeutic means, and a multicenter, partially randomized clinical/pharmacogenomic study (Genome-based Therapeutic Drugs for Depression [GENDEP], N = 809). Symptoms were evaluated up to week 16 (or discharge) in MARS and week 12 in GENDEP. Clustering was performed on 809 MARS patients (discovery sample) using a mixed model with the integrated completed likelihood criterion for the assessment of cluster stability, and validated through a distinct MARS validation sample and GENDEP. A random forest algorithm was used to identify prediction patterns based on 50 clinical baseline items. From the clustering of the MARS discovery sample, seven TRCs emerged ranging from fast and complete response (average 4.9 weeks until discharge, 94% remitted patients) to slow and incomplete response (10% remitted patients at week 16). These proved stable representations of treatment response dynamics in both the MARS and the GENDEP validation sample. TRCs were strongly associated with established response markers, particularly the rate of remitted patients at discharge. TRCs were predictable from clinical items, particularly personality items, life events, episode duration, and specific psychopathological features. Prediction accuracy improved significantly when cluster-derived slopes were modelled instead of individual slopes. In conclusion, model-based clustering identified distinct and clinically meaningful treatment response classes in MDD that proved robust with regard to capturing response profiles of differently designed studies. Response classes were predictable from clinical baseline characteristics. Conceptually, model-based clustering is translatable to any outcome measure and could advance the large-scale integration of studies on treatment efficacy or the neurobiology of treatment response

Epigenetic upregulation of FKBP5 by aging and stress contributes to NF-kappa B-driven inflammation and cardiovascular risk

Aging and psychosocial stress are associated with increased inflammation and disease risk, but the underlying molecular mechanisms are unclear. Because both aging and stress are also associated with lasting epigenetic changes, a plausible hypothesis is that stress along the lifespan could confer disease risk through epigenetic effects on molecules involved in inflammatory processes. Here, by combining large-scale analyses in human cohorts with experiments in cells, we report that FKBP5, a protein implicated in stress physiology, contributes to these relations. Across independent human cohorts (total n > 3,000), aging synergized with stress-related phenotypes, measured with childhood trauma and major depression questionnaires, to epigenetically up-regulate FKBP5 expression. These age/stress-related epigenetic effects were recapitulated in a cellular model of replicative senescence, whereby we exposed replicating human fibroblasts to stress (glucocorticoid) hormones. Unbiased genome-wide analyses in human blood linked higher FKBP5 mRNA with a proinflammatory profile and altered NF-kappa B-related gene networks. Accordingly, experiments in immune cells showed that higher FKBP5 promotes inflammation by strengthening the interactions of NF-kappa B regulatory kinases, whereas opposing FKBP5 either by genetic deletion (CRISPR/Cas9-mediated) or selective pharmacological inhibition prevented the effects on NF-kappa B. Further, the age/stress-related epigenetic signature enhanced FKBP5 response to NF-kappa B through a positive feedback loop and was present in individuals with a history of acute myocardial infarction, a disease state linked to peripheral inflammation. These findings suggest that aging/stress-driven FKBP5-NF-kappa B signaling mediates inflammation, potentially contributing to cardiovascular risk, and may thus point to novel biomarker and treatment possibilities.Peer reviewe

Genetic Contribution to Alcohol Dependence: Investigation of a Heterogeneous German Sample of Individuals with Alcohol Dependence, Chronic Alcoholic Pancreatitis, and Alcohol-Related Cirrhosis

The present study investigated the genetic contribution to alcohol dependence (AD) using genome-wide association data from three German samples. These comprised patients with: (i) AD; (ii) chronic alcoholic pancreatitis (ACP); and (iii) alcohol-related liver cirrhosis (ALC). Single marker, gene-based, and pathway analyses were conducted. A significant association was detected for the ADH1B locus in a gene-based approach (puncorrected = 1.2 × 10−6; pcorrected = 0.020). This was driven by the AD subsample. No association with ADH1B was found in the combined ACP + ALC sample. On first inspection, this seems surprising, since ADH1B is a robustly replicated risk gene for AD and may therefore be expected to be associated also with subgroups of AD patients. The negative finding in the ACP + ALC sample, however, may reflect genetic stratification as well as random fluctuation of allele frequencies in the cases and controls, demonstrating the importance of large samples in which the phenotype is well assessed

Genome-wide regional heritability mapping identifies a locus within the<i> TOX2</i> gene associated with Major Depressive Disorder

Background: Major depressive disorder (MDD) is the second largest cause of global disease burden. It has an estimated heritability of 37%, but published genome-wide association studies have so far identified few risk loci. Haplotype-block-based regional heritability mapping (HRHM) estimates the localized genetic variance explained by common variants within haplotype blocks, integrating the effects of multiple variants, and may be more powerful for identifying MDD-associated genomic regions. Methods: We applied HRHM to Generation Scotland: The Scottish Family Health Study, a large family- and population-based Scottish cohort (N = 19,896). Single-single nucleotide polymorphism (SNP) and haplotype-based association tests were used to localize the association signal within the regions identified by HRHM. Functional prediction was used to investigate the effect of MDD-associated SNPs within the regions. Results: A haplotype block across a 24-kb region within the TOX2 gene reached genome-wide significance in HRHM. Single-SNP- and haplotype-based association tests demonstrated that five of nine genotyped SNPs and two haplotypes within this block were significantly associated with MDD. The expression of TOX2 and a brain-specific long noncoding RNA RP1-269M15.3 in frontal cortex and nucleus accumbens basal ganglia, respectively, were significantly regulated by MDD-associated SNPs within this region. Both the regional heritability and single-SNP associations within this block were replicated in the UK–Ireland group of the most recent release of the Psychiatric Genomics Consortium (PGC), the PGC2–MDD (Major Depression Dataset). The SNP association was also replicated in a depressive symptom sample that shares some individuals with the PGC2–MDD. Conclusions: This study highlights the value of HRHM for MDD and provides an important target within TOX2 for further functional studies

Examining sex differences in neurodevelopmental and psychiatric genetic risk in anxiety and depression

Anxiety and depression are common mental health disorders and have a higher prevalence in females. They are modestly heritable, share genetic liability with other psychiatric disorders, and are highly heterogeneous. There is evidence that genetic liability to neurodevelopmental disorders, such as attention deficit hyperactivity disorder (ADHD) is associated with anxiety and depression, particularly in females. We investigated sex differences in family history for neurodevelopmental and psychiatric disorders and neurodevelopmental genetic risk burden (indexed by ADHD polygenic risk scores (PRS) and rare copy number variants; CNVs) in individuals with anxiety and depression, also taking into account age at onset. We used two complementary datasets: 1) participants with a self-reported diagnosis of anxiety or depression (N = 4,178, 65.5% female; mean age = 41.5 years; N = 1,315 with genetic data) from the National Centre for Mental Health (NCMH) cohort and 2) a clinical sample of 13,273 (67.6% female; mean age = 45.2 years) patients with major depressive disorder (MDD) from the Psychiatric Genomics Consortium (PGC). We tested for sex differences in family history of psychiatric problems and presence of rare CNVs (neurodevelopmental and >500kb loci) in NCMH only and for sex differences in ADHD PRS in both datasets. In the NCMH cohort, females were more likely to report family history of neurodevelopmental and psychiatric disorders, but there were no robust sex differences in ADHD PRS or presence of rare CNVs. There was weak evidence of higher ADHD PRS in females compared to males in the PGC MDD sample, particularly in those with an early onset of MDD. These results do not provide strong evidence of sex differences in neurodevelopmental genetic risk burden in adults with anxiety and depression. This indicates that sex may not be a major index of neurodevelopmental genetic heterogeneity, that is captured by ADHD PRS and rare CNV burden, in adults with anxiety and depression

Genomewide Association Scan of Suicidal Thoughts and Behaviour in Major Depression

Background Suicidal behaviour can be conceptualised as a continuum from suicidal ideation, to suicidal attempts to completed suicide. In this study we identify genes contributing to suicidal behaviour in the depression study RADIANT. Methodology/Principal Findings A quantitative suicidality score was composed of two items from the SCAN interview. In addition, the 251 depression cases with a history of serious suicide attempts were classified to form a discrete trait. The quantitative trait was correlated with younger onset of depression and number of episodes of depression, but not with gender. A genome-wide association study of 2,023 depression cases was performed to identify genes that may contribute to suicidal behaviour. Two Munich depression studies were used as replication cohorts to test the most strongly associated SNPs. No SNP was associated at genome-wide significance level. For the quantitative trait, evidence of association was detected at GFRA1, a receptor for the neurotrophin GDRA (p = 2e-06). For the discrete trait of suicide attempt, SNPs in KIAA1244 and RGS18 attained p-values of <5e-6. None of these SNPs showed evidence for replication in the additional cohorts tested. Candidate gene analysis provided some support for a polymorphism in NTRK2, which was previously associated with suicidality. Conclusions/Significance This study provides a genome-wide assessment of possible genetic contribution to suicidal behaviour in depression but indicates a genetic architecture of multiple genes with small effects. Large cohorts will be required to dissect this further

Gene set enrichment analysis and expression pattern exploration implicate an involvement of neurodevelopmental processes in bipolar disorder

Background Bipolar disorder (BD) is a common and highly heritable disorder of mood. Genome-wide association studies (GWAS) have identified several independent susceptibility loci. In order to extract more biological information from GWAS data, multi-locus approaches represent powerful tools since they utilize knowledge about biological processes to integrate functional sets of genes at strongly to moderately associated loci. Methods We conducted gene set enrichment analyses (GSEA) using 2.3 million single-nucleotide polymorphisms, 397 Reactome pathways and 24,025 patients with BD and controls. RNA expression of implicated individual genes and gene sets were examined in post-mortem brains across lifespan. Results Two pathways showed a significant enrichment after correction for multiple comparisons in the GSEA: GRB2 events in ERBB2 signaling, for which 6 of 21 genes were BD associated (P = 0.0377), and NCAM signaling for neurite out-growth, for which 11 out of 62 genes were BD associated (P = 0.0451). Most pathway genes showed peaks of RNA co-expression during fetal development and infancy and mapped to neocortical areas and parts of the limbic system. Limitations Pathway associations were technically reproduced by two methods, although they were not formally replicated in independent samples. Gene expression was explored in controls but not in patients. Conclusions Pathway analysis in large GWAS data of BD and follow-up of gene expression patterns in healthy brains provide support for an involvement of neurodevelopmental processes in the etiology of this neuropsychiatric disease. Future studies are required to further evaluate the relevance of the implicated genes on pathway functioning and clinical aspects of BD

Genome-wide association for major depression through age at onset stratification:Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

Background Major depressive disorder (MDD) is a disabling mood disorder and, despite a known heritable component, a large meta-analysis of GWAS revealed no replicable genetic risk variants. Given prior evidence of heterogeneity by age-at-onset (AAO) in MDD, we tested whether genome-wide significant risk variants for MDD could be identified in cases subdivided by AAO. Method Discovery case-control GWASs were performed where cases were stratified using increasing/decreasing AAO-cutoffs; significant SNPs were tested in nine independent replication samples, giving a total sample of 22,158 cases and 133,749 controls for sub-setting. Polygenic score analysis was used to examine if differences in shared genetic risk exists between earlier and adult onset MDD with commonly co-morbid disorders of schizophrenia, bipolar disorder, Alzheimer’s disease, and coronary artery disease. Results We identify one replicated genome-wide significant locus associated with adult-onset (>27 years) MDD (rs7647854, OR=1.16, 95%CI=1.11-1.21, p=5.2x10-11). Using polygenic score analyses, we show that earlier-onset MDD is genetically more similar to schizophrenia and bipolar disorder than adult-onset. 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

An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype

AbstractBackgroundThe genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder.MethodsWe analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a p-value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures.ResultsThe SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 × 10–9) located in an intron of the FHIT gene. We replicated this SNP in independent samples (p = .02) and the overall meta-analysis of the discovery and replication cohorts (1.0 × 10–9).ConclusionsThis large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression

Association of the OPRM1 Variant rs1799971 (A118G) with Non-Specific Liability to Substance Dependence in a Collaborative de novo Meta-Analysis of European-Ancestry Cohorts

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