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Highlights from the article: B Overall Abstract: b In many branches of medicine the earliest clinical impact of genomic research has been in the field of pharmacogenetics. Genome-wide significant variants implicate enzymatic genes that trace the metabolic pathways of clozapine and nor-clozapine. Dr Sophie Legge will present the first genome-wide analysis of clozapine-associated neutropenia in those of African ancestry, a group underserved by clinical services and under-represented in research.

Highlights from the article: B Overall Abstract: b Alcohol dependence (AD) is 50% heritable and there is also strong evidence for environmental influences on risk. AD genome wide association studies (GWAS) have detected genome-wide significant associations (p < 5x10-8) with alcohol metabolizing genes and also variably with several other genes. AD is frequently found to be comorbid with a range of psychiatric illnesses and the relative contribution of risk factors for these comorbidities is likely to have an influence on the.

Precision psychiatry is an emerging field with transformative opportunities for mental health. However, the use of clinical prediction models carries unprecedented ethical challenges, which must be addressed before accessing the potential benefits of precision psychiatry. This critical review covers multidisciplinary areas, including psychiatry, ethics, statistics and machine-learning, healthcare and academia, as well as input from people with lived experience of mental disorders, their family, and carers. We aimed to identify core ethical considerations for precision psychiatry and mitigate concerns by designing a roadmap for research and clinical practice. We identified priorities: learning from somatic medicine; identifying precision psychiatry use cases; enhancing transparency and generalizability; fostering implementation; promoting mental health literacy; communicating risk estimates; data protection and privacy; and fostering the equitable distribution of mental health care. We hope this blueprint will advance research and practice and enable people with mental health problems to benefit from precision psychiatry. [ABSTRACT FROM AUTHOR]

Abstract: Recent studies have emphasized an important role for neurotrophins, such as brain-derived neurotrophic factor (BDNF), in regulating the plasticity of neural circuits involved in the pathophysiology of stress-related diseases. The aim of the present study was to examine the interplay of the BDNF Val66Met and the serotonin transporter promoter (5-HTTLPR) polymorphisms in moderating the impact of early-life adversity on BDNF plasma concentration and depressive symptoms. Participants were taken from an epidemiological cohort study following the long-term outcome of early risk factors from birth into young adulthood. In 259 individuals (119 males, 140 females), genotyped for the BDNF Val66Met and the 5-HTTLPR polymorphisms, plasma BDNF was assessed at the age of 19 years. In addition, participants completed the Beck Depression Inventory (BDI). Early adversity was determined according to a family adversity index assessed at 3 months of age. Results indicated that individuals homozygous for both the BDNF Val and the 5-HTTLPR L allele showed significantly reduced BDNF levels following exposure to high adversity. In contrast, BDNF levels appeared to be unaffected by early psychosocial adversity in carriers of the BDNF Met or the 5-HTTLPR S allele. While the former group appeared to be most susceptible to depressive symptoms, the impact of early adversity was less pronounced in the latter group. This is the first preliminary evidence indicating that early-life adverse experiences may have lasting sequelae for plasma BDNF levels in humans, highlighting that the susceptibility to this effect is moderated by BDNF Val66Met and 5-HTTLPR genotype. [Copyright &y& Elsevier]

Bipolar disorder (BD) might be associated with higher infection rates of coronavirus disease (COVID-19) which in turn could result in worsening the clinical course and outcome. This may be due to a high prevalence of somatic comorbidities and an increased risk of delays in and poorer treatment of somatic disease in patients with severe mental illness in general. Vaccination is the most important public health intervention to tackle the ongoing pandemic. We undertook a systematic review regarding the data on vaccinations in individuals with BD. Proportion of prevalence rates, efficacy and specific side effects of vaccinations and in individuals with BD were searched. Results show that only five studies have investigated vaccinations in individuals with BD, which substantially limits the interpretation of overall findings. Studies on antibody production after vaccinations in BD are very limited and results are inconsistent. Also, the evidence-based science on side effects of vaccinations in individuals with BD so far is poor. [ABSTRACT FROM AUTHOR]

Highlights from the article: To allow data from these consortia to flow together, three common cross-sectional platforms for biomaterials, clinical data and imaging data were established. B Results: b A data protection concept and a broad informed consent based on the national data protection guidelines was developed which was positively assessed by the Munich ethics commission (LMU) and serves as an example for further ethics commissions. Pseudonyms used in each research consortium within the research network are converted again into another pseudonym.

Sex-specific differences in schizophrenia (SCZ) are pervasive and have been reported for various aspects of the disease. Previous authors have therefore hypothesized that genetic risk factors on the X chromosome play a role in the complex interplay that leads to the development of this multifactorial and highly polygenic disorder. Nevertheless, few studies specifically targeted the investigation of these sex-specific genetic risk factors. In recent years, large-scale systematic genetic studies in SCZ have broadened the spectrum of genetic variation contributing to the disease and identified, among others, several X-chromosomal risk-associated loci. The world´s largest copy number variant (CNV) analysis for SCZ reported the first potential risk-associated CNV on the X chromosome. Duplications in Xq28,distal confer risk to SCZ in both sexes and span eight different protein-coding genes. Due to the shared genomic breakpoints of the duplications described to date, the issue of which gene/s at this locus is/are relevant in terms of SCZ pathogenesis remains unclear. In order to detect an enrichment of rare and potentially damaging variants in possible disease-relevant genes, the objective was to provide a detailed analysis of the genetic burden within the Xq28,distal locus using high-throughput, multiplex targeted sequencing. All coding regions of the implicated genes were sequenced in a large, European SCZ case-control cohort (n= 1935 patients with SCZ and n=1905 population-based controls) using the single molecule molecular inversion probe method on an Illumina HiSeq2500. To identify rare and potentially damaging variants, the analyses focused on non-synonymous single-nucleotide variants and Indels with a minor allele frequency ≤ 0.1% and a Combined Annotation Dependent Depletion score ≥ 20. The burden analysis was performed in a gene-wise manner and with sex as a covariate using the X-chromosomal model of the Optimal Unified Sequence Kernel Association Test adjusting for possible sex-specific effects. A total of n=73 independent variants passed the applied quality control criteria. After filtering for rare and potentially damaging variants, a total of n= 13 independent variants, as identified in four cases and eleven controls, were subjected to the consecutive burden analysis. For the genes within the Xq28,distal locus, no significant single-gene association was identified (smallest value in BRCC3 with p=0.103, p-adjusted=0.515), on the level of rare and potentially damaging variants. Overall, the present study confirms the recent gene-based results for the implicated genes of the Xq28, distal locus in the latest meta-analysis of exome sequencing data in SCZ conducted by the SCHEMA Consortium. The small number of identified variants is partly explained by the strict filter criteria and limited sample size. These findings might indicate a possible contribution of ultra-rare variants locus and a high degree of conservation within this region. Moreover, this may point towards alternative pathomechanisms not investigated in the present analyses; such as the involvement of sex-dependent risk factors, a genuine overexpression of a disease-relevant gene or the disruption of topologically associated domains in the context of duplications at Xq28,distal. Although inconclusive, the present findings highlight the need for more research into the role of X-chromosomal genetic risk factors in SCZ. [ABSTRACT FROM AUTHOR]

This narrative review summarizes and discusses the implications of the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 and the upcoming International Classification of Diseases (ICD)-11 classification systems on the prevalence of bipolar disorder and on the validity of the DSM-5 diagnosis of bipolar disorder according to the Robin and Guze criteria of diagnostic validity. Here we review and discuss current data on the prevalence of bipolar disorder diagnosed according to DSM-5 versus DSM-IV, and data on characteristics of bipolar disorder in the two diagnostic systems in relation to extended Robin and Guze criteria: 1) clinical presentation, 2) associations with para-clinical data such as brain imaging and blood-based biomarkers, 3) delimitation from other disorders, 4) associations with family history / genetics, 5) prognosis and long-term follow-up, and 6) treatment effects. The review highlights that few studies have investigated consequences for the prevalence of the diagnosis of bipolar disorder and for the validity of the diagnosis. Findings from these studies suggest a substantial decrease in the point prevalence of a diagnosis of bipolar with DSM-5 compared with DSM-IV, ranging from 30–50%, but a smaller decrease in the prevalence during lifetime, corresponding to a 6% reduction. It is concluded that it is likely that the use of DSM-5 and ICD-11 will result in diagnostic delay and delayed early intervention in bipolar disorder. Finally, we recommend areas for future research. [ABSTRACT FROM AUTHOR]

Cognitive abilities are widely regarded as the traits that most distinguish humans from other animals. The evolution of cognitive abilities has been studied for a long time by the fields of neuroanatomy and psychology, and only recently has become tractable by evolutionary genetics. Comparative genomic approaches have permitted the deep study of a handful of genes involved in cognition and language, of which the most notable is probably FOXP2. However, the intrinsic poligenicity of cognitive phenotypes has hindered progress in this area. In 2009, Konopka and Geschwind (Neuron 21: 231–244) reasoned that comprehensive evolutionary analyses in cognitive or psychiatric complex traits required the integration of multiple levels of phenotype and genotype data. Currently, high resolution genomic data has become available for most human populations, primate species and even from extinct archaic hominins, such as Neandertals or Denisovans. This symposium will host presentations that will show how this data can be combined with the analytic pipelines commonly used in clinical genetic research, and how genomic signatures of natural selection can be found in psychiatric disorders and related phenotypes. The speakers will also discuss the relevance of these findings for the long term goals of the psychiatric research community, including the prioritization of genes for functional studies and the greater understanding of the nature of psychiatric disorders. [ABSTRACT FROM AUTHOR]

Bipolar disorder (BD) is a major healthcare and socio-economic challenge. Despite its substantial burden on society, the research activity in BD is much smaller than its economic impact appears to demand. There is a consensus that the accurate identification of the underlying pathophysiology for BD is fundamental to realize major health benefits through better treatment and preventive regimens. However, to achieve these goals requires coordinated action and innovative approaches to boost the discovery of the neurobiological underpinnings of BD, and rapid translation of research findings into development and testing of better and more specific treatments. To this end, we here propose that only a large-scale coordinated action can be successful in integrating international big-data approaches with real-world clinical interventions. This could be achieved through the creation of a Global Bipolar Disorder Foundation, which could bring government, industry and philanthropy together in common cause. A global initiative for BD research would come at a highly opportune time given the seminal advances promised for our understanding of the genetic and brain basis of the disease and the obvious areas of unmet clinical need. Such an endeavour would embrace the principles of open science and see the strong involvement of user groups and integration of dissemination and public involvement with the research programs. We believe the time is right for a step change in our approach to understanding, treating and even preventing BD effectively. [ABSTRACT FROM AUTHOR]

Although preclinical studies clearly indicate an effect of 5-HTTLPR genotype on 5-HT transporter (5-HTT) expression, studies in humans provided inconclusive results, hypothetically due to environmental factors and differences in individual behavior. For example, nicotine and other constituents of tobacco smoke elevate serotonin (5-HT) levels in the brain and may thereby cause homeostatic adaptations in 5-HTT availability that moderate effects of 5-HTTLPR genotype. To test whether 5-HTT availability in the midbrain is affected by smoking status and 5-HTTLPR genotype, we pooled data from prior studies on in vivo 5-HTT availability (BP ND) measured with positron emission tomography (PET) and [11C]DASB. In total, we reanalyzed 5-HTT availability in 116 subjects using ANCOVA statistics. ROI analysis revealed that current smokers and non-smokers do not differ in midbrain BP ND. Interestingly, smoking status significantly interacted with 5-HTTLPR genotype: active smoking was associated with reduced 5-HTT availability only in LL subjects but not in carriers of the S-allele. From the perspective of genotype effects, non-smokers showed the expected association with 5-HTTLPR, i.e. higher 5-HTT availability in LL subjects compared to carriers of the S-allele, whereas this pattern was actually reversed for active smokers. Our study indicates that smoking status moderates the association of 5-HTTLPR genotype and 5-HTT expression, which may help to explain inconsistent findings in previous studies. Regarding the mechanism, we suggest that smoking may induce epigenetic processes such as methylation of SLC6A4, which can differ depending on its genetic constitution. [ABSTRACT FROM AUTHOR]

Abstract Although preclinical studies clearly indicate an effect of 5-HTTLPR genotype on 5-HT transporter (5-HTT) expression, studies in humans provided inconclusive results, hypothetically due to environmental factors and differences in individual behavior. For example, nicotine and other constituents of tobacco smoke elevate serotonin (5-HT) levels in the brain and may thereby cause homeostatic adaptations in 5-HTT availability that moderate effects of 5-HTTLPR genotype. To test whether 5-HTT availability in the midbrain is affected by smoking status and 5-HTTLPR genotype, we pooled data from prior studies on in vivo 5-HTT availability (BP ND) measured with positron emission tomography (PET) and [11C]DASB. In total, we reanalyzed 5-HTT availability in 116 subjects using ANCOVA statistics. ROI analysis revealed that current smokers and non-smokers do not differ in midbrain BP ND. Interestingly, smoking status significantly interacted with 5-HTTLPR genotype: active smoking was associated with reduced 5-HTT availability only in LL subjects but not in carriers of the S-allele. From the perspective of genotype effects, non-smokers showed the expected association with 5-HTTLPR, i.e. higher 5-HTT availability in LL subjects compared to carriers of the S-allele, whereas this pattern was actually reversed for active smokers. Our study indicates that smoking status moderates the association of 5-HTTLPR genotype and 5-HTT expression, which may help to explain inconsistent findings in previous studies. Regarding the mechanism, we suggest that smoking may induce epigenetic processes such as methylation of SLC6A4, which can differ depending on its genetic constitution. [ABSTRACT FROM AUTHOR]

Cytochrome (CYP) P450 enzymes have a primary role in antidepressant metabolism and variants in these polymorphic genes are targets for pharmacogenetic investigation. This is the first meta-analysis to investigate how CYP2C19 polymorphisms predict citalopram/escitalopram efficacy and side effects. CYP2C19 metabolic phenotypes comprise poor metabolizers (PM), intermediate and intermediate+ metabolizers (IM; IM+), extensive and extensive+ metabolizers (EM [wild type]; EM+) and ultra-rapid metabolizers (UM) defined by the two most common CYP2C19 functional polymorphisms (rs4244285 and rs12248560) in Caucasians. These polymorphisms were genotyped or imputed from genome-wide data in four samples treated with citalopram or escitalopram (GENDEP, STAR*D, GenPod, PGRN-AMPS). Treatment efficacy was assessed by standardized percentage symptom improvement and by remission. Side effect data were available at weeks 2–4, 6 and 9 in three samples. A fixed-effects meta-analysis was performed using EM as the reference group. Analysis of 2558 patients for efficacy and 2037 patients for side effects showed that PMs had higher symptom improvement (SMD = 0.43, CI = 0.19–0.66) and higher remission rates (OR = 1.55, CI = 1.23–1.96) compared to EMs. At weeks 2–4, PMs showed higher risk of gastro-intestinal (OR = 1.26, CI = 1.08–1.47), neurological (OR = 1.28, CI = 1.07–1.53) and sexual side effects (OR = 1.52, CI = 1.23–1.87; week 6 values were similar). No difference was seen at week 9 or in total side effect burden. PMs did not have higher risk of dropout at week 4 compared to EMs. Antidepressant dose was not different among CYP2C19 groups. CYP2C19 polymorphisms may provide helpful information for guiding citalopram/escitalopram treatment, despite PMs being relatively rare among Caucasians (∼2%). [ABSTRACT FROM AUTHOR]

Overall Abstract Single gene and GWAS analyses of pharmacological treatment response in depression and bipolar disorder have had varying success in identifying functionally relevant genes associated with pharmacological treatment response such as response to SSRI in depression and lithium in bipolar disorder. Hence, the need to better understand the complex genetic underpinnings of pharmacoresponse may include methodologies such as RNA-seq and microarray analyses. Such approaches contribute to a more in in-depth functional characterization of risk loci related to treatment response and to characterize the genetic underpinnings of both adverse events (e.g. induction of mania by antidepressants) and of medical comorbidity contributing to poor treatment response. In addition, gene expression profile and eQTLs can assist an improved understanding of the functional genomics of mood disorders. Specifically, recent large-scale GWAS meta-analyses (ConLiGen) have implicated multiple novel loci, two of which met the threshold for genome-wide significance: GADL1 (Chen et al., 2014) and an intergenic locus on chromosome 21 (Hou et al., 2016). The functional implications of the related genes remain to be described. In a first presentation, results will be presented from whole blood RNA-seq-data in a subsample of ConLiGen to validate and characterize these associations with clinical lithium treatment response and how these loci impact gene function and lithium response (David Stacey). Addressing the need to investigate the genetic underpinning of a broader range of treatment outcomes and adverse events, the genetic contribution of a potential induction of mania by antidepressants will be discussed in a second presentation, that shows results from a GWAS of antidepressant-induced mania (Joanna Biernacka). Among other factors, the co-morbidity of depression with other psychiatric and cardiometabolic disorders may negatively influence antidepressants treatment outcome. Moreover, response to antidepressants is a complex trait with substantial contribution from a large number of common genetic variants of small effect. Hence, use of polygenic scores (PGS) could be a better alternative to estimate the overall effect of genetic factors on treatment response and assess the importance of co-morbidities and related phenotypes. To investigate this further, we evaluated whether PGS derived from 25 recognized comorbid cardiometabolic and psychiatric disorders, personality traits and educational attainment predict treatment outcome to SSRIs in major depressive disorder using the ISPC data (Bernhard Baune). Previous studies aiming to identify the transcriptome signature of depression are inconsistent with low replicability at the single gene level in both brain and peripheral tissues. In a fourth presentation, results from analyses of whole blood transcriptomes of 521 elderly people from the general population (The Sydney Memory and Age Study, MAS, Sydney) are shown to describe molecular networks involved in geriatric depression. Functional characterisation of two out of 29 modules of the co-expression network indicated that abnormalities in structural constituents of ribosome may be involved in the pathophysiology of geriatric depression. In addition, results of pathway analyses using Ingenuity Pathway Analysis software will be shown (Liliana Ciobanu). [ABSTRACT FROM AUTHOR]

Schizophrenia has a considerable genetic background. Epidemiological studies suggest an inverse clinical association between schizophrenia and migraine. However, it is unclear to what extent this inverse comorbidity can be explained by genetic mechanisms or by schizophrenia-related behavioral factors. For both disorders hypotheses of glutamate N-methyl- D -aspartate (NMDA) receptor dysfunction have been developed in the past. We hypothesized that both conditions share common genetic factors with inverse effects, primary in the glutamatergic system and genes involved in NMDA activation. Data from the population based Study of Health in Pomerania ( N =3973) were used. Based on the results from the recent genome-wide association study for schizophrenia, we calculated polygenic scores (PRS) for subsets of SNPs with different p -value cutoffs and for biological sub-entities. These scores were tested for an association of distinct biological pathways with migraine. The PRS for schizophrenia was inversely associated with migraine in our sample. This association was exclusively based on the genome-wide hits and on single nucleotide polymorphisms near or within genes encoding proteins involved in glutamatergic neurotransmission. This association could be attributed to a single intronic variant rs4523957 in SRR encoding serine-racemase. Additional expression quantitative trait loci analyses of functional variants in SRR and gene-by-gene interaction analyses further supported the validity of this finding. SRR represents the rate limiting enzyme for the synthesis of D -serine, an important co-agonist of the NMDA receptor. According to our results, a decreased versus increased activation of NMDA receptors may play a role in the etiology of schizophrenia, as well as in migraine. [ABSTRACT FROM AUTHOR]

The mechanisms by which antidepressants have their effects are not clear and the reasons for variability in treatment outcomes are also unknown. However, there is evidence from candidate gene research that indicates gene expression changes may be involved in antidepressant action. In this study, we examined antidepressant-induced alterations in gene expression on a transcriptome-wide scale, exploring associations with treatment response. Blood samples were taken from a subset of depressed patients from the GENDEP study ( n =136) before and after eight weeks of treatment with either escitalopram or nortriptyline. Transcriptomic data were obtained from these samples using Illumina HumanHT-12 v4 Expression BeadChip microarrays. When analysing individual genes, we observed that changes in the expression of two genes ( MMP28 and KXD1 ) were associated with better response to nortriptyline. Considering connectivity between genes, we identified modules of genes that were highly coexpressed. In the whole sample, changes in one of the ten identified coexpression modules showed significant correlation with treatment response (cor=0.27, p =0.0029). Using transcriptomic approaches, we have identified gene expression correlates of the therapeutic effects of antidepressants, highlighting possible molecular pathways involved in efficacious antidepressant treatment. [ABSTRACT FROM AUTHOR]

Sex is a powerful modulator of disease susceptibility, course and outcome. The gene CACNA1C is among the best replicated vulnerability genes of bipolar disorder and schizophrenia. The aim of the present study was to investigate whether sex and a variant in CACNA1C (rs10774035 as a proxy for the well-acknowledged risk variant rs1006737) influence psychosocial adaptation in a large German patient sample with schizophrenia-spectrum ( n =297) and bipolar ( n =516) disorders. We analyzed Global Assessment of Functioning (GAF) scores, retrospectively collected for different time points during disease course. We investigated whether CACNA1C sex-dependently modulates longitudinal GAF scores and recovery from episodes of psychiatric disturbance in the above mentioned disorders. Psychosocial recovery was measured as difference score between the current GAF score (assessing the last remission) and the worst GAF score ever during an illness episode. Covariate- adjusted association analyses revealed a sex × rs10774035 genotype interaction on longitudinal GAF and recovery from illness episodes only in schizophrenia-spectrum but not in bipolar disorders. In schizophrenia-spectrum affected males, rs10774035 minor allele (T) carriers had higher GAF scores at three time points (premorbid, worst ever, current). In contrast, females carrying rs10774035 minor alleles had impaired recovery from schizophrenia-spectrum episodes. These results encourage further investigations of gene × sex interactions and longitudinal quantitative phenotypes to unravel the rich variety of behavioral consequences of genetic individuality. [ABSTRACT FROM AUTHOR]

The endogenous opioid system is involved in the pathophysiology of alcohol-use disorders. Genetic variants of the opioid system alter neural and behavioral responses to alcohol. In particular, a single nucleotide polymorphism rs1799971 (A118G) in the mu-opioid receptor gene ( OPRM1 ) is suggested to modulate alcohol-related phenotypes and neural response in the mesocorticolimbic dopaminergic system. Little is known about the clinical implications of these changes. The current study investigated the relationship of genotype effects on subjective and neural responses to alcohol cues and relapse in a sample of abstinent alcohol-dependent patients. Functional magnetic resonance imaging (fMRI) was used to investigate alcohol cue-reactivity and drinking outcome of 81 abstinent alcohol-dependent patients. G-allele carriers displayed increased fMRI cue-reactivity in the left dorsal striatum and bilateral insulae. Neural responses to alcohol cues in these brain regions correlated positively with subjective craving for alcohol and positive expectations of alcohol׳s effects. Moreover, alcohol cue-reactivity in the left dorsal striatum predicted time to first severe relapse. Current results show that alcohol-dependent G-allele carriers׳ increased cue-reactivity is associated with an increased relapse risk. This suggests that genotype effects on cue-reactivity might link the OPRM1 A118G risk allele with an increased relapse risk that was reported in earlier studies. From a clinical perspective, risk-allele carriers might benefit from treatments, such as neuro-feedback or extinction-based therapy that are suggested to reduce mesolimbic reactivity. [ABSTRACT FROM AUTHOR]

Abstract: Recent research suggests an important role of FKBP5, a glucocorticoid receptor regulating co-chaperone, in the development of stress-related diseases such as depression and anxiety disorders. The present study aimed to replicate and extend previous evidence indicating that FKBP5 polymorphisms moderate hypothalamus–pituitary–adrenal (HPA) function by examining whether FKBP5 rs1360780 genotype and different measures of childhood adversity interact to predict stress-induced cortisol secretion. At age 19 years, 195 young adults (90 males, 105 females) participating in an epidemiological cohort study completed the Trier Social Stress Test (TSST) to assess cortisol stress responsiveness and were genotyped for the FKBP5 rs1360780. Childhood adversity was assessed using the Childhood Trauma Questionnaire (CTQ) and by a standardized parent interview yielding an index of family adversity. A significant interaction between genotype and childhood adversity on cortisol response to stress was demonstrated for exposure to childhood maltreatment as assessed by retrospective self-report (CTQ), but not for prospectively ascertained objective family adversity. Severity of childhood maltreatment was significantly associated with attenuated cortisol levels among carriers of the rs1360780 CC genotype, while no such effect emerged in carriers of the T allele. These findings point towards the functional involvement of FKBP5 in long-term alterations of neuroendocrine stress regulation related to childhood maltreatment, which have been suggested to represent a premorbid risk or resilience factor in the context of stress-related disorders. [Copyright &y& Elsevier]

Abstract: Factors contributing to treatment-emergent suicidal ideation (TESI) using antidepressants have been in the focus of recent research strategies. We investigated previously established clinical predictors of TESI and combined these with several polymorphisms of candidate genes in patients with major depressive disorder. Common polymorphisms involved in the tryptophan hydroxylase 1 (TPH1) and 2 (TPH2), serotonin transporter, monoamine oxidase A (MAOA) and brain-derived neurotrophic factor (BDNF) were investigated in a naturalistic inpatient study of the German research network on depression. We compared patients showing TESI with non-TESI suicidal patients and with non-suicidal patients using univariate tests to detect relevant factors, which were further tested in logistic regression and CART (Classification and Regression Trees) analyses. Of the 269 patients, TESI occurred in 22 patients (17 female), 117 patients were defined as non-TESI suicidal patients, and 130 patients were classified as non-suicidal. When comparing cases with both control groups we found the TPH2 rs1386494 (C/T) polymorphism to be moderately associated with TESI (Univariate tests: TESI vs. non-suicidality: p=0.005; adjusted: p=0.09; TESI vs. non-TESI suicidal patients: p=0.0024; adjusted: p=0.086). This polymorphism remained the only significant genetic factor in addition to clinical predictors in logistic regression and CART analyses. CART analyses suggested interactions with several clinical predictors. Haplotype analyses further supported a contribution of this polymorphism in TESI. The TPH2 rs1386494 (C/T) polymorphism might contribute to the genetic background of TESI. This polymorphism has been previously associated with committed suicide and major depressive disorder. The small number of cases warrants replication in larger patient samples. Lack of a placebo control group hampers definite conclusions on an association with antidepressive treatment. [Copyright &y& Elsevier]

Abstract: Accumulating research suggests a moderating role for the corticotropin-releasing hormone receptor 1 gene (CRHR1) in the association between childhood adversity and adult depression. The present study aims to replicate recent findings using different genetic variants and measures of early adversity assessed both prospectively and retrospectively. Data were collected in the context of an ongoing epidemiological cohort study following the outcome of early risk factors from birth into adulthood. 300 participants (137 males, 163 females) were genotyped for four CRHR1 SNPs (rs7209436, rs110402, rs242924, and rs17689882) and completed the Beck Depression Inventory at ages 19, 22 and 23 years. Childhood adversity was assessed using the Childhood Trauma Questionnaire and by a standardized parent interview yielding an index of family adversity. Our results indicate that CRHR1 and childhood adversity interacted to predict depressive symptoms in young adults. Specifically, we found that the impact of childhood maltreatment on adult depressive symptoms was significantly higher in individuals (i) with two copies of the CRHR1 TAT haplotype, and (ii) homozygous for the G allele of rs17689882. The interaction was demonstrated for exposure to childhood maltreatment as assessed by retrospective self-report, but not to prospectively ascertain objective family adversity. The present study partially replicates recent findings of a CRHR1 by childhood adversity interaction with regard to adult depression highlighting the subjective characteristics of the environmental pathogen that is operative in this interaction. [Copyright &y& Elsevier]

Abstract: Sustained attention as measured by the Continuous Performance Test (CPT) has proved a valuable endophenotype for schizophrenia. Recently pharmacological studies suggested a role of the serotonin (5-HT) 3 receptor in schizophrenia. The 5-HT3 receptors are the only ligand-gated ion channels within the 5-HT receptor family. Applying an endophenotype approach, we investigated a potential impact of the genes of the 5-HT3A and 5-HT3B subunits as well as the novel 5-HT3C, 5-HT3D, and 5-HT3E subunits on CPT performance in subjects with schizophrenia. The study included 196 patients with schizophrenia, 113 of their parents, and 205 healthy controls recruited from community registers. Sustained attention was assessed with the Continuous Performance Test-Identical Pairs (CPT-IP). Assessing functional and coding variants of the 5-HT3 receptor subunit genes, we found the GG genotype of the 5-HT3E subunit gene (rs7627615; Thr86Ala) to be associated with better attentional capacities in subjects with schizophrenia and healthy controls. This study provides additional evidence for a role of the serotonergic system and the 5-HT3 receptor in schizophrenia. [Copyright &y& Elsevier]

Abstract: In recent years, evidence has been accumulating indicating a major role of glutamate in the pathogenesis and pathophysiology of schizophrenia. Of particular importance in this regard are the metabotropic glutamate receptors (GRM). Thus, a recently published trial of the amino acid analogue LY2140023, which exerts its effects through the activation of the glutamate receptors GRM3/GRM2, showed an improvement of positive and negative symptoms comparable to treatment with olanzapine. A functional variant of GRM3 has been described which modulates synaptic glutamate levels. We assessed whether this functional variant rs6465084 is related to schizophrenia in a large sample of patients and controls. We found an increased frequency of the A allele (p =0.027) and the AA genotype (p =0.024) in schizophrenia patients. Moreover, in an assessment of schizophrenia endophenotypes, patients of the AA genotype performed poorly in the digit symbol test, a measure of attention (p =0.008). Our results provide further evidence for the potential importance of the glutamate receptor GRM3 in schizophrenia, and indicate that the novel antipsychotic LY2140023 may actually be targeting a pathogenic pathway of schizophrenia. [Copyright &y& Elsevier]

For example, the largest genome-wide association study for schizophrenia to date did not include samples from Africa and overall only included a smaller number of non-European samples. For this purpose, we merged our data with the 1000 genomes data for the African populations (661 samples in total). [Extracted from the article]

B Background: b Major depressive disorder (MDD) is projected to be the global leading cause of disability-adjusted life years by 2030. The aim of this analysis was to identify markers associated with adverse drug reactions (ADRs) to both medications used in the genome-based therapeutic drugs for depression (GENDEP) study. Given that we were interested in markers associated with side effects to either medication, we used all available ASEC data for week one for both medications, and included both the randomly allocated participants and the non-randomly allocated. [Extracted from the article]

B Background: b Electroconvulsive therapy (ECT) is the treatment of choice for severe and treatment-resistant depression. B Methods: b In this study, we analysed epigenome-wide DNA methylation of 34 severely depressed patients before and after ECT treatment using the Illumina Infinium Methylation BeadChip which contains >850.000 CpG sites. B Discussion: b This is the first feasibility study analyzing methylation profiles in patients with severe and treatment resistant depression before and after ECT. [Extracted from the article]

Highlights from the article: Su37increased genetic risk load for major depression in patients assigned to electroconvulsive therapy B Background: b Electroconvulsive therapy (ECT) is the treatment of choice for severe and treatment-resistant depression, but its underlying mechanisms remain poorly understood; unfavorable treatment response is thought to be influenced by genetic factors. In association analyses, MD-PRS explained a significant proportion of disease status between ECT patients and healthy controls (p = 0.022, R2=1.173%); patients showed significantly higher MD-PRS.

Highlights from the article: B Background: b Bipolar Disorder (BD) is a genetically complex neuropsychiatric disorder with an estimated heritability of approximately 70%. We conducted a gene set/pathway analysis for the resulting genes using Ingenuity Pathway Analysis and ConsensusPathDB. Gene set enrichment analyses (IPA and ConsensusPathDB) mainly highlight immunological genes suggesting a possible role of immunological processes in BD which has also been reported for schizophrenia.

Highlights from the article: To prioritize the implicated genes for the follow-up analyses, large publicly available and inhouse WES datasets (> 3.000 SCZ patients) were analysed for additional pathogenic mutations in the newly identified candidate genes. In a subsequent multi-tier approach, we combined the WES data with gene expression data derived from brain tissues (both from publicly available datasets and our own inhouse SCZ brain samples), and complex protein-protein-interaction analyses. Additionally, the PPI analysis showed that both brain expressed genes, SMARCC1 and MECP2, were tightly connected with previously reported SCZ candidate genes.

Highlights from the article: We calculated polygenic risk scores (PRS) of schizophrenia for our participants, using the summary statistics of the GWAS on schizophrenia published in 2014 by the Psychiatric Genomics Consortium. B Results: b Our polygenic risk score analysis showed that PRS for schizophrenia predicted population density in our discovery and replication cohorts, so a higher genetic risk for the disease was associated with a denser area of residence. Our results show that the distribution of the genetic risk for the disorder is not uniform and concentrates in more populated, providing empirical evidence that the increased schizophrenia prevalence in urbanized areas is not only due to the environmental stressors of the city but also on the genetic risk for the disease.

Highlights from the article: 38whole exome sequencing of multiplex bipolar disorder families and follow-up resequencing implicate rare variants in cell adhesion genes contributing to disease etiology Interestingly, CDH23 encodes a calcium-dependent cell adhesion protein that may play a role in neurogenesis and that was previously implicated in risk for BD and other major psychiatric disorders. B Discussion: b Our preliminary results strongly suggest that rare and highly-penetrant variants in neuronal and cell adhesion genes contribute to BD etiology.

Sleep Deprivation (SD) treatment is known for its striking and immediate, but transient effects improving symptoms in 50–70% of patients suffering from depression. SD thus offers the opportunity to study clinical and biological factors preceding and accompanying mood changes and to identify underlying mechanisms of depression. The aim of this naturalistic study was to examine i.) clinical and genetic factors predicting response to SD, ii.) clinical and behavioural changes during the course of SD and iii.) the impact of SD on further course of the disorder. Patients undergoing an episode of major depression (n=78, 34 F/44 M, 71 major depression, 7 bipolar) underwent one night of SD. Depressive symptoms were assessed via standardized expert and self-ratings the day before and up to one month after SD. From the morning prior to SD until the evening after, mood and tiredness were assessed every 2 hours via visual analogue scales, and locomotor activity was concurrently measured via actigraphy. Genome-wide genotyping was carried out using the GSA chip and polygenic risk scores (PRS) were calculated based on genome-wide association data from the PGC MDD consortium. Response to SD was evaluated the day after SD based on global clinical impression (CGI). Logistic regression and mixed models were applied to analyse factors predicting SD and explore the trajectory of changes during and after SD. 70% of patients showed immediate antidepressant response. Before SD, responders and non-responders did not differ in self and expert-ratings of depression. A binary logistic regression model found that lower age and later age at disease onset were significantly associated with higher likelihood of response; lower polygenic score for depression, male sex, positive family history of psychiatric disorder and diagnosis of bipolar disorder were associated with increased likelihood response at the trend level. No effects were found for season, diurnal variation, depressive symptom scores and thyroid stimulating hormone levels. Through the course of SD, responders and non-responders differed in mood, with diverging mood trajectories becoming clear the morning and afternoon after SD. Meanwhile, tiredness did not differ between groups. Increased locomotor activity was observed in non-responders in the evening before SD until midnight. Following SD, depressive symptom scores decreased in both groups, but more in responders, in whom the effect was sustained over the entire time of observation. The current research shows that, in accordance with previous findings, response to SD is associated with specific clinical features and locomotor activity. Furthermore, PRS were examined in this context for the first time, suggesting that a genetic component may contribute to response to SD. In-depth investigation of the underlying causes of these results is a promising approach for future research in depression. [ABSTRACT FROM AUTHOR]

Bipolar Disorder (BD) is a complex neuropsychiatric disorder characterized by recurrent episodes of mania and depression. It is a severe disorder of mood with a lifetime prevalence of about 1% and a high heritability of about 70%. Models of illness are most consistent with a polygenic contribution of common and rare variants to disease susceptibility. As the cumulative impact of common alleles with small effect may only explain around 25–38% of the phenotypic variance for BD, rare variants of high penetrance have been suggested to contribute to BD susceptibility. One way to evaluate this hypothesis is to investigate large pedigrees densely affected with BD, in which the existence of a genetic variant of strong effect inherited from a common ancestor may be more likely. In the present study, we investigated 226 individuals of 68 large multiply affected families of European origin using Whole Exome Sequencing (WES). In each family, two to five affected individuals with BD or recurrent major depression were selected for sequencing. WES was performed on the Illumina HiSeq. 2500 platform and the Varbank pipeline of the Cologne Center for Genomics was used for data analysis. All identified variants shared within each family were filtered for a minor allele frequency <0.1% using data of the Exome Aggregation Consortium (http://exac.broadinstitute.org, non-psychiatric subsets) and potentially damaging effects predicted by at least four of five different bioinformatics tools (Purcell et al., 2014). We identified a total of 1214 rare, segregating and functional variants implicating 1122 different genes, of which 903 were brain expressed. Subsequently, we applied the Residual Variation Intolerance Scores (Petrovski et al., 2013) and identified 294 genes that were ranked among the 20% most "intolerant" genes in the genome. Gene enrichment analysis of these genes showed a significant enrichment for 18 pathways (p<0.001) including neuron projection, axon development and cell adhesion. We prioritized genes that were (i) found in at least two unrelated families in the present study, (ii) previously reported in next generation sequencing or GWAS studies of BD, or (iii) predominantly driving the significant pathways in our gene enrichment analysis. The different approaches of prioritization yielded 42 promising candidate genes including CDH22 which encodes a calcium-dependent cell adhesion protein that plays an important role in the morphogenesis of neural cells during brain development. Our preliminary results strongly suggest that rare and highly-penetrant variants in neuronal and cell adhesion genes contribute to BD etiology. The 42 prioritized candidate genes are currently being followed up by resequencing in cohorts of about 2500 independent BD cases and 2500 controls of European ancestry. For resequencing, we use the single molecule molecular inversion probes (smMIPs) technology that enables multiplex targeted resequencing in large cohorts. The smMIPs sequences have been designed with the empirically trained design algorithm MIPgen (Boyle et al., 2014) and sequencing is currently performed on the Illumina HiSeq. 2500 platform. The resequencing results will provide further insights into the particular genes and pathways which are involved in BD development. [ABSTRACT FROM AUTHOR]