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This is to determine whether health beliefs regarding colorectal cancer (CRC) screening could predict discomfort with a change to CRC surveillance proposing regular faecal immunochemical tests (FIT) instead of colonoscopy.Eight hundred individuals enrolled in a South Australian colonoscopy surveillance programme were invited to complete a survey on surveillance preferences. Responses were analysed using binary logistic regression predicting discomfort with a hypothetical FIT-based surveillance change. Predictor variables included constructs based on the Health Belief Model: perceived threat of CRC, perceived confidence to complete FIT and colonoscopy (self-efficacy), perceived benefits from current surveillance and perceived barriers to FIT and colonoscopy.A total of 408 participants (51%) returned the survey (complete data n = 303; mean age 62 years, 52% male). Most participants (72%) were uncomfortable with FIT-based surveillance reducing colonoscopy frequency. This attitude was predicted by a higher perceived threat of CRC (OR = 1.03 [95% CI 1.01-1.04]), higher colonoscopy self-efficacy (OR = 1.34 [95% CI 1.13-1.59]) and lower perceived barriers to colonoscopy (OR = 0.92 [95% CI 0.86-0.99]).Health beliefs regarding colonoscopy and perceived threat of CRC may be important to consider when changing CRC surveillance protocols. If guideline changes were introduced, these factors should be addressed to provide patients reassurance concerning the efficacy of the alternative protocol.

Childhood socioeconomic position (SEP) is associated with the development of adult psychological outcomes, with DNA methylation (DNAm) as a mechanism to potentially explain these changes. We present the first systematic review synthesising the literature investigating childhood SEP and DNAm. Thirty-two publications were included. Seventeen studies focused on candidate genes, typically focusing on genes implicated with the stress response and/or development of psychiatric conditions. These studies typically investigated different regions of the genes, which revealed inconsistent results. Six studies calculated epigenetic age, with a small number revealing an elevated significant association with childhood SEP. Epigenome-wide studies revealed altered patterns of DNAm which varied between the nine studies. This research area is emerging and demonstrated great variance in findings with no clear patterns identified across studies. Multiple methodological shortcomings are identified, including at the phenotypic level where construct validity of childhood SEP is highly inconsistent, with studies using a wide range of measures. Larger cohorts will be required with international collaborations to strengthen this research area.

Background At present, no predictive markers for Major Depressive Disorder (MDD) exist. The search for such markers has been challenging due to clinical and molecular heterogeneity of MDD, the lack of statistical power in studies and suboptimal statistical tools applied to multidimensional data. Machine learning is a powerful approach to mitigate some of these limitations. Methods We aimed to identify the predictive markers of recurrent MDD in the elderly using peripheral whole blood from the Sydney Memory and Aging Study (SMAS) (N = 521, aged over 65) and adopting machine learning methodology on transcriptome data. Fuzzy Forests is a Random Forests-based classification algorithm that takes advantage of the co-expression network structure between genes; it allows to alleviate the problem of p >> n via reducing the dimensionality of transcriptomic feature space. Results By adopting Fuzzy Forests on transcriptome data, we found that the downregulated TFRC (transferrin receptor) can predict recurrent MDD with an accuracy of 63%. Limitations Although we corrected our data for several important confounders, we were not able to account for the comorbidities and medication taken, which may be numerous in the elderly and might have affected the levels of gene transcription. Conclusions We found that downregulated TFRC is predictive of recurrent MDD, which is consistent with the previous literature, indicating the role of the innate immune system in depression. This study is the first to successfully apply Fuzzy Forests methodology on psychiatric condition, opening, therefore, a methodological avenue that can lead to clinically useful predictive markers of complex traits.

While peanut oral immunotherapy (POIT) represents a promising treatment for peanut allergies in children, safety concerns remain a common barrier to widespread adoption. We aimed to systematically assess available evidence to determine the risk and frequency of adverse events occurring during POIT, and examine study-level characteristics associated with their occurrence and severity. A systematic search of MEDLINE, EMBASE, and Web of Science was conducted through April 2019. Controlled and non-controlled studies evaluating POIT were eligible. Twenty-seven studies, involving 1488 subjects, were included. Adverse events to POIT were common and led to treatment discontinuation in 6.6% of children (95% CI 4.4–9.0; 27 studies, I2 = 48.7%). Adverse events requiring treatment with epinephrine occurred among 7.6% (4.5–11.4; 26 studies, I2 = 75.5%) of participants, at a rate of 2.0 per 10,000 doses (0.8–3.7; 15 studies, I2 = 64.4). Use of a rush treatment phase and targeting a higher maintenance dose were associated with a higher risk and frequency of epinephrine use, while using co-treatments in addition to POIT was associated with a lower risk of treatment discontinuation due to adverse events. While adverse events to POIT are common, this study provides promising explorative evidence that certain modifications to existing treatment protocols could significantly improve treatment outcomes.

Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3–2.8, one-sided p = 6.0 × 10−4), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ., International Bipolar Sequencing Consortium (NIMH) R01 MH 110437, Whole Genome Sequencing for Schizophrenia and Biopolar Disorder in the GPS (NIMH) UO1 MH105653, Whole Genome and Exome Sequencing for Bipolar Disorder (NIMH) R01 MH 094145, Multi-ethnic GWAS of Bipolar I Disorder (NIH) R01 MH 085543, Genetic Epidemiology Research in Adult Health and Aging (GERA) RC2 AG036607, Kaiser Permanente Research Program on Genes, Environment, and Health, Rare Bipolar Loci Identification Through Synaptome Sequencing (NIMH) R01 MH 087979 MH 087992, 2/2 Large Scale Genetic Studies of Schizophrenia in Sweden R01MH095034, 1/3 Genetic Analysis of the International Cohort Collection for Bipolar Disorder R01MH106531, 1/2 Large Scale Genetic Studies of Schizophrenia in Sweden R01MH077139, 2/3 Genetic Analysis of the International Cohort Collection for Bipolar Disorder R01MH106527, Dalio Foundation

BackgroundElevated levels of pro-inflammatory cytokines are consistently reported in schizophrenia (SZ) and bipolar-I disorder (BD), as well as among individuals who have been exposed to childhood trauma. However, higher levels of inflammatory markers in these disorders are yet to be investigated with respect to levels of exposure to different types of childhood trauma.MethodsParticipants were 68 cases with a diagnosis of schizophrenia/schizoaffective disorder (SZ), 69 cases with a diagnosis of psychotic BD and 72 healthy controls (HC). Serum levels of interleukin 6 (IL-6), tumour necrosis factor-α (TNF-α) and C-reactive protein (CRP) were quantified, and childhood trauma exposure was assessed with the Childhood Trauma Questionnaire.ResultsThe SZ group had significantly higher levels of IL-6, TNF-α and CRP when compared with the HC group (all p < 0.05, d = 0.41–0.63), as well as higher levels of TNF-α when compared with the BD group (p = 0.014, d = 0.50); there were no differences between the BD and HC groups for any markers. Exposure to sexual abuse was positively associated (standardised β = 0.326, t = 2.459, p = 0.018) with levels of CRP in the SZ group, but there were no significant associations between any form of trauma exposure and cytokine levels in the HC or BD groups.ConclusionsThese results contribute to the evidence for a chronic state of inflammation in SZ but not BD cases. Differential associations between trauma exposure and levels of pro-inflammatory cytokines across the diagnostic categories suggest that trauma may impact biological (stress and immune) systems differently in these patient groups.

The molecular factors involved in the pathophysiology of major depressive disorder (MDD) remain poorly understood. One approach to examine the molecular basis of MDD is co-expression network analysis, which facilitates the examination of complex interactions between expression levels of individual genes and how they influence biological pathways affected in MDD. Here, we applied an unsupervised gene-network based approach to a prospective experimental design using microarray genome-wide gene expression from the peripheral whole blood of older adults. We utilised the Sydney Memory and Ageing Study (sMAS, N = 521) and the Older Australian Twins Study (OATS, N = 186) as discovery and replication cohorts, respectively. We constructed networks using Weighted Gene Co-expression Network Analysis (WGCNA), and correlated identified modules with four subtypes of depression: single episode, current, recurrent, and lifetime MDD. Four modules of highly co-expressed genes were associated with recurrent MDD (N = 27) in our discovery cohort (FDR0.2), with no significant findings for a single episode, current or lifetime MDD. Functional characterisation of these modules revealed a complex interplay between dysregulated protein processing in the endoplasmic reticulum (ER), and innate and adaptive immune response signalling, with possible involvement of pathogen-related pathways. We were underpowered to replicate findings at the network level in an independent cohort (OATS), however; we found a significant overlap for 9 individual genes with similar co-expression and dysregulation patterns associated with recurrent MDD in both cohorts. Overall, our findings support other reports on dysregulated immune response and protein processing in the ER in MDD and provide novel insights into the pathophysiology of depression.

Major depressive disorder (MDD) is a prevalent disorder with moderate heritability. Both MDD and interpersonal adversity, including childhood maltreatment, have been consistently associated with elevated inflammatory markers. We investigated interaction between exposure to childhood maltreatment and extensive genetic variation within the inflammation pathway (CRP, IL1b, IL-6, IL11, TNF, TNFR1, and TNFR2) in relation to depression diagnosis. The discovery RADIANT sample included 262 cases with recurrent DSM-IV/ICD-10 MDD, and 288 unaffected controls. The replication Münster cohort included 277 cases with DSM-IV MDD, and 316 unaffected controls. We identified twenty-five single nucleotide polymorphisms (SNPs) following multiple testing correction that interacted with childhood maltreatment to predict depression in the discovery cohort. Seven SNPs representing independent signals (rs1818879, rs1041981, rs4149576, rs616645, rs17882988, rs1061622, and rs3093077) were taken forward for replication. Meta-analyses of the two samples presented evidence for interaction with rs1818879 (IL6) (RD=0.059, SE=0.016, p < 0.001), with the replication Münster sample approaching statistical significance in analyses restricted to recurrent MDD and controls following correction for multiple testing (q=0.066). The CRP locus (rs3093077) showed a similar level of evidence for interaction in the meta-analysis (RD=0.092, SE=0.029, p=0.002), but less compelling evidence in the replication sample alone (recurrent MDD q=0.198; all MDD q=0.126). Here we present evidence suggestive of interaction with childhood maltreatment for novel loci in IL-6 (rs1818879) and CRP (rs3093077), increasing risk of depression. Replication is needed by independent groups, targeting these specific variants and interaction with childhood maltreatment on depression risk.

Background Childhood maltreatment (abuse and neglect) can have long-term deleterious consequences, including increased risk for medical and psychiatric illnesses, such as bipolar disorder in adulthood. Emerging evidence suggests that a history of childhood maltreatment is linked to the comorbidity between medical illnesses and mood disorders. However, existing studies on bipolar disorder have not yet explored the specific influence of child neglect and have not included comparisons with individuals without mood disorders (controls). This study aimed to extend the existing literature by examining the differential influence of child abuse and child neglect on medical morbidity in a sample of bipolar cases and controls. Methods The study included 72 participants with bipolar disorder and 354 psychiatrically healthy controls (average age of both groups was 48 years), who completed the Childhood Trauma Questionnaire, and were interviewed regarding various medical disorders. Results A history of any type of childhood maltreatment was significantly associated with a diagnosis of any medical illness (adjusted OR = 6.28, 95% confidence intervals 1.70–23.12, p = 0.006) and an increased number of medical illnesses (adjusted OR = 3.77, 95% confidence intervals 1.34–10.57, p = 0.012) among adults with bipolar disorder. Exposure to child abuse was more strongly associated with medical disorders than child neglect. No association between childhood maltreatment and medical morbidity was detected among controls. Conclusions To summarise, individuals with bipolar disorder who reported experiencing maltreatment during childhood, especially abuse, were at increased risk of suffering from medical illnesses and warrant greater clinical attention.

The gene D-amino acid oxidase activator (DAOA), which has a former name of G72, and the D-amino acid oxidase (DAO) gene have been suggested as candidate genes of schizophrenia. However, association studies have so far yielded equivocal results. We analyzed one single nucleotide polymorphism (SNP) for DAO (rs3741775) and seven SNPs for G72 (rs3916956, rs2391191, rs9558562, rs947267, rs778292, rs3918342, and rs1421292) in this study enrolling 248 schizophrenia cases and 267 controls in the Taiwanese samples. In SNP-based single locus association analyses, the rs778292 in the DAOA gene showed significant association with schizophrenia. The rs3741775 in the DAO gene could not withstand statistically significant after multiple corrections. Additionally, a three-SNP haplotype (rs778292-rs3918342-rs1421292) in the DAOA gene were observed to be significantly associated with schizophrenia. Among them, the TCT haplotype presented higher prevalence in controls than in cases whereas the TTT and CTT haplotype were significantly more frequent in cases than in controls. The study also provides significant evidence for epistatic interactions among DAOA and DAO gene in the development of schizophrenia. These results provide additional evidence and indicate that the DAOA gene and DAOA-DAO gene-gene interactions might play a role for schizophrenia in a Taiwanese sample.

Background: A small body of research suggests that gene-environment interactions play an important role in the development of bipolar disorder. The aim of the present study is to contribute to this work by exploring the relationship between stressful life events and the COMT Val158Met polymorphism in bipolar disorder. Methods: A total of 482 bipolar cases and 205 psychiatrically healthy controls completed the List of Threatening Experiences Questionnaire. Bipolar cases reported the events experienced 6 months before their worst depressive and manic episodes; controls reported those events experienced 6 months prior to their interview. The genotypic information for the COMT Val158Met variant (rs4680) was extracted from GWAS analysis of the sample. Results: The impact of stressful life events was moderated by the COMT genotype for the worst depressive episode using a Val dominant model (adjusted Risk Difference = 0.09, 95% confidence intervals 0.003-0.18, p=0.04). For the worst manic episodes no significant interactions between COMT and stressful life events were detected. Conclusions: This is the first study to explore the relationship between stressful life events and the COMT Val158Met polymorphism focusing solely on bipolar disorder. The results of this study highlight the importance of the interplay between genetic and environmental factors for bipolar depression.

Abstract. This paper evaluates the results of a longitudinal investigation of the potential benefits of yoga in a nonclinical sample of chronically stressed women (N = 116). Women undertook a twice weekly, hour-long yoga class for a period of 2 months, measuring psychological and physical indicators of health periodically. Changes in both areas were compared against a wait-list control group. The reported energy expenditure between groups was estimated to be similar, which suggests that the control group engaged in physical activities other than yoga. Of the six psychological outcomes measured, we found improvements in three. Specifically, those in the practicing yoga group experienced increases in positive affect, decreases in levels of distress and stress, as well as a decrease in waist circumference and increased flexibility. No between-group differences were found in mindfulness, well-being, and negative affect. These findings are generally consistent with an emerging literature, suggesting that yoga may provide both psychological and physiological effects that extend beyond its more obvious physical benefits, and are discussed in terms of the body’s allostatic load. These results should be considered in light of this study’s limitations, which include its small sample size, lack of an “active” control group, and female-only participants.

Schizophrenia and bipolar disorder share biological features and environmental risk factors that may be associated with altered DNA methylation. In this study we sought to: 1) construct a novel ‘Poly-Methylomic Profile Score (PMPS)’ by transforming schizophrenia-associated epigenome-wide methylation from a previously published epigenome-wide association study (EWAS) into a single quantitative metric; and 2) examine associations between the PMPS and clinical status in an independent sample of 57 schizophrenia (SZ) cases, 59 bipolar disorder (BD) cases and 55 healthy controls (HC) for whom blood-derived DNA methylation was quantified using the Illumina 450 K methylation beadchip. We constructed five PMPSs at different p-value thresholds by summing methylation beta-values weighted by individual-CpG effect sizes from the meta-analysis of a previously published schizophrenia EWAS (comprising three separate cohorts with 675 [353 SZ and 322 HC] discovery cohort participants, 847 [414 SZ and 433 HC] replication cohort participants, and 96 monozygotic twin-pairs discordant for SZ). All SZ PMPSs were elevated in SZ participants relative to HCs, with the score calculated at a p-value threshold of 1 × 10−5 accounting for the greatest amount of variance. All PMPSs were elevated in SZ relative to BD and none of the PMPSs were increased in BD, or in a combined cohort of BD and SZ cases, relative to HCs. PMPSs were also not associated with positive or negative symptom severity. That this SZ-derived PMPSs was elevated in SZ, but not BD, suggests that epigenome-wide methylation patterns may represent distinct pathophysiology that is yet to be elucidated.

Schizophrenia (SZ) and bipolar disorder (BD) share numerous clinical and biological features as well as environmental risk factors that may be associated with altered DNA methylation. In this study we sought to construct a Poly-Methylomic Profile Score (PMPS) for SZ, representing the degree of epigenome-wide methylation according to previously published findings; we then examined its association with SZ and BD in an independent sample. DNA methylation for 57 SZ, 59 BD cases and 55 healthy controls (HCs) was quantified using the Illumina 450K methylation beadchip. We constructed five PMPSs for different p-value thresholds using summary statistics reported in a large epigenome-wide schizophrenia case-control association study, weighted by individual CpG effect sizes. All SZ PMPSs were significantly elevated in SZ cases relative to HCs, with the score calculated at the most stringent threshold accounting for the greatest amount of variance in SZ (compared to other PMPSs derived at more inclusivep-value thresholds). However, none of the PMPSs were associated with BD, or a combined cohort of BD and SZ cases relative to HCs. Results demonstrating elevated PMPSs in SZ relative to BD did not survive correction for multiple testing. PMPSs were also not associated with positive or negative symptom severity. That this SZ-derived PMPSs was elevated among SZ, but not BD participants, suggests that epigenome-wide methylation patterns associated with schizophrenia may represent distinct pathophysiology that is yet to be elucidated. Whether this PMPS may be associated with neuroanatomical or other biological endophenotypes relevant to SZ and/or BD remains to be determined.

Neuroethics is central to the Australian Brain Initiative’s aim to sustain a thriving and responsible neurotechnology industry. Diverse and inclusive community and stakeholder engagement and a trans-disciplinary approach to neuroethics will be key to the success of the Australian Brain Initiative. Refereed/Peer-reviewed

Background Elevated levels of systemic inflammation are consistently reported in both schizophrenia (SZ) and bipolar-I disorder (BD), and are associated with childhood trauma exposure. We tested whether childhood trauma exposure moderates associations between systemic inflammation and brain morphology in people with these diagnoses. Methods Participants were 55 SZ cases, 52 BD cases and 59 healthy controls (HC) who underwent magnetic resonance imaging. Systemic inflammation was measured using a composite z-score derived from serum concentrations of interleukin 6, tumor necrosis factor alpha and C-reactive protein. Indices of grey matter volume covariation (GMC) were derived from independent component analysis. Childhood trauma was measured using the Childhood Trauma Questionnaire (CTQ Total score). Results A series of moderated moderation analyses indicated that increased systemic inflammation were associated with increased GMC in the striatum and cerebellum among all participants. Severity of childhood trauma exposure moderated the relationship between systemic inflammation and GMC in one component, differently among the groups. Specifically, decreased GMC in the PCC/precuneus, parietal lobule and postcentral gyrus, and increased GMC in the left middle temporal gyrus was associated with increased systemic inflammation in HC individuals exposed to high (but not low or average) levels of trauma and in SZ cases exposed to low (but not average or high) levels of trauma, but not in BD cases. Conclusions Increased systemic inflammation is associated with grey matter changes in people with psychosis, and these relationships may be partially and differentially moderated by childhood trauma exposure according to diagnosis.

© 2019 Elsevier Inc. Neuroethics is central to the Australian Brain Initiative's aim to sustain a thriving and responsible neurotechnology industry. Diverse and inclusive community and stakeholder engagement and a trans-disciplinary approach to neuroethics will be key to the success of the Australian Brain Initiative.

Anorexia nervosa (AN) is a complex and serious eating disorder, occurring in ~1% of individuals. Despite having the highest mortality rate of any psychiatric disorder, little is known about the aetiology of AN, and few effective treatments exist.Global efforts to collect large sample sizes of individuals with AN have been highly successful, and a recent study consequently identified the first genome-wide significant locus involved in AN. This result, coupled with other recent studies and epidemiological evidence, suggest that previous characterizations of AN as a purely psychiatric disorder are over-simplified. Rather, both neurological and metabolic pathways may also be involved.In order to elucidate more of the system-specific aetiology of AN, we applied transcriptomic imputation methods to 3,495 cases and 10,982 controls, collected by the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED). Transcriptomic Imputation (TI) methods approaches use machine-learning methods to impute tissue-specific gene expression from large genotype data using curated eQTL reference panels. These offer an exciting opportunity to compare gene associations across neurological and metabolic tissues. Here, we applied CommonMind Consortium (CMC) and GTEx-derived gene expression prediction models for 13 brain tissues and 12 tissues with potential metabolic involvement (adipose, adrenal gland, 2 colon, 3 esophagus, liver, pancreas, small intestine, spleen, stomach).We identified 35 significant gene-tissue associations within the large chromosome 12 region described in the recent PGC-ED GWAS. We applied forward stepwise conditional analyses and FINEMAP to associations within this locus to identify putatively causal signals. We identified four independently associated genes;RPS26, C12orf49, SUOX, andRDH16.We also identified two further genome-wide significant gene-tissue associations, both in brain tissues;REEP5, in the dorso-lateral pre-frontal cortex (DLPFC; p=8.52×10−07), andCUL3, in the caudate basal ganglia (p=1.8×10−06). These genes are significantly enriched for associations with anthropometric phenotypes in the UK BioBank, as well as multiple psychiatric, addiction, and appetite/satiety pathways. Our results support a model of AN risk influenced by both metabolic and psychiatric factors.

Objectives Childhood trauma is a common risk factor for adult psychiatric disorders, such as schizophrenia (SZ) and bipolar-I disorder (BD). However, its association with schizotypal personality traits, as well as cognitive and social cognitive abilities, is less well studied in these populations. Methods In a cohort of 79 SZ cases, 84 BD cases, and 75 healthy controls (HCs), clinically significant levels of childhood trauma exposure (according to scores on the Childhood Trauma Questionnaire; CTQ) were evident in 54 SZ, 55 BD, and 26 HC individuals. Trauma-exposed and non-exposed groups were compared on schizotypal personality features (schizotypy) measured with the Schizotypal Personality Questionnaire (SPQ). Cognitive assessments included executive function, working memory, attention, and immediate and delayed memory. Social cognitive measures assessed facial emotion processing and theory-of-mind abilities. Results Trauma-exposed participants showed higher levels of schizotypy, especially suspiciousness, relative to non-exposed individuals, regardless of clinical or HC status. Furthermore, trauma-exposed individuals showed deficits specifically in social cognitive, but not general cognitive abilities, regardless of clinical or HC status. These trauma-related results were found in the context of higher schizotypy levels in both SZ and BD relative to HC, and lower cognitive and social cognitive performance in SZ, relative to BD and HC groups. Conclusions These findings suggest that childhood trauma exposure impacts long-term schizotypy outcomes, especially paranoid ideation (suspiciousness), as well as complex social cognitive abilities in both healthy and psychotic populations. However, cognitive deficits associated with psychotic illness may not be distinguishable from those related to trauma exposure in previous studies. Practitioner points Findings Childhood trauma exposure is associated with increased schizotypal features (in particular paranoid ideation) and complex social cognitive abilities, independently of the diagnosis of psychotic disorder. Cognitive and social cognitive deficits were larger in schizophrenia compared to bipolar-I cases and healthy controls, but increased schizotypal features were observed in both schizophrenia and bipolar-I disorder relative to healthy controls. Limitations We were unable to distinguish the specific effects of particular childhood trauma exposures due to the high rate of exposure to more than one type of maltreatment. Retrospective assessment of childhood trauma in adulthood cannot be externally validated, and associations with behavioural traits in later life may be confounded by other factors not studied here.

The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 data sets containing 38 802 European ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analysed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis) with qualifying unpublished data, were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalisable, but must be of modest effect size and only observable in limited situations.Molecular Psychiatry advance online publication, 4 April 2017; doi:10.1038/mp.2017.44.

Learning is one of our most adaptive abilities, allowing us to adjust our expectations about future events. Aberrant learning processes may underlie disorders such as anxiety, motivating the search for the neural mechanisms that underpin learning. Animal studies have shown that the neurotransmitter GABA is required for the computation of prediction errors, the mismatches between anticipated and experienced outcomes, which drive new learning. Given that evidence from human studies is lacking, we sought to determine whether these findings extend to humans. Here, in two samples of Caucasian individuals, we investigated whether genetically determined individual differences in GABA neurotransmission predict the P3 event-related potential, an EEG component known to reflect prediction error processing. Consistent with the results of animal studies, we show that a weighted genetic risk score computed from the number of GABRB2 rs1816072 A alleles (associated with increased expression of the GABAA receptor β2 subunit gene) and the number of ErbB4 rs7598440 T alleles (associated with increased GABA concentration) predicts optimal prediction error processing during aversive classical conditioning with both visual (Experiment 1, N = 90; p = .010) and auditory (Experiment 2; N = 92; p = .031) unconditioned stimuli. Our finding that optimal processing of aversive prediction errors is reduced in individuals genetically predisposed towards decreased GABA neurotransmission suggests a potential mechanism linking GABA and anxiety. Specifically, reduced GABA signalling via GABAA receptors could result in aberrant learning from aversive experiences and vulnerability to anxiety disorders.

Meta-analyses of genome-wide association studies (meta-GWAS) and candidate gene studies have identified genetic variants associated with cardiovascular diseases, metabolic diseases, and mood disorders. Although previous efforts were successful for individual disease conditions (single disease), limited information exists on shared genetic risk between these disorders. This article presents a detailed review and analysis of cardio-metabolic diseases risk (CMD-R) genes that are also associated with mood disorders. Firstly, we reviewed meta-GWA studies published until January 2016, for the diseases “type 2 diabetes, coronary artery disease, hypertension” and/or for the risk factors “blood pressure, obesity, plasma lipid levels, insulin and glucose related traits”. We then searched the literature for published associations of these CMD-R genes with mood disorders. We considered studies that reported a significant association of at least one of the CMD-R genes and “depressive disorder” OR “depressive symptoms” OR “bipolar disorder” OR “lithium treatment”, OR “serotonin reuptake inhibitors treatment”. Our review revealed 24 potential pleiotropic genes that are likely to be shared between mood disorders and CMD-Rs. These genes include MTHFR, CACNA1D, CACNB2, GNAS, ADRB1, NCAN, REST, FTO, POMC, BDNF, CREB, ITIH4, LEP, GSK3B, SLC18A1, TLR4, PPP1R1B, APOE, CRY2, HTR1A, ADRA2A, TCF7L2, MTNR1B, and IGF1. A pathway analysis of these genes revealed significant pathways: corticotrophin-releasing hormone signaling, AMPK signaling, cAMP-mediated or G-protein coupled receptor signaling, axonal guidance signaling, serotonin and dopamine receptors signaling, dopamine-DARPP32 feedback in cAMP signaling, circadian rhythm signaling and leptin signaling. Our findings provide insights in to the shared biological mechanisms of mood disorders and cardio-metabolic diseases.

Background and Objectives: Chronic stress contributes to psychopathology and the practise of yoga is suggested to decrease stress and improve well-being. However, the literature often reports methodological problems (cross-sectional designs, sample sizes ≤ 20, and limited exploration of community populations). The aim of this study was to address these limitations and evaluate the potential psychological benefits of yoga to a non-clinical population. Methods: Women (N = 116) reporting chronic stress participated in this longitudinal study. Participants were allocated to a twice-weekly, hour-long yoga class for a period of two months, or a waitlist-control. Indicators of psychological well-being were measured at baseline, post-test and one-month follow-up. Results: Psychological distress decreased over time in both groups, however the control group experienced decreases in positive effect compared with the yoga group. Curvilinear trends were observed, indicating that trajectories of improvement seen at post-test were not robustly seen at follow-up. Conclusion: The study indicates that short-term yoga practise may yield some benefits to stressed individuals, but that evaluation over a longer term of practise may be required to determine the optimal dose for improvements and maintenance. Differential treatment effects may be difficult to detect in studies with populations that may already be motivated to improve their health.

OBJECTIVES: Co-morbidity between depression and anxiety disorders is common. In this study we define a quantitative measure of anxiety by summating four anxiety items from the SCAN interview in a large collection of major depression (MDD) cases to identify genes contributing to this complex phenotype.METHODS: A total of 1522 MDD cases dichotomised according to those with at least one anxiety item scored (n = 1080) and those without anxiety (n = 442) were analysed, and also compared to 1588 healthy controls at a genome-wide level, to identify genes that may contribute to anxiety in MDD.RESULTS: For the quantitative trait, suggestive evidence of association was detected for two SNPs, and for the dichotomous anxiety present/absent ratings for three SNPs at genome-wide level. In the genome-wide analysis of MDD cases with co-morbid anxiety and healthy controls, two SNPs attained P values of < 5 × 10⁻⁶. Analysing candidate genes, P values ≤ 0.0005 were found with three SNPs for the quantitative trait and three SNPs for the dichotomous trait.CONCLUSIONS: This study provides an initial genome-wide assessment of possible genetic contribution to anxiety in MDD. Although suggestive evidence of association was found for several SNPs, our findings suggest that there are no common variants strongly associated with anxious depression.

Background Polymorphisms in the serotonin transporter gene (5-HTTLPR) modulate amygdala activity in healthy individuals. Increased responses to negative stimuli in carriers of low transcription alleles have been proposed to contribute to the pathogenesis of depression. We sought to investigate the effects of genotype as well as diagnosis in patients with depression. Methods Subjects with recurrent depression ( n =67) and matched healthy controls ( n =49) participated in a fMRI task of implicit processing of sad facial stimuli. Effects of biallelic (short (S) and long (L) alleles) and triallelic (including rs25531 A/G single nucleotide variation) models of 5-HTTLPR polymorphisms on amygdala activity and connectivity were investigated. Results Significant effects were observed of both genotype and diagnosis on amygdala activity. Increased amygdala activity was associated with 5-HTTLPR genotype in low transcription allele carriers as well as with a diagnosis of depression. The connectivity analysis revealed a main effect of genotype with reduced connectivity to the subgenual region of the anterior cingulate in carriers of the low transcription alleles. There was also a main effect of diagnosis with reduced connectivity to the dorsal region of the anterior cingulate and to the dorsolateral prefrontal cortex in depression. There were no interaction effects between genotype and diagnosis in amygdala activity or connectivity. Conclusions Significant independent effects of genotype and diagnosis on amygdala responsivity were revealed. The effects of genotype and diagnosis on amygdala connectivity showed a regional segregation, suggesting that 5-HTTLPR polymorphisms bias frontal-limbic connectivity while the development of depression involves more extensive neural disturbances. These findings point to the potential of connectivity maps as a diagnostic biomarker for depression.

Background: While cytokines have been implicated in the pathophysiology of depression in adults, the potential role in younger age groups such as adolescents is less clear. This article therefore reviews the literature (a) to explore the relationship between cytokines and depression in adolescents, and (b) to examine how cytokines may be related to adolescent depression in the context of other neurobiological theories of depression. Method: A systematic review of the scientific literature on the subject was conducted in February 2013, searching the Web of Knowledge, PubMed (Medline), PsycInfo and Cochrane electronic databases. Results: Eighteen studies were identified measuring both depression or depressive symptoms and cytokines or immune markers in adolescents. Adolescents with depression show age-specific characteristics of the immune and inflammatory system, specifically in NK cell activity and in pro-inflammatory cytokines (such as IL-1 beta and TNF-alpha). In addition, the role of cytokines in adolescent depression is influenced by neurodevelopment, hormonal changes, stress and trauma. Conclusions: There may be differences in the neurobiology of adolescent major depressive disorder (MDD) compared with adult MDD. Increased understanding of the role of cytokines in adolescent MDD may lead to improved outcomes in the treatment of adolescent depression.

BackgroundAlthough usually thought of as external environmental stressors, a significant heritable component has been reported for measures of stressful life events (SLEs) in twin studies.MethodWe examined the variance in SLEs captured by common genetic variants from a genome-wide association study (GWAS) of 2578 individuals. Genome-wide complex trait analysis (GCTA) was used to estimate the phenotypic variance tagged by single nucleotide polymorphisms (SNPs). We also performed a GWAS on the number of SLEs, and looked at correlations between siblings.ResultsA significant proportion of variance in SLEs was captured by SNPs (30%, p = 0.04). When events were divided into those considered to be dependent or independent, an equal amount of variance was explained for both. This ‘heritability’ was in part confounded by personality measures of neuroticism and psychoticism. A GWAS for the total number of SLEs revealed one SNP that reached genome-wide significance (p = 4 × 10−8), although this association was not replicated in separate samples. Using available sibling data for 744 individuals, we also found a significant positive correlation of R2 = 0.08 in SLEs (p = 0.03).ConclusionsThese results provide independent validation from molecular data for the heritability of reporting environmental measures, and show that this heritability is in part due to both common variants and the confounding effect of personality.

A small body of research suggests that gene-environment interactions play an important role in the development of bipolar disorder. The aim of the present study is to contribute to this work by exploring the relationship between stressful life events and the catechol-O-methyl-transferase (COMT) ValFour hundred eighty-two bipolar cases and 205 psychiatrically healthy controls completed the List of Threatening Experiences Questionnaire. Bipolar cases reported the events experienced 6 months before their worst depressive and manic episodes; controls reported those events experienced 6 months prior to their interview. The genotypic information for the COMT ValThe impact of stressful life events was moderated by the COMT genotype for the worst depressive episode using a Val dominant model (adjusted risk difference = 0.09, 95% confidence intervals = 0.003-0.18, P = .04). For the worst manic episodes no significant interactions between COMT and stressful life events were detected.This is the first study to explore the relationship between stressful life events and the COMT Val

There is a growing body of research investigating the gene expression signature of depression at the genome-wide level, with potential for the discovery of novel pathophysiological mechanisms of depression. However, heterogeneity of depression, dynamic nature of gene expression patterns and various sources of noise have resulted in inconsistent findings. We systematically review the current state of transcriptome profiling of depression in the brain and peripheral tissues with a particular focus on replicated findings at the single gene level. By examining 16 brain regions and 5 cell types from the periphery, we identified 57 replicated differentially expressed genes in the brain and 21 in peripheral tissues. Functional overlap between brain and periphery strongly implicates shared pathways in a comorbid phenotype of depression and cardiovascular disease. The findings highlight dermal fibroblasts as a promising experimental model for depression biomarker research, provide partial support for all major theories of depression and suggest a novel candidate gene, PXMP2, which plays a critical role in lipid and reactive oxygen species metabolism. Refereed/Peer-reviewed

Candidate gene and genome-wide association studies have not identified common variants, which are reliably associated with depression. The recent identification of obesity predisposing genes that are highly expressed in the brain raises the possibility of their genetic contribution to depression. As variation in the intron 1 of the fat mass- and obesity-associated (FTO) gene contributes to polygenic obesity, we assessed the possibility that FTO gene may contribute to depression in a cross-sectional multi-ethnic sample of 6561 depression cases and 21,932 controls selected from the EpiDREAM, INTERHEART, DeCC (depression case-control study) and Cohorte Lausannoise (CoLaus) studies. Major depression was defined according to DSM IV diagnostic criteria. Association analyses were performed under the additive genetic model. A meta-analysis of the four studies showed a significant inverse association between the obesity risk FTO rs9939609 A variant and depression (odds ratio=0.92 (0.89, 0.97), P=3 × 10(-4)) adjusted for age, sex, ethnicity/population structure and body-mass index (BMI) with no significant between-study heterogeneity (I(2)=0%, P=0.63). The FTO rs9939609 A variant was also associated with increased BMI in the four studies (β 0.30 (0.08, 0.51), P=0.0064) adjusted for age, sex and ethnicity/population structure. In conclusion, we provide the first evidence that the FTO rs9939609 A variant may be associated with a lower risk of depression independently of its effect on BMI. This study highlights the potential importance of obesity predisposing genes on depression.

BackgroundIt has been well established that both genes and non-shared environment contribute substantially to the underlying aetiology of major depressive disorder (MDD). A comprehensive overview of genetic research in MDD is presented.MethodPapers were retrieved from PubMed up to December 2011, using many keywords including: depression, major depressive disorder, genetics, rare variants, gene–environment, whole genome, epigenetics, and specific candidate genes and variants. These were combined in a variety of permutations.ResultsLinkage studies have yielded some promising chromosomal regions in MDD. However, there is a continued lack of consistency in association studies, in both candidate gene and genome-wide association studies (GWAS). Numerous factors may account for variable results including the use of different diagnostic approaches, small samples in early studies, population stratification, epigenetic phenomena, copy number variation (CNV), rare variation, and phenotypic and allelic heterogeneity. The conflicting results are also probably, in part, a consequence of environmental factors not being considered or controlled for.ConclusionsEach research group has to identify what issues their sample may best address. We suggest that, where possible, more emphasis should be placed on the environment in molecular behavioural genetics to identify individuals at environmental high risk in addition to genetic high risk. Sequencing should be used to identify rare and alternative variation that may act as a risk factor, and a systems biology approach including gene–gene interactions and pathway analyses would be advantageous. GWAS may require even larger samples with reliably defined (sub)phenotypes.

Objective: The purpose of this study was to find loci for major depression via linkage analysis of a large sibling pair sample. Method: The authors conducted a genome-wide linkage analysis of 839 families consisting of 971 affected sibling pairs with severe recurrent major depression, comprising waves I and II of the Depression Network Study cohort. In addition to examining affected status, linkage analyses in the full data set were performed using diagnoses restricted by impairment severity, and association mapping of hits in a large case-control data set was attempted. Results: The authors identified genome-wide significant linkage to chromosome 3p25-26 when the diagnoses were restricted by severity, which was a maximum LOD score of 4.0 centered at the linkage marker D3S1515. The linkage signal identified was genome-wide significant after correction for the multiple phenotypes tested, although subsequent association mapping of the region in a genome-wide association study of a U.K. depression sample did not provide significant results. Conclusions: The authors report a genome-wide significant locus for depression that implicates genes that are highly plausible for involvement in the etiology of recurrent depression. Despite the fact that association mapping in the region was negative, the linkage finding was replicated by another group who found genome-wide-significant linkage for depression in the same region. This suggests that 3p25-26 is a new locus for severe recurrent depression. This represents the first report of a genome-wide significant locus for depression that also has an independent genome-wide significant replication.

Neuroimaging research implicates the hippocampus in the aetiology of major depressive disorder (MDD). Imaging genetics studies have investigated the influence of the serotonin transporter-linked polymorphic region (5HTTLPR) and brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on the hippocampus in healthy individuals and patients with depression (MDD). However, conflicting results have led to inconclusive evidence about the effect of 5HTTLPR or BDNF on hippocampal volume (HCV). We hypothesized that analysis methods based on three-dimensional (3D) hippocampal shape mapping could offer improved sensitivity to clarify these effects. Magnetic resonance imaging data were collected in parallel samples of 111 healthy individuals and 84 MDD patients. Manual hippocampal segmentation was conducted and the resulting data used to investigate the influence of 5HTTLPR and BDNF Val66Met genotypes on HCV and 3D shape within each sample. Hippocampal volume normalized by intracranial volume (ICV) showed no significant difference between 5HTTLPR S allele carriers and L/L homozygotes or between BDNF Met allele carriers and Val/Val homozygotes in the group of healthy individuals. Moreover, there was no significant difference in normalized HCV between 5HTTLPR diallelic and triallelic classifications or between the BDNF Val66Met genotypes in MDD patients, although there was a relationship between BDNF Val66Met and ICV. Shape analysis detected dispersed between-group differences, but these effects did not survive multiple testing correction. In this study, there was no evidence of a genetic effect for 5HTTLPR or BDNF Val66Met on hippocampal morphology in either healthy individuals or MDD patients despite the relatively large sample sizes and sensitive methodology.

Objectives. We identified a bipolar disorder (BPD) susceptibility region on chromosome 3q29 in a genome-wide linkage scan (Bailer et al. 2002 (Biol Psychiatry 52: 40), NPL-score 4.09) and follow-up linkage analysis (Schosser et al. 2004 (J Psychiatr Res 38(3): 357), NPL-scores >3 with five markers). These findings were supported by further fine-mapping of this region (Schosser et al. 2007 (Eur Neuropsychopharmacol 17(6–7): 501)), finding NPL-scores >3.9 with SNPs (single nucleotide polymorphisms) spanning a region of 3.46 Mbp in BPD families. Since genetic association studies are more powerful than linkage studies for detecting susceptibility genes of small effect size, we aimed to replicate these findings in an independent case-control sample collected in London (UK) and Vienna (Austria). Methods. A total of 51 SNPs were genotyped using Sequenom MassARRAY® iPLEX Gold and tested for association in a sample of 526 cases suffering from DSM-IV and/or ICD-10 diagnosis of BPD and 691 controls. Results. No genotypic and/or allelic association, as well as no haplotypic association, was found for any SNP after multiple testing correction. Conclusions. However, we cannot exclude the possibility that our sample might not have the power to detect rare variants associated with susceptibility to BPD.

Bipolar disorder (BD) is a complex genetic disease for which the underlying pathophysiology has yet to be fully explained. 5,10-Methylenetetrahydrofolate reductase (MTHFR) is a crucial enzyme in folate-mediated one-carbon metabolism and folate deficiency can be associated with psychiatric symptoms. A single base variant in MTHFR gene (C677T) results in the production of a mildly dysfunctional thermolabile enzyme and has recently been implicated in BD. We conducted an association study of this polymorphism in 897 patients with bipolar I or bipolar II disorder, and 1,687 healthy control subjects. We found no evidence for genotypic or allelic association in this sample. We also performed a meta-analysis of our own, and all published data, and report no evidence for association. Our findings suggest that the MTHFR C677T polymorphism is not involved in the genetic etiology of clinically significant BD.

Udgivelsesdato: 2010-May OBJECTIVE: The purpose of this study was to identify genetic variants underlying the considerable individual differences in response to antidepressant treatment. The authors performed a genome-wide association analysis of improvement of depression severity with two antidepressant drugs. METHOD: High-quality Illumina Human610-quad chip genotyping data were available for 706 unrelated participants of European ancestry treated for major depression with escitalopram (N=394) or nortriptyline (N=312) over a 12-week period in the Genome-Based Therapeutic Drugs for Depression (GENDEP) project, a partially randomized open-label pharmacogenetic trial. RESULTS: Single nucleotide polymorphisms in two intergenic regions containing copy number variants on chromosomes 1 and 10 were associated with the outcome of treatment with escitalopram or nortriptyline at suggestive levels of significance and with a high posterior likelihood of true association. Drug-specific analyses revealed a genome-wide significant association between marker rs2500535 in the uronyl 2-sulphotransferase gene and response to nortriptyline. Response to escitalopram was best predicted by a marker in the interleukin-11 (IL11) gene. A set of 72 a priori-selected candidate genes did not show pharmacogenetic associations above a chance level, but an association with response to escitalopram was detected in the interleukin-6 gene, which is a close homologue of IL11. CONCLUSIONS: While limited statistical power means that a number of true associations may have been missed, these results suggest that efficacy of antidepressants may be predicted by genetic markers other than traditional candidates. Genome-wide studies, if properly replicated, may thus be important steps in the elucidation of the genetic basis of pharmacological response.

Background Childhood trauma is a transdiagnostic risk factor for adult psychiatric disorders, including schizophrenia and bipolar-I disorder. Recent meta-analytic and epidemiological studies suggest a 3-fold increase in risk for psychotic symptoms in adulthood, following childhood trauma exposure. However, associations between trauma exposure and schizotypal personality traits, as well as cognitive and social cognitive abilities, have been less well studied in clinical populations spanning the psychotic-mood spectrum. Methods Participants were 79 schizophrenia cases, 84 bipolar disorder cases, and 75 healthy control participants who completed the Childhood Trauma Questionnaire (CTQ), the Schizotypal Personality Questionnaire (SPQ), and a standard battery of cognitive tests (to measure executive functions, working memory, attention, immediate and delayed memory), as well as social cognitive tests of facial emotion processing (the Ekman 60 faces task) and Theory-of-Mind (The Awareness of Social Inference Test; TASIT). The CTQ measures childhood trauma exposure on 5 domains (physical abuse, emotional abuse, sexual abuse, physical neglect, emotional neglect); clinically significant levels of childhood trauma exposure on at least one domain (according to specified thresholds for each domain) were evident in 54 schizophrenia cases, 55 bipolar disorder cases, and 26 healthy individuals. Trauma-exposed and non-exposed groups were compared on schizotypal personality features (referred to as ‘schizotypy’), cognitive and social cognitive abilities. Results In both the clinical groups and healthy controls, trauma-exposed participants reported higher levels of schizotypy, especially suspiciousness, relative to non-exposed individuals; this was revealed in the context of higher overall schizotypy levels in both schizophrenia and bipolar disorder, relative to healthy controls. Similarly, while the schizophrenia group showed lower social cognitive and cognitive performances relative to both the bipolar disorder and healthy control groups, trauma-exposed individuals showed deficits in social cognitive, but not general cognitive abilities, regardless of case versus control status. Discussion These findings suggest that childhood trauma exposure has long-term effects on schizotypy, especially suspiciousness, and complex social cognitive abilities in both healthy and psychotic populations. However, there was no interaction of clinical group with trauma exposure in relation to schizotypal personality dimensions, and the influence of early life trauma on cognitive functions was not distinguishable from the effects of psychotic illness in adulthood. It is possible that traumagenic processes contribute to paranoid ideation and social cognitive disturbances that contribute to psychosis-proneness in the general population, consistent with historical models of schizotypy as latent liability for schizophrenia and related psychotic disorders.

Objective 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. Method 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 Genotypage 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. Results 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. Conclusions 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.