Attention-deficit/hyperactivity disorder and other neurodevelopmental disorders in offspring of parents with depression and bipolar disorder.

BACKGROUND: Offspring of parents with major mood disorders (MDDs) are at increased risk for early psychopathology. We aim to compare the rates of neurodevelopmental disorders in offspring of parents with bipolar disorder, major depressive disorder, and controls. METHOD: We established a lifetime diagnosis of neurodevelopmental disorders [attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, communication disorders, intellectual disabilities, specific learning disorders, and motor disorders] using the Kiddie Schedule for Affective Disorders and Schizophrenia, Present and Lifetime Version in 400 participants (mean age 11.3 + s.d. 3.9 years), including 93 offspring of parents with bipolar disorder, 182 offspring of parents with major depressive disorder, and 125 control offspring of parents with no mood disorder. RESULTS: Neurodevelopmental disorders were elevated in offspring of parents with bipolar disorder [odds ratio (OR) 2.34, 95% confidence interval (CI) 1.23-4.47, p = 0.010] and major depressive disorder (OR 1.87, 95% CI 1.03-3.39, p = 0.035) compared to controls. This difference was driven by the rates of ADHD, which were highest among offspring of parents with bipolar disorder (30.1%), intermediate in offspring of parents with major depressive disorder (24.2%), and lowest in controls (14.4%). There were no significant differences in frequencies of other neurodevelopmental disorders between the three groups. Chronic course of mood disorder in parents was associated with higher rates of any neurodevelopmental disorder and higher rates of ADHD in offspring. CONCLUSIONS: Our findings suggest monitoring for ADHD and other neurodevelopmental disorders in offspring of parents with MDDs may be indicated to improve early diagnosis and treatment.

Observed psychopathology in offspring of parents with major depressive disorder, bipolar disorder and schizophrenia.

BACKGROUND: Children of parents with mood and psychotic disorders are at elevated risk for a range of behavioral and emotional problems. However, as the usual reporter of psychopathology in children is the parent, reports of early problems in children of parents with mood and psychotic disorders may be biased by the parents' own experience of mental illness and their mental state. METHODS: Independent observers rated psychopathology using the Test Observation Form in 378 children and youth between the ages of 4 and 24 (mean = 11.01, s.d. = 4.40) who had a parent with major depressive disorder, bipolar disorder, schizophrenia, or no history of mood and psychotic disorders. RESULTS: Observed attentional problems were elevated in offspring of parents with major depressive disorder, bipolar disorder and schizophrenia (effect sizes ranging between 0.31 and 0.56). Oppositional behavior and language/thought problems showed variable degrees of elevation (effect sizes 0.17 to 0.57) across the three high-risk groups, with the greatest difficulties observed in offspring of parents with bipolar disorder. Observed anxiety was increased in offspring of parents with major depressive disorder and bipolar disorder (effect sizes 0.19 and 0.25 respectively) but not in offspring of parents with schizophrenia. CONCLUSIONS: Our results suggest that externalizing problems and cognitive and language difficulties may represent a general manifestation of familial risk for mood and psychotic disorders, while anxiety may be a specific marker of liability for mood disorders. Observer assessment may improve early identification of risk and selection of youth who may benefit from targeted prevention.

Larger right inferior frontal gyrus volume and surface area in participants at genetic risk for bipolar disorders.

BACKGROUND: Larger grey matter volume of the inferior frontal gyrus (IFG) is among the most replicated biomarkers of genetic risk for bipolar disorders (BD). However, the IFG is a heterogeneous prefrontal region, and volumetric findings can be attributable to changes in cortical thickness (CT), surface area (SA) or gyrification. Here, we investigated the morphometry of IFG in participants at genetic risk for BD. METHODS: We quantified the IFG cortical grey matter volume in 29 affected, 32 unaffected relatives of BD probands, and 42 controls. We then examined SA, CT, and cortical folding in subregions of the IFG. RESULTS: We found volumetric group differences in the right IFG, with the largest volumes in unaffected high-risk and smallest in control participants (F2,192 = 3.07, p = 0.01). The volume alterations were localized to the pars triangularis of the IFG (F2,97 = 4.05, p = 0.02), with no differences in pars opercularis or pars orbitalis. Pars triangularis volume was highly correlated with its SA [Pearson r(101) = 0.88, p < 0.001], which significantly differed between the groups (F2,97 = 4.45, p = 0.01). As with volume, the mean SA of the pars triangularis was greater in unaffected (corrected p = 0.02) and affected relatives (corrected p = 0.05) compared with controls. We did not find group differences in pars triangularis CT or gyrification. CONCLUSIONS: These findings strengthen prior knowledge about the volumetric findings in this region and provide a new insight into the localization and topology of IFG alterations. The unique nature of rIFG morphology in BD, with larger volume and SA early in the course of illness, could have practical implications for detection of participants at risk for BD.

Like father like daughter: sex-specific parent-of-origin effects in the transmission of liability for psychotic symptoms to offspring.

Children of parents with major mood and psychotic disorders are at increased risk of psychopathology, including psychotic symptoms. It has been suggested that the risk of psychosis may be more often transmitted from parent to opposite-sex offspring (e.g., from father to daughter) than to same-sex offspring (e.g., from father to son). To test whether sex-specific transmission extends to early manifestations of psychosis, we examined sex-specific contributions to psychotic symptoms among offspring of mothers and fathers with depression, bipolar disorder and schizophrenia. We assessed psychotic symptoms in 309 offspring (160 daughters and 149 sons) aged 8-24 years (mean=13.1, s.d.=4.3), of whom 113 had a mother with schizophrenia, bipolar disorder or major depression and 43 had a father with schizophrenia, bipolar disorder or major depression. In semi-structured interviews, 130 (42%) offspring had definite psychotic symptoms established and confirmed by psychiatrists on one or more assessments. We tested the effects of mental illness in parents on same-sex and opposite-sex offspring psychotic symptoms in mixed-effect logistic regression models. Psychotic symptoms were more prevalent among daughters of affected fathers and sons of affected mothers than among offspring of the same sex as their affected parent. Mental illness in the opposite-sex parent increased the odds of psychotic symptoms (odds ratio (OR)=2.65, 95% confidence interval (CI) 1.43-4.91, P=0.002), but mental illness in the same-sex parent did not have a significant effect on psychotic symptoms in offspring (OR=1.13, 95% CI 0.61-2.07, P=0.697). The opposite-sex-specific parent-of-origin effects may suggest X chromosome-linked genetic transmission or inherited chromosomal modifications in the etiology of psychotic symptoms.

New insights into the pharmacogenomics of antidepressant response from the GENDEP and STAR*D studies: rare variant analysis and high-density imputation.

Genome-wide association studies have generally failed to identify polymorphisms associated with antidepressant response. Possible reasons include limited coverage of genetic variants that this study tried to address by exome genotyping and dense imputation. A meta-analysis of Genome-Based Therapeutic Drugs for Depression (GENDEP) and Sequenced Treatment Alternatives to Relieve Depression (STAR*D) studies was performed at the single-nucleotide polymorphism (SNP), gene and pathway levels. Coverage of genetic variants was increased compared with previous studies by adding exome genotypes to previously available genome-wide data and using the Haplotype Reference Consortium panel for imputation. Standard quality control was applied. Phenotypes were symptom improvement and remission after 12 weeks of antidepressant treatment. Significant findings were investigated in NEWMEDS consortium samples and Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) for replication. A total of 7062 950 SNPs were analyzed in GENDEP (n=738) and STAR*D (n=1409). rs116692768 (P=1.80e-08, ITGA9 (integrin α9)) and rs76191705 (P=2.59e-08, NRXN3 (neurexin 3)) were significantly associated with symptom improvement during citalopram/escitalopram treatment. At the gene level, no consistent effect was found. At the pathway level, the Gene Ontology (GO) terms GO: 0005694 (chromosome) and GO: 0044427 (chromosomal part) were associated with improvement (corrected P=0.007 and 0.045, respectively). The association between rs116692768 and symptom improvement was replicated in PGRN-AMPS (P=0.047), whereas rs76191705 was not. The two SNPs did not replicate in NEWMEDS. ITGA9 codes for a membrane receptor for neurotrophins and NRXN3 is a transmembrane neuronal adhesion receptor involved in synaptic differentiation. Despite their meaningful biological rationale for being involved in antidepressant effect, replication was partial. Further studies may help in clarifying their role.

Interaction between childhood maltreatment on immunogenetic risk in depression: Discovery and replication in clinical case-control samples.

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.

Hot and cold executive functions in youth with psychotic symptoms.

BACKGROUND: Psychotic symptoms are common in children and adolescents and may be early manifestations of liability to severe mental illness (SMI), including schizophrenia. SMI and psychotic symptoms are associated with impairment in executive functions. However, previous studies have not differentiated between 'cold' and 'hot' executive functions. We hypothesized that the propensity for psychotic symptoms is specifically associated with impairment in 'hot' executive functions, such as decision-making in the context of uncertain rewards and losses. METHODS: In a cohort of 156 youth (mean age 12.5, range 7-24 years) enriched for familial risk of SMI, we measured cold and hot executive functions with the spatial working memory (SWM) task (total errors) and the Cambridge Gambling Task (decision-making), respectively. We assessed psychotic symptoms using the semi-structured Kiddie Schedule for Affective Disorders and Schizophrenia interview, Structured Interview for Prodromal Syndromes, Funny Feelings, and Schizophrenia Proneness Instrument - Child and Youth version. RESULTS: In total 69 (44.23%) youth reported psychotic symptoms on one or more assessments. Cold executive functioning, indexed with SWM errors, was not significantly related to psychotic symptoms [odds ratio (OR) 1.36, 95% confidence interval (CI) 0.85-2.17, p = 0.204). Poor hot executive functioning, indexed as decision-making score, was associated with psychotic symptoms after adjustment for age, sex and familial clustering (OR 2.37, 95% CI 1.25-4.50, p = 0.008). The association between worse hot executive functions and psychotic symptoms remained significant in sensitivity analyses controlling for general cognitive ability and cold executive functions. CONCLUSIONS: Impaired hot executive functions may be an indicator of risk and a target for pre-emptive early interventions in youth.

Autism risk following antidepressant medication during pregnancy.

BACKGROUND: Previous studies have examined if maternal antidepressant medication during pregnancy increase the risk of autism spectrum disorder (ASD) in the offspring, but the results have been conflicting. METHODS: In a population-based cohort of 179 007 children born in 2006 and 2007 and followed through 2014 when aged 7 and 8, we estimated relative risks (RRs) of ASD and 95% confidence intervals (CIs) from Cox regression in children exposed to any antidepressant medication during pregnancy, and nine specific antidepressant drugs. Analyses were adjusted for potential confounders and were conducted in the full population sample, and in a clinically relevant sub-sample of mothers with at least one diagnosis of depression or anxiety during life. RESULTS: The adjusted RR of ASD in children of mothers who used antidepressant medication during pregnancy was estimated at 1.23 (95% CI 0.96-1.57), and at 1.07 (95% CI 0.80-1.43) in women with a history of depression or anxiety. Analyses of specific antidepressants initially revealed increased RRs of offspring ASD confined to citalopram and escitalopram (RR: 1.47; 95% CI 0.92-2.35) and clomipramine (RR: 2.86; 95% CI 1.04-7.82). CONCLUSION: Medication with antidepressants during pregnancy does not appear to be causally associated with an increased risk of ASD in the offspring. Instead, the results suggest that the association is explained by factors related to the underlying susceptibility to psychiatric disorders. Based on these findings, the risk of ASD in the offspring should not be a consideration to withhold treatment with commonly used antidepressant drugs from pregnant women.

Prevalence of current anxiety disorders in people with bipolar disorder during euthymia: a meta-analysis.

BACKGROUND: Anxiety disorders are highly prevalent in people with bipolar disorder, but it is not clear how many have anxiety disorders even at times when they are free of major mood episodes. We aimed to establish what proportion of euthymic individuals with bipolar disorder meet diagnostic criteria for anxiety disorders. METHOD: We performed a random-effects meta-analysis of prevalence rates of current DSM-III- and DSM-IV-defined anxiety disorders (panic disorder, agoraphobia, social anxiety disorder, generalized anxiety disorder, specific phobia, obsessive-compulsive disorder, post-traumatic stress disorder, and anxiety disorder not otherwise specified) in euthymic adults with bipolar disorder in studies published by 31 December 2015. RESULTS: Across 10 samples with 2120 individuals with bipolar disorder, 34.7% met diagnostic criteria for one or more anxiety disorders during euthymia [95% confidence interval (CI) 23.9-45.5%]. Direct comparison of 189 euthymic individuals with bipolar disorder and 17 109 population controls across three studies showed a 4.6-fold increase (risk ratio 4.60, 95% CI 2.37-8.92, p < 0.001) in prevalence of anxiety disorders in those with bipolar disorder. CONCLUSIONS: These findings suggest that anxiety disorders are common in people with bipolar disorder even when their mood is adequately controlled. Euthymic people with bipolar disorder should be routinely assessed for anxiety disorders and anxiety-focused treatment should be initiated if indicated.

Polygenic interactions with environmental adversity in the aetiology of major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is a common and disabling condition with well-established heritability and environmental risk factors. Gene-environment interaction studies in MDD have typically investigated candidate genes, though the disorder is known to be highly polygenic. This study aims to test for interaction between polygenic risk and stressful life events (SLEs) or childhood trauma (CT) in the aetiology of MDD. METHOD: The RADIANT UK sample consists of 1605 MDD cases and 1064 controls with SLE data, and a subset of 240 cases and 272 controls with CT data. Polygenic risk scores (PRS) were constructed using results from a mega-analysis on MDD by the Psychiatric Genomics Consortium. PRS and environmental factors were tested for association with case/control status and for interaction between them. RESULTS: PRS significantly predicted depression, explaining 1.1% of variance in phenotype (p = 1.9 × 10(-6)). SLEs and CT were also associated with MDD status (p = 2.19 × 10(-4) and p = 5.12 × 10(-20), respectively). No interactions were found between PRS and SLEs. Significant PRSxCT interactions were found (p = 0.002), but showed an inverse association with MDD status, as cases who experienced more severe CT tended to have a lower PRS than other cases or controls. This relationship between PRS and CT was not observed in independent replication samples. CONCLUSIONS: CT is a strong risk factor for MDD but may have greater effect in individuals with lower genetic liability for the disorder. Including environmental risk along with genetics is important in studying the aetiology of MDD and PRS provide a useful approach to investigating gene-environment interactions in complex traits.

Evidence-based guidelines for treating depressive disorders with antidepressants: A revision of the 2008 British Association for Psychopharmacology guidelines.

A revision of the 2008 British Association for Psychopharmacology evidence-based guidelines for treating depressive disorders with antidepressants was undertaken in order to incorporate new evidence and to update the recommendations where appropriate. A consensus meeting involving experts in depressive disorders and their management was held in September 2012. Key areas in treating depression were reviewed and the strength of evidence and clinical implications were considered. The guidelines were then revised after extensive feedback from participants and interested parties. A literature review is provided which identifies the quality of evidence upon which the recommendations are made. These guidelines cover the nature and detection of depressive disorders, acute treatment with antidepressant drugs, choice of drug versus alternative treatment, practical issues in prescribing and management, next-step treatment, relapse prevention, treatment of relapse and stopping treatment. Significant changes since the last guidelines were published in 2008 include the availability of new antidepressant treatment options, improved evidence supporting certain augmentation strategies (drug and non-drug), management of potential long-term side effects, updated guidance for prescribing in elderly and adolescent populations and updated guidance for optimal prescribing. Suggestions for future research priorities are also made.

Familiality and SNP heritability of age at onset and episodicity in major depressive disorder.

BACKGROUND: Strategies to dissect phenotypic and genetic heterogeneity of major depressive disorder (MDD) have mainly relied on subphenotypes, such as age at onset (AAO) and recurrence/episodicity. Yet, evidence on whether these subphenotypes are familial or heritable is scarce. The aims of this study are to investigate the familiality of AAO and episode frequency in MDD and to assess the proportion of their variance explained by common single nucleotide polymorphisms (SNP heritability). METHOD: For investigating familiality, we used 691 families with 2-5 full siblings with recurrent MDD from the DeNt study. We fitted (square root) AAO and episode count in a linear and a negative binomial mixed model, respectively, with family as random effect and adjusting for sex, age and center. The strength of familiality was assessed with intraclass correlation coefficients (ICC). For estimating SNP heritabilities, we used 3468 unrelated MDD cases from the RADIANT and GSK Munich studies. After similarly adjusting for covariates, derived residuals were used with the GREML method in GCTA (genome-wide complex trait analysis) software. RESULTS: Significant familial clustering was found for both AAO (ICC = 0.28) and episodicity (ICC = 0.07). We calculated from respective ICC estimates the maximal additive heritability of AAO (0.56) and episodicity (0.15). SNP heritability of AAO was 0.17 (p = 0.04); analysis was underpowered for calculating SNP heritability of episodicity. CONCLUSIONS: AAO and episodicity aggregate in families to a moderate and small degree, respectively. AAO is under stronger additive genetic control than episodicity. Larger samples are needed to calculate the SNP heritability of episodicity. The described statistical framework could be useful in future analyses.

Investigation of blood mRNA biomarkers for suicidality in an independent sample.

Changes in the blood expression levels of SAT1, PTEN, MAP3K3 and MARCKS genes have been reported as biomarkers of high versus low suicidality state (Le-Niculescu et al.). Here, we investigate these expression biomarkers in the Genome-Based Therapeutic Drugs for Depression (GENDEP) study, of patients with major depressive disorder on a 12-week antidepressant treatment. Blood gene expression levels were available at baseline and week 8 for patients who experienced suicidal ideation during the study (n=20) versus those who did not (n=37). The analysis is well powered to detect the effect sizes reported in the original paper. Within either group, there was no significant change in the expression of these four genes over the course of the study, despite increasing suicidal ideation or initiation of antidepressant treatment. Comparison of the groups showed that the gene expression did not differ between patients with or without treatment-related suicidality. This independent study does not support the validity of the proposed biomarkers.

Copy number variants and therapeutic response to antidepressant medication in major depressive disorder.

It would be beneficial to find genetic predictors of antidepressant response to help personalise treatment of major depressive disorder (MDD). Rare copy number variants (CNVs) have been implicated in several psychiatric disorders, including MDD, but their role in antidepressant response has yet to be investigated. CNV data were available for 1565 individuals with MDD from the NEWMEDS (Novel Methods leading to New Medications in Depression and Schizophrenia) consortium with prospective data on treatment outcome with either a serotonergic or noradrenergic antidepressant. No association was seen between the presence of CNV (rare or common), the overall number of CNVs or genomic CNV 'burden' and antidepressant response. Specific CNVs were nominally associated with antidepressant response, including 15q13.3 duplications and exonic NRXN1 deletions. These were associated with poor response to antidepressants. Overall burden of CNVs is unlikely to contribute to personalising antidepressant treatment. Specific CNVs associated with antidepressant treatment require replication and further study to confirm their role in the therapeutic action of antidepressant.

Neuroprotective effect of lithium on hippocampal volumes in bipolar disorder independent of long-term treatment response.

BACKGROUND: Neuroimaging studies have demonstrated an association between lithium (Li) treatment and brain structure in human subjects. A crucial unresolved question is whether this association reflects direct neurochemical effects of Li or indirect effects secondary to treatment or prevention of episodes of bipolar disorder (BD). METHOD: To address this knowledge gap, we compared manually traced hippocampal volumes in 37 BD patients with at least 2 years of Li treatment (Li group), 19 BD patients with <3 months of lifetime Li exposure over 2 years ago (non-Li group) and 50 healthy controls. All BD participants were followed prospectively and had at least 10 years of illness and a minimum of five episodes. We established illness course and long-term treatment response to Li using National Institute of Mental Health (NIMH) life charts. RESULTS: The non-Li group had smaller hippocampal volumes than the controls or the Li group (F 2,102 = 4.97, p = 0.009). However, the time spent in a mood episode on the current mood stabilizer was more than three times longer in the Li than in the non-Li group (t(51) = 2.00, p = 0.05). Even Li-treated patients with BD episodes while on Li had hippocampal volumes comparable to healthy controls and significantly larger than non-Li patients (t(43) = 2.62, corrected p = 0.02). CONCLUSIONS: Our findings support the neuroprotective effects of Li. The association between Li treatment and hippocampal volume seems to be independent of long-term treatment response and occurred even in subjects with episodes of BD while on Li. Consequently, these effects of Li on brain structure may generalize to patients with neuropsychiatric illnesses other than BD.

DNA methylation in interleukin-11 predicts clinical response to antidepressants in GENDEP.

Transcriptional differences in interleukin-11 (IL11) after antidepressant treatment have been found to correspond to clinical response in major depressive disorder (MDD) patients. Expression differences were partly mediated by a single-nucleotide polymorphism (rs1126757), identified as a predictor of antidepressant response as part of a genome-wide association study. Here we attempt to identify whether DNA methylation, another baseline factor known to affect transcription factor binding, might also predict antidepressant response, using samples collected from the Genome-based Therapeutic Drugs for Depression project (GENDEP). DNA samples from 113 MDD individuals from the GENDEP project, who were treated with either escitalopram (n=80) or nortriptyline (n=33) for 12 weeks, were randomly selected. Percentage change in Montgomery-Åsberg Depression Rating Scale scores between baseline and week 12 were utilized as our measure of antidepressant response. The Sequenom EpiTYPER platform was used to assess DNA methylation across the only CpG island located in the IL11 gene. Regression analyses were then used to explore the relationship between CpG unit methylation and antidepressant response. We identified a CpG unit predictor of general antidepressant response, a drug by CpG unit interaction predictor of response, and a CpG unit by rs1126757 interaction predictor of antidepressant response. The current study is the first to investigate the potential utility of pharmaco-epigenetic biomarkers for the prediction of antidepressant response. Our results suggest that DNA methylation in IL11 might be useful in identifying those patients likely to respond to antidepressants, and if so, the best drug suited to each individual.

Typology of clinical course in bipolar disorder based on 18-month naturalistic follow-up.

BACKGROUND: Individual variation in the clinical course of bipolar disorder may have prognostic and therapeutic implications but is poorly reflected in current classifications. We aimed to establish a typology of the individual clinical trajectories based on detailed prospective medium-term follow-up. Method Latent class analysis (LCA) of nine characteristics of clinical course (time depressed, severity of depression, stability of depression, time manic, severity of mania, stability of mania, mixed symptoms, mania-to-depression and depression-to-mania phase switching) derived from life charts prospectively tracking the onsets and offsets of (hypo)manic, depressive, mixed and subsyndromal episodes in a representative sample of 176 patients with bipolar disorder. RESULTS: The best-fitting model separated patients with bipolar disorder into large classes of episodic bipolar (47%) and depressive type (32%), moderately sized classes characterized by prolonged hypomanias (10%) and mixed episodes (5%) and five small classes with unusual course characteristics including mania-to-depression and depression-to-mania transitions and chronic mixed affective symptoms. This empirical typology is relatively independent of the distinction between bipolar disorder type I and type II. Lifetime co-morbidity of alcohol use disorders is characteristic of the episodic bipolar course type. CONCLUSIONS: There is potential for a new typology of clinical course based on medium-term naturalistic follow-up of a representative clinical sample of patients with bipolar disorder. Predictive validity and stability over longer follow-up periods remain to be established.

Estimating the heritability of reporting stressful life events captured by common genetic variants.

BACKGROUND: Although usually thought of as external environmental stressors, a significant heritable component has been reported for measures of stressful life events (SLEs) in twin studies. Method We 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. RESULTS: A 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 R 2 = 0.08 in SLEs (p = 0.03). CONCLUSIONS: These 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.