Accurate diagnosis of bipolar disorder (BPD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A depressive episode often precedes the first manic episode, making it difficult to distinguish BPD from unipolar major depressive disorder (MDD).

We use genome-wide association analyses (GWAS) to identify differential genetic factors and to develop predictors based on polygenic risk scores (PRS) that may aid early differential diagnosis.

Based on individual genotypes from case–control cohorts of BPD and MDD shared through the Psychiatric Genomics Consortium, we compile case–case–control cohorts, applying a careful quality control procedure. In a resulting cohort of 51 149 individuals (15 532 BPD patients, 12 920 MDD patients and 22 697 controls), we perform a variety of GWAS and PRS analyses.

Although our GWAS is not well powered to identify genome-wide significant loci, we find significant chip heritability and demonstrate the ability of the resulting PRS to distinguish BPD from MDD, including BPD cases with depressive onset (BPD-D). We replicate our PRS findings in an independent Danish cohort (iPSYCH 2015, N = 25 966). We observe strong genetic correlation between our case–case GWAS and that of case–control BPD.

We find that MDD and BPD, including BPD-D are genetically distinct. Our findings support that controls, MDD and BPD patients primarily lie on a continuum of genetic risk. Future studies with larger and richer samples will likely yield a better understanding of these findings and enable the development of better genetic predictors distinguishing BPD and, importantly, BPD-D from MDD.

Obesity is highly prevalent and disabling, especially in individuals with severe mental illness including bipolar disorders (BD). The brain is a target organ for both obesity and BD. Yet, we do not understand how cortical brain alterations in BD and obesity interact.

We obtained body mass index (BMI) and MRI-derived regional cortical thickness, surface area from 1231 BD and 1601 control individuals from 13 countries within the ENIGMA-BD Working Group. We jointly modeled the statistical effects of BD and BMI on brain structure using mixed effects and tested for interaction and mediation. We also investigated the impact of medications on the BMI-related associations.

BMI and BD additively impacted the structure of many of the same brain regions. Both BMI and BD were negatively associated with cortical thickness, but not surface area. In most regions the number of jointly used psychiatric medication classes remained associated with lower cortical thickness when controlling for BMI. In a single region, fusiform gyrus, about a third of the negative association between number of jointly used psychiatric medications and cortical thickness was mediated by association between the number of medications and higher BMI.

We confirmed consistent associations between higher BMI and lower cortical thickness, but not surface area, across the cerebral mantle, in regions which were also associated with BD. Higher BMI in people with BD indicated more pronounced brain alterations. BMI is important for understanding the neuroanatomical changes in BD and the effects of psychiatric medications on the brain.

Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment.

To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder.

This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework.

The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data.

Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.

While previous studies have suggested that higher levels of cognitive performance may be related to greater wellbeing and resilience, little is known about the associations between neural circuits engaged by cognitive tasks and wellbeing and resilience, and whether genetics or environment contribute to these associations.

The current study consisted of 253 monozygotic and dizygotic adult twins, including a subsample of 187 early-life trauma-exposed twins, with functional Magnetic Resonance Imaging data from the TWIN-E study. Wellbeing was measured using the COMPAS-W Wellbeing Scale while resilience was defined as a higher level of positive adaptation (higher levels of wellbeing) in the presence of trauma exposure. We probed both sustained attention and working memory processes using a Continuous Performance Task in the scanner.

We found significant negative associations between resilience and activation in the bilateral anterior insula engaged during sustained attention. Multivariate twin modelling showed that the association between resilience and the left and right insula activation was mostly driven by common genetic factors, accounting for 71% and 87% of the total phenotypic correlation between these variables, respectively. There were no significant associations between wellbeing/resilience and neural activity engaged during working memory updating.

The findings suggest that greater resilience to trauma is associated with less activation of the anterior insula during a condition requiring sustained attention but not working memory updating. This possibly suggests a pattern of ‘neural efficiency’ (i.e. more efficient and/or attenuated activity) in people who may be more resilient to trauma.

Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.

To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.

Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.

Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.

AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.

Although mental wellbeing has been linked with positive health outcomes, including longevity and improved emotional and cognitive functioning, studies examining the underlying neural mechanisms of both subjective and psychological wellbeing have been sparse. We assessed whether both forms of wellbeing are associated with neural activity engaged during positive and negative emotion processing and the extent to which this association is driven by genetics or environment.

We assessed mental wellbeing in 230 healthy adult monozygotic and dizygotic twins using a previously validated questionnaire (COMPAS-W) and undertook functional magnetic resonance imaging during a facial emotion viewing task. We used linear mixed models to analyse the association between COMPAS-W scores and emotion-elicited neural activation. Univariate twin modelling was used to evaluate heritability of each brain region. Multivariate twin modelling was used to compare twin pairs to assess the contributions of genetic and environmental factors to this association.

Higher levels of wellbeing were associated with greater neural activity in the dorsolateral prefrontal cortex, localised in the right inferior frontal gyrus (IFG), in response to positive emotional expressions of happiness. Univariate twin modelling showed activity in the IFG to have 20% heritability. Multivariate twin modelling suggested that the association between wellbeing and positive emotion-elicited neural activity was driven by common variance from unique environment (r = 0.208) rather than shared genetics.

Higher mental wellbeing may have a basis in greater engagement of prefrontal neural regions in response to positive emotion, and this association may be modifiable by unique life experiences.

Bipolar disorder is a highly heritable polygenic disorder. Recent enrichment analyses suggest that there may be true risk variants for bipolar disorder in the expression quantitative trait loci (eQTL) in the brain.

We sought to assess the impact of eQTL variants on bipolar disorder risk by combining data from both bipolar disorder genome-wide association studies (GWAS) and brain eQTL.

To detect single nucleotide polymorphisms (SNPs) that influence expression levels of genes associated with bipolar disorder, we jointly analysed data from a bipolar disorder GWAS (7481 cases and 9250 controls) and a genome-wide brain (cortical) eQTL (193 healthy controls) using a Bayesian statistical method, with independent follow-up replications. The identified risk SNP was then further tested for association with hippocampal volume (n = 5775) and cognitive performance (n = 342) among healthy individuals.

Integrative analysis revealed a significant association between a brain eQTL rs6088662 on chromosome 20q11.22 and bipolar disorder (log Bayes factor = 5.48; bipolar disorder P = 5.85×10–5). Follow-up studies across multiple independent samples confirmed the association of the risk SNP (rs6088662) with gene expression and bipolar disorder susceptibility (P = 3.54×10–8). Further exploratory analysis revealed that rs6088662 is also associated with hippocampal volume and cognitive performance in healthy individuals.

Our findings suggest that 20q11.22 is likely a risk region for bipolar disorder; they also highlight the informative value of integrating functional annotation of genetic variants for gene expression in advancing our understanding of the biological basis underlying complex disorders, such as bipolar disorder.

Recent studies show that adverse life events have a significantly greater impact on depression onset for those with the s/s allele of the genotype for the 5-HT gene-linked promoter region. Research in genes related to risk of depression leads to the question of how this information is received by individuals.

To investigate factors related to the response to receiving one's own serotonin transporter genotype results.

Predictors of the impact of receiving individual genotype data were assessed in 128 participants in a study of gene–environment interaction in depression onset.

Two-thirds decided to learn their individual genotype results (receivers) and prior to disclosure this decision was associated with a perception of greater benefit from receipt of the information (P=0.001). Receivers completing the 2-week (n=76) and 3-month follow-up (n=78) generally reported feeling pleased with the information and having had a more positive experience than distress. However, distress was related to genotype, with those with the s/s allele being most affected.

There was high interest in, and satisfaction with, learning about one's serotonin transporter genotype. Participants appeared to understand that the gene conferred susceptibility to depression rather than a direct causal effect.

For families with multiple cases of bipolar disorder this study explored: attitudes towards childbearing; causal attributions for bipolar disorder, in particular the degree to which a genetic model is endorsed and its impact on the perceived stigma of bipolar disorder; and predictors of psychological distress.

Two hundred individuals (95 unaffected and 105 affected with either bipolar disorder, schizo-affective disorder – manic type, or recurrent major disorder) were surveyed, using mailed, self-administered questionnaires.

Thirty-five (35%) participants reported being ‘not at all willing to have children’ or ‘less willing to have children’ as a result of having a strong family history of bipolar disorder. Being not at all or less willing to have children was associated with perceived stigma of bipolar disorder [odds ratio (OR) 2·42, p=0·002], endorsement of a genetic model (OR 1·76, p=0·046), and being affected (OR 2·16, p=0·01). Among unaffected participants only, endorsement of a genetic model was strongly correlated with perceived stigma (rs=0·30, p=0·004). Perceiving the family environment as an important factor in causing bipolar disorder was significantly associated with psychological distress (OR 1·58, p=0·043) among unaffected participants. Among affected participants, perceived stigma was significantly correlated with psychological distress (OR 2·44, p=0·02), controlling for severity of symptoms (p<0·001).

Having a genetic explanation for bipolar disorder may exacerbate associative stigma among unaffected members from families with multiple cases of bipolar disorder, while it does not impact on perceived stigma among affected family members. Affected family members may benefit from interventions to ameliorate the adverse effects of perceived stigma.

A relationship between the serotonin transporter gene, adverse events and onset of major depression has been reported.

To replicate a gene × environment interaction in a cohort with longitudinal data for life events, experience of depression, parental bonding and neuroticism.

Atthe 25-year follow-up, genomic DNA was obtained from 127 cohort members (mean age 48 years) to determine the genotype of the serotonin transporter gene-linked promoter region (5-HTTLPR). Associations were investigated between the 5-HTTLPR genotype, positive and adverse life events and the gene × environment interaction, and also between the 5-HTTLPR genotype and risk factors for depression.

No relationship was found between 5-HTTLPR genotype and either risk factors for depression or positive life events. Adverse life events had a significantly greater impact on the onset of depression for individuals with the s/s genotype.

The 5-HTTLPR genotype is a significant predictor of onset of major depression following multiple adverse events. This is one of the more robust findings concerning specific biological risk factors for depression.