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.

Psychotic disorders are highly heritable such that the unaffected relatives of patients may manifest characteristics, or endophenotypes, that are more closely related to risk genes than the overt clinical condition. Facial affect processing is dependent on a distributed cortico-limbic network that is disrupted in psychosis. This study assessed facial affect processing and related brain structure as a candidate endophenotype of first-episode psychosis (FEP).

Three samples comprising 30 FEP patients, 30 of their first-degree relatives and 31 unrelated healthy controls underwent assessment of facial affect processing and structural magnetic resonance imaging (sMRI) data. Multivariate analysis (partial least squares, PLS) was used to identify a grey matter (GM) system in which anatomical variation was associated with variation in facial affect processing speed.

The groups did not differ in their accuracy of facial affect intensity rating but differed significantly in speed of response, with controls responding faster than relatives, who responded faster than patients. Within the control group, variation in speed of affect processing was significantly associated with variation of GM density in amygdala, lateral temporal cortex, frontal cortex and cerebellum. However, this association between cortico-limbic GM density and speed of facial affect processing was absent in patients and their relatives.

Speed of facial affect processing presents as a candidate endophenotype of FEP. The normal association between speed of facial affect processing and cortico-limbic GM variation was disrupted in FEP patients and their relatives.

There is good evidence that psychotic symptoms segregate into symptom dimensions. However, it is still unclear how these dimensions are associated with risk indicators and other clinical variables, and whether they have advantages over categorical diagnosis in clinical practice. We investigated symptom dimensions in a first-onset psychosis sample and examined their associations with risk indicators and clinical variables. We then examined the relationship of categorical diagnoses to the same variables.

We recruited 536 patients as part of a population-based, incidence study of psychosis. Psychopathology was assessed using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN). A principal axis factor analysis was performed on symptom scores. The relationship of dimension scores with risk indicators and with clinical variables was then examined employing regression analyses. Finally, regression models were compared to assess the contribution of dimensions versus diagnosis in explaining these variables.

Factor analysis gave rise to a five-factor solution of manic, reality distortion, negative, depressive and disorganization symptom dimensions. The scores of identified dimensions were differentially associated with specific variables. The manic dimension had the highest number of significant associations; strong correlations were observed with shorter duration of untreated psychosis, acute mode of onset and compulsory admission. Adding dimensional scores to diagnostic categories significantly increased the amount of variability explained in predicting these variables; the reverse was also true but to a lesser extent.

Categorical and dimensional representations of psychosis are complementary. Using both appears to be a promising strategy in conceptualising psychotic illnesses.

An increased prevalence of minor physical anomalies (MPAs) has been extensively documented in schizophrenia but their specificity for the disorder remains unclear. We investigated the prevalence and the predictive power of MPAs in a large sample of first-episode psychotic patients across a range of diagnoses.

MPAs were examined in 242 subjects with first-episode psychosis (50% schizophrenia, 45% affective psychosis and 5% substance-induced psychosis) and 158 healthy controls. Categorical principal components analysis and analysis of variance were undertaken, and individual items with the highest loading were tested using the χ2 test.

Overall facial asymmetry, assymetry of the orbital landmarks, and frankfurt horizontal significantly differentiated patients with schizophrenia and affective psychosis from controls, as did a ‘V-shaped’ palate, reduced palatal ridges, abnormality of the left ear surface and the shape of the left and right ears. Patients with affective psychosis had significantly lowered eye fissures compared with control subjects.

MPAs are not specific to schizophrenia, suggesting a common developmental pathway for non-affective and affective psychoses. The topographical distribution of MPAs in this study is suggestive of an insult occurring during organogenesis in the first trimester of pregnancy.

Minor physical anomalies are more prevalent among people with psychosis. This supports a neurodevelopmental aetiology for psychotic disorders, since these anomalies and the brain are both ectodermally derived. However, little is understood about the brain regions implicated in this association.

To examine the relationship between minor physical anomalies and grey matter structure in a sample of patients with first-episode psychosis.

Sixty patients underwent assessment of minor physical anomalies with the Lane scale. High-resolution magnetic resonance images and voxel-based methods of image analysis were used to investigate brain structure in these patients.

The total anomalies score was associated with a grey matter reduction in the prefrontal cortex and precuneus and with a grey matter excess in the basal ganglia, thalamus and lingual gyrus.

Minor physical anomalies in a sample of patients with first-episode psychosis are associated with regional grey matter changes. These regional changes may be important in the pathogenesis of psychotic disorder.