Rare coding variants in ten genes confer substantial risk for schizophrenia.

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3-50, P < 2.14 × 10-6) and 32 genes at a false discovery rate of <5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure and function of the synapse. The associations of the NMDA (N-methyl-D-aspartate) receptor subunit GRIN2A and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GRIA3 provide support for dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk among schizophrenia, autism spectrum disorders1, epilepsy and severe neurodevelopmental disorders2, although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach.

Migraine associated with early onset postpartum depression in women with major depressive disorder.

Major depressive disorder (MDD) and migraine are both more common among women than men. Women's reproductive years are associated with increased susceptibility to recurrence of both conditions, suggesting a potential role of sex hormones in aetiology. We examined associations between comorbid migraine and clinical features of MDD in women, including relationships with lifetime reproductive events such as childbirth. Lifetime clinical characteristics and reproductive events in a well-characterised sample of 222 UK women with recurrent MDD, with (n = 98) and without (n = 124) migraine were compared. Women had all been recruited as part of a UK-based ongoing programme of research into the genetic and non-genetic determinants of mood disorders. Multivariate analysis showed a specific association between the lifetime presence of migraine and postpartum depression (PPD) within 6 weeks of delivery (OR = 2.555; 95% CI: 1.037-6.295, p = 0.041). This association did not extend to a broader definition of PPD with onset up to 6 months postpartum. All other factors included in the analysis were not significantly associated with the presence of migraine: family history of depression, younger age at depression onset, history of suicide attempt and severe premenstrual syndrome symptoms. The finding that women with MDD and comorbid migraine may be particularly sensitive to hormonal changes early in the postpartum period leads to aetiological hypotheses and suggests this group may be useful for future studies attempting to characterise PPD and MDD phenotypes. The refinement of such phenotypes has implications for individualising risk and treatment and for future biological and genetic studies.

Identification of loci associated with schizophrenia by genome-wide association and follow-up.

We carried out a genome-wide association study of schizophrenia (479 cases, 2,937 controls) and tested loci with P < 10(-5) in up to 16,726 additional subjects. Of 12 loci followed up, 3 had strong independent support (P < 5 x 10(-4)), and the overall pattern of replication was unlikely to occur by chance (P = 9 x 10(-8)). Meta-analysis provided strongest evidence for association around ZNF804A (P = 1.61 x 10(-7)) and this strengthened when the affected phenotype included bipolar disorder (P = 9.96 x 10(-9)).

De novo CNVs in bipolar affective disorder and schizophrenia.

An increased rate of de novo copy number variants (CNVs) has been found in schizophrenia (SZ), autism and developmental delay. An increased rate has also been reported in bipolar affective disorder (BD). Here, in a larger BD sample, we aimed to replicate these findings and compare de novo CNVs between SZ and BD. We used Illumina microarrays to genotype 368 BD probands, 76 SZ probands and all their parents. Copy number variants were called by PennCNV and filtered for frequency (<1%) and size (>10 kb). Putative de novo CNVs were validated with the z-score algorithm, manual inspection of log R ratios (LRR) and qPCR probes. We found 15 de novo CNVs in BD (4.1% rate) and 6 in SZ (7.9% rate). Combining results with previous studies and using a cut-off of >100 kb, the rate of de novo CNVs in BD was intermediate between controls and SZ: 1.5% in controls, 2.2% in BD and 4.3% in SZ. Only the differences between SZ and BD and SZ and controls were significant. The median size of de novo CNVs in BD (448 kb) was also intermediate between SZ (613 kb) and controls (338 kb), but only the comparison between SZ and controls was significant. Only one de novo CNV in BD was in a confirmed SZ locus (16p11.2). Sporadic or early onset cases were not more likely to have de novo CNVs. We conclude that de novo CNVs play a smaller role in BD compared with SZ. Patients with a positive family history can also harbour de novo mutations.

Association of Occupational Dysfunction and Hospital Admissions With Different Polygenic Profiles in Bipolar Disorder.

OBJECTIVE: Many but not all persons with bipolar disorder require hospital care because of severe mood episodes. Likewise, some but not all patients experience long-term occupational dysfunction that extends beyond acute mood episodes. It is not known whether these dissimilar outcomes of bipolar disorder are driven by different polygenic profiles. Here, polygenic scores (PGSs) for major psychiatric disorders and educational attainment were assessed for associations with occupational functioning and psychiatric hospital admissions in bipolar disorder. METHODS: A total of 4,782 patients with bipolar disorder and 2,963 control subjects were genotyped and linked to Swedish national registers. Longitudinal measures from at least 10 years of registry data were used to derive percentage of years without employment, percentage of years with long-term sick leave, and mean number of psychiatric hospital admissions per year. Ordinal regression was used to test associations between outcomes and PGSs for bipolar disorder, schizophrenia, major depressive disorder, attention deficit hyperactivity disorder (ADHD), and educational attainment. Replication analyses of hospital admissions were conducted with data from the Bipolar Disorder Research Network cohort (N=4,219). RESULTS: Long-term sick leave and unemployment in bipolar disorder were significantly associated with PGSs for schizophrenia, ADHD, major depressive disorder, and educational attainment, but not with the PGS for bipolar disorder. By contrast, the number of hospital admissions per year was associated with higher PGSs for bipolar disorder and schizophrenia, but not with the other PGSs. CONCLUSIONS: Bipolar disorder severity (indexed by hospital admissions) was associated with a different polygenic profile than long-term occupational dysfunction. These findings have clinical implications, suggesting that mitigating occupational dysfunction requires interventions other than those deployed to prevent mood episodes.

Fine-mapping genomic loci refines bipolar disorder risk genes.

Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 17 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of genes involved in neurotransmission and neurodevelopment including SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, CRTC3, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, DPH1, GSDMB, MED24 and THRA in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance of BD polygenic risk scores across diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).

Most genome-wide significant susceptibility loci for schizophrenia and bipolar disorder reported to date cross-traditional diagnostic boundaries.

Recent findings from genetic epidemiology and from genome-wide association studies point strongly to a partial overlap in the genes that contribute susceptibility to schizophrenia and bipolar disorder (BD). Previous data have also directly implicated one of the best supported schizophrenia-associated loci, zinc finger binding protein 804A (ZNF804A), as showing trans-disorder effects, and the same is true for one of the best supported bipolar loci, calcium channel, voltage-dependent, L type, alpha 1C subunit (CACNA1C) which has also been associated with schizophrenia. We have undertaken a cross-phenotype study based upon the remaining variants that show genome-wide evidence for association in large schizophrenia and BD meta-analyses. These comprise in schizophrenia, SNPs in or in the vicinity of transcription factor 4 (TCF4), neurogranin (NRGN) and an extended region covering the MHC locus on chromosome 6. For BD, the strongly supported variants are in the vicinity of ankyrin 3, node of Ranvier (ANK3) and polybromo-1 (PBRM1). Using data sets entirely independent of their original discoveries, we observed strong evidence that the PBRM1 locus is also associated with schizophrenia (P = 0.00015) and nominally significant evidence (P < 0.05) that the NRGN and the extended MHC region are associated with BD. Moreover, considering this highly restricted set of loci as a group, the evidence for trans-disorder effects is compelling (P = 4.7 × 10(-5)). Including earlier reported data for trans-disorder effects for ZNF804A and CACNA1C, six out of eight of the most robustly associated loci for either disorder show trans-disorder effects.

Dissection of the genetics of Parkinson's disease identifies an additional association 5' of SNCA and multiple associated haplotypes at 17q21.

We performed a genome-wide association study (GWAS) in 1705 Parkinson's disease (PD) UK patients and 5175 UK controls, the largest sample size so far for a PD GWAS. Replication was attempted in an additional cohort of 1039 French PD cases and 1984 controls for the 27 regions showing the strongest evidence of association (P< 10(-4)). We replicated published associations in the 4q22/SNCA and 17q21/MAPT chromosome regions (P< 10(-10)) and found evidence for an additional independent association in 4q22/SNCA. A detailed analysis of the haplotype structure at 17q21 showed that there are three separate risk groups within this region. We found weak but consistent evidence of association for common variants located in three previously published associated regions (4p15/BST1, 4p16/GAK and 1q32/PARK16). We found no support for the previously reported SNP association in 12q12/LRRK2. We also found an association of the two SNPs in 4q22/SNCA with the age of onset of the disease.

Specificity of polygenic signatures across symptom dimensions in bipolar disorder: an analysis of UK Bipolar Disorder Research Network data.

BACKGROUND: Current definitions and clinical heterogeneity in bipolar disorder are major concerns as they obstruct aetiological research and impede drug development. Therefore, stratification of bipolar disorder is a high priority. To inform stratification, our analysis aimed to examine the patterns and relationships between polygenic liability for bipolar disorder, major depressive disorder (MDD), and schizophrenia with multidimensional symptom representations of bipolar disorder. METHODS: In this analysis, data from the UK Bipolar Disorder Research Network (BDRN) were assessed with the Operational Checklist for Psychotic Disorders. Individuals with bipolar disorder as defined in DSM-IV, of European ancestry (self-reported), aged 18 years or older at time of interview, living in the UK, and registered with the BDRN were eligible for inclusion. Psychopathological variables obtained via interview by trained research psychologists or psychiatrists and psychiatric case notes were used to identify statistically distinct symptom dimensions, calibrated with exploratory factor analysis and validated with confirmatory factor analysis (CFA). CFA was extended to include three polygenic risk scores (PRSs) indexing liability for bipolar disorder, MDD, and schizophrenia in a multiple indicator multiple cause (MIMIC) structural equation model to estimate PRS relationships with symptom dimensions. FINDINGS: Of 4198 individuals potentially eligible for inclusion, 4148 (2804 [67·6%] female individuals and 1344 [32·4%] male individuals) with a mean age at interview of 45 years (SD 12·03) were available for analysis. Three reliable dimensions (mania, depression, and psychosis) were identified. The MIMIC model fitted the data well (root mean square error of approximation 0·021, 90% CI 0·019-0·023; comparative fit index 0·99) and suggests statistically distinct symptom dimensions also have distinct polygenic profiles. The PRS for MDD was strongly associated with the depression dimension (standardised ß 0·125, 95% CI 0·080-0·171) and the PRS for schizophrenia was strongly associated with the psychosis dimension (0·108, 0·082-0·175). For the mania dimension, the PRS for bipolar disorder was weakly associated (0·050, 0·002-0·097). INTERPRETATION: Our findings support the hypothesis that genetic heterogeneity underpins clinical heterogeneity, suggesting that different symptom dimensions within bipolar disorder have partly distinct causes. Furthermore, our results suggest that a specific symptom dimension has a similar cause regardless of the primary psychiatric diagnosis, supporting the use of symptom dimensions in precision psychiatry. FUNDING: Wellcome Trust and UK Medical Research Council.

DRAGON-Data: a platform and protocol for integrating genomic and phenotypic data across large psychiatric cohorts.

BACKGROUND: Current psychiatric diagnoses, although heritable, have not been clearly mapped onto distinct underlying pathogenic processes. The same symptoms often occur in multiple disorders, and a substantial proportion of both genetic and environmental risk factors are shared across disorders. However, the relationship between shared symptoms and shared genetic liability is still poorly understood. AIMS: Well-characterised, cross-disorder samples are needed to investigate this matter, but few currently exist. Our aim is to develop procedures to purposely curate and aggregate genotypic and phenotypic data in psychiatric research. METHOD: As part of the Cardiff MRC Mental Health Data Pathfinder initiative, we have curated and harmonised phenotypic and genetic information from 15 studies to create a new data repository, DRAGON-Data. To date, DRAGON-Data includes over 45 000 individuals: adults and children with neurodevelopmental or psychiatric diagnoses, affected probands within collected families and individuals who carry a known neurodevelopmental risk copy number variant. RESULTS: We have processed the available phenotype information to derive core variables that can be reliably analysed across groups. In addition, all data-sets with genotype information have undergone rigorous quality control, imputation, copy number variant calling and polygenic score generation. CONCLUSIONS: DRAGON-Data combines genetic and non-genetic information, and is available as a resource for research across traditional psychiatric diagnostic categories. Algorithms and pipelines used for data harmonisation are currently publicly available for the scientific community, and an appropriate data-sharing protocol will be developed as part of ongoing projects (DATAMIND) in partnership with Health Data Research UK.

Genetic Liabilities Differentiating Bipolar Disorder, Schizophrenia, and Major Depressive Disorder, and Phenotypic Heterogeneity in Bipolar Disorder.

Importance: Understanding the origins of clinical heterogeneity in bipolar disorder (BD) will inform new approaches to stratification and studies of underlying mechanisms. Objective: To identify components of genetic liability that are shared between BD, schizophrenia, and major depressive disorder (MDD) and those that differentiate each disorder from the others and to examine associations between heterogeneity for key BD symptoms and each component. Design, Setting, and Participants: Using data from the Bipolar Disorder Research Network in the United Kingdom, components of liability were identified by applying genomic structural equation modeling to genome-wide association studies of schizophrenia, BD, and MDD. Polygenic risk scores (PRS) representing each component were tested for association with symptoms in an independent BD data set. Adults with DSM-IV BD or schizoaffective disorder, bipolar type, were included. Data were collected from January 2000 to December 2013, and data were analyzed from June 2020 to February 2022. Main Outcomes and Measures: PRS representing the components of liability were tested for association with mania and depression, psychosis, and mood incongruence of psychosis in participants with BD, measured using the Bipolar Affective Disorder Dimensional Scale. Results: Of 4429 included participants, 3012 (68.0%) were female, and the mean (SD) age was 46.2 (12.3) years. Mania and psychosis were associated with the shared liability component (mania ß = 0.29; 95% CI, 0.23-0.34; P = 3.04 × 10-25; psychosis ß = 0.05; 95% CI, 0.04-0.07; P = 2.33 × 10-13) and the components that differentiate each of schizophrenia (mania ß = 0.08; 95% CI, 0.03-0.14; P = .002; psychosis ß = 0.03; 95% CI, 0.01-0.04; P = 1.0 × 10-4) and BD (mania ß = 0.14; 95% CI, 0.09-0.20; P = 1.99 × 10-7; psychosis ß = 0.02; 95% CI, 0.01-0.03; P = .006) from the other disorders. The BD differentiating component was associated with mania independently of effects on psychosis (ß = 0.14; 95% CI, 0.08-0.20; P = 4.32 × 10-6) but not with psychosis independently of mania. Conversely, the schizophrenia differentiating component was associated with psychosis independently of effects on mania (ß = 0.01; 95% CI, 0.003-0.03; P = .02), but not with mania independently of psychosis. Mood incongruence of psychosis was associated only with the schizophrenia differentiating component (ß = 0.03; 95% CI, 0.01-0.05; P = .005). Depression was associated with higher MDD differentiating component (ß = 0.07; 95% CI, 0.01-0.12; P = .01) but lower BD differentiating component (ß = -0.11; 95% CI, -0.17 to -0.06; P = 7.06 × 10-5). Conclusions and Relevance: In this study of BD, clinical heterogeneity reflected the burden of liability to BD and the contribution of alleles that have differentiating effects on risk for other disorders; mania, psychosis, and depression were associated with the components of genetic liability differentiating BD, MDD, and schizophrenia, respectively. Understanding the basis of this etiological heterogeneity will be critical for identifying the different pathophysiological processes underlying BD, stratifying patients, and developing precision therapeutics.

Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia.

We report results from the Bipolar Exome (BipEx) collaboration analysis of whole-exome sequencing of 13,933 patients with bipolar disorder (BD) matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in patients with BD among genes under strong evolutionary constraint in both major BD subtypes. We find enrichment of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from genome-wide association studies (GWASs) of BD, however, are not significantly enriched for ultra-rare PTVs. Combining gene-level results with SCHEMA, AKAP11 emerges as a definitive risk gene (odds ratio (OR) = 7.06, P = 2.83 × 10-9). At the protein level, AKAP-11 interacts with GSK3B, the hypothesized target of lithium, a primary treatment for BD. Our results lend support to BD's polygenicity, demonstrating a role for rare coding variation as a significant risk factor in BD etiology.

Neurodevelopmental hypothesis of schizophrenia.

The neurodevelopmental hypothesis of schizophrenia provided a valuable framework that allowed a condition that usually presents with frank disorder in adolescence or early adulthood to be understood at least in part as a consequence of events occurring early in development. However, the implications of the neurodevelopmental hypothesis for nosological conceptions of the disorder can only now be fully appreciated. Recent research indicates genetic overlap between schizophrenia and syndromes in which psychopathology is manifest in childhood and that are often grouped together as 'neurodevelopmental disorders' such as autism-spectrum disorders, intellectual disability and attention-deficit hyperactivity disorder. These findings challenge the aetiological basis of current diagnostic categories and, together with evidence for frequent comorbidity, suggest that we should view the functional psychoses as members of a group of related and overlapping syndromes that result in part from a combination of genetic and environmental effects on brain development and that are associated with specific and general impairments of cognitive function. This has important implications for future research and for the configuration of psychiatric services.

Genome-wide association identifies a common variant in the reelin gene that increases the risk of schizophrenia only in women.

Sex differences in schizophrenia are well known, but their genetic basis has not been identified. We performed a genome-wide association scan for schizophrenia in an Ashkenazi Jewish population using DNA pooling. We found a female-specific association with rs7341475, a SNP in the fourth intron of the reelin (RELN) gene (p = 2.9 x 10(-5) in women), with a significant gene-sex effect (p = 1.8 x 10(-4)). We studied rs7341475 in four additional populations, totaling 2,274 cases and 4,401 controls. A significant effect was observed only in women, replicating the initial result (p = 2.1 x 10(-3) in women; p = 4.2 x 10(-3) for gene-sex interaction). Based on all populations the estimated relative risk of women carrying the common genotype is 1.58 (p = 8.8 x 10(-7); p = 1.6 x 10(-5) for gene-sex interaction). The female-specific association between RELN and schizophrenia is one of the few examples of a replicated sex-specific genetic association in any disease.

Phenotype evaluation and genomewide linkage study of clinical variables in schizophrenia.

Genetic factors are likely to influence clinical variation in schizophrenia, but it is unclear which variables are most suitable as phenotypes and which molecular genetic loci are involved. We evaluated clinical variable phenotypes and applied suitable phenotypes in genome-wide covariate linkage analysis. We ascertained 170 affected relative pairs (168 sibling-pairs and two avuncular pairs) with DSM-IV schizophrenia or schizoaffective disorder from the United Kingdom. We defined psychotic symptom dimensions, age at onset (AAO), and illness course using the OPCRIT checklist. We evaluated phenotypes using within sibling-pair correlations and applied suitable phenotypes in multipoint covariate linkage analysis based on 372 microsatellite markers at ∼10 cM intervals. The statistical significance of linkage results was assessed by simulation. The positive and disorganized symptom dimensions, AAO, and illness course qualified as suitable phenotypes. There were no genome-wide significant linkage results. There was suggestive evidence of linkage for the positive dimension on chromosomes 2q32, 10q26, and 20q12; the disorganized dimension on 8p21 and 17q21; and illness course on 2q33 and 22q11. The linkage peak for disorganization on 17q21 remained suggestive after correction for multiple testing. To our knowledge, this is the first study to integrate phenotype evaluation and genome-wide covariate linkage analysis for symptom dimensions and illness history variables in sibling-pairs with schizophrenia. The significant within-pair correlations strengthen the evidence that some clinical variables within schizophrenia are suitable phenotypes for molecular genetic investigations. At present there are no genome-wide significant linkage results for these phenotypes, but a number of suggestive findings warrant further investigation.

Strong evidence that GNB1L is associated with schizophrenia.

Evidence that a gene or genes on chromosome 22 is involved in susceptibility to schizophrenia comes from two sources: the increased incidence of schizophrenia in individuals with 22q11 deletion syndrome (22q11DS) and genetic linkage studies. In mice, hemizygous deletion of either Tbx1 or Gnb1l can cause deficits in pre-pulse inhibition, a sensory motor gating defect which is associated with schizophrenia. We tested the hypothesis that variation at this locus confers risk of schizophrenia and related disorders in a series of case-control association studies. First, we found evidence for a male-specific genotypic association (P = 0.00017) TBX1/GNB1L in 662 schizophrenia cases and 1416 controls from the UK. Moreover, we replicated this finding in two independent case-control samples (additional 746 cases and 1330 controls) (meta analysis P = 1.8 x 10(-5)) and also observed significant evidence for genotypic association in an independent sample of 480 schizophrenia parent-proband trios from Bulgaria with markers at this locus, which was again strongest in the male probands (P = 0.004). Genotyping the most significant SNPs in a sample of 83 subjects with 22q11DS with and without psychosis again revealed a significant allelic association with psychosis in males with 22q11DS (P = 0.01). Finally, using allele specific expression analysis, we have shown that the markers associated with psychosis are also correlated with alterations in GNB1L expression, raising the hypothesis that the risk to develop psychosis at this locus could be mediated in a dose sensitive manner via gene expression. However, other explanations are possible, and further analyses will be required to clarify the correct functional mechanism.

Association Between Schizophrenia-Related Polygenic Liability and the Occurrence and Level of Mood-Incongruent Psychotic Symptoms in Bipolar Disorder.

Importance: Bipolar disorder (BD) overlaps schizophrenia in its clinical presentation and genetic liability. Alternative approaches to patient stratification beyond current diagnostic categories are needed to understand the underlying disease processes and mechanisms. Objective: To investigate the association between common-variant liability for schizophrenia, indexed by polygenic risk scores (PRSs), and psychotic presentations of BD. Design, Setting, and Participants: This case-control study in the United Kingdom used multinomial logistic regression to estimate differential PRS associations across categories of cases and controls. Participants included in the final analyses were 4436 cases of BD from the Bipolar Disorder Research Network. These cases were compared with the genotypic data for 4976 cases of schizophrenia and 9012 controls from the Type 1 Diabetes Genetics Consortium study and the Generation Scotland study. Data were collected between January 1, 2000, and December 31, 2013. Data analysis was conducted from March 1, 2016, to February 28, 2017. Exposures: Standardized PRSs, calculated using alleles with an association threshold of P < .05 in the second Psychiatric Genomics Consortium genome-wide association study of schizophrenia, were adjusted for the first 10 population principal components and genotyping platforms. Main Outcomes and Measures: Multinomial logit models estimated PRS associations with BD stratified by Research Diagnostic Criteria subtypes of BD, by lifetime occurrence of psychosis, and by lifetime mood-incongruent psychotic features. Ordinal logistic regression examined PRS associations across levels of mood incongruence. Ratings were derived from the Schedules for Clinical Assessment in Neuropsychiatry interview and the Bipolar Affective Disorder Dimension Scale. Results: Of the 4436 cases of BD, 2966 (67%) were female patients, and the mean (SD) age at interview was 46 [12] years. Across clinical phenotypes, there was an exposure-response gradient, with the strongest PRS association for schizophrenia (risk ratio [RR] = 1.94; 95% CI, 1.86-2.01), followed by schizoaffective BD (RR = 1.37; 95% CI, 1.22-1.54), bipolar I disorder subtype (RR = 1.30; 95% CI, 1.24-1.36), and bipolar II disorder subtype (RR = 1.04; 95% CI, 0.97-1.11). Within BD cases, there was an effect gradient, indexed by the nature of psychosis. Prominent mood-incongruent psychotic features had the strongest association (RR = 1.46; 95% CI, 1.36-1.57), followed by mood-congruent psychosis (RR = 1.24; 95% CI, 1.17-1.33) and BD with no history of psychosis (RR = 1.09; 95% CI, 1.04-1.15). Conclusions and Relevance: For the first time to date, a study shows a polygenic-risk gradient across schizophrenia and BD, indexed by the occurrence and level of mood-incongruent psychotic symptoms.

Mental health resilience in the adolescent offspring of parents with depression: a prospective longitudinal study.

BACKGROUND: Young people whose parents have depression have a greatly increased risk of developing a psychiatric disorder, but poor outcomes are not inevitable. Identification of the contributors to mental health resilience in young people at high familial risk is an internationally recognised priority. Our objectives were to identify protective factors that predict sustained good mental health in adolescents with a parent with depression and to test whether these contribute beyond what is explained by parent illness severity. METHODS: The Early Prediction of Adolescent Depression study (EPAD) is a prospective longitudinal study of offspring of parents with recurrent depression. Parents with recurrent major depressive disorder, co-parents, and offspring (aged 9-17 years at baseline) were assessed three times over 4 years in a community setting. Offspring outcomes were operationalised as absence of mental health disorder, subthreshold symptoms, or suicidality on all three study occasions (sustained good mental health); and better than expected mental health (mood and behavioural symptoms at follow-up lower than predicted given severity of parental depression). Family, social, cognitive, and health behaviour predictor variables were assessed using interview and questionnaire measures. FINDINGS: Between February and June, 2007, we screened 337 families at baseline, of which 331 were eligible. Of these, 262 completed the three assessments and were included in the data for sustained mental health. Adolescent mental health problems were common, but 53 (20%) of the 262 adolescents showed sustained good mental health. Index parent positive expressed emotion (odds ratio 1·91 [95% CI 1·31-2·79]; p=0·001), co-parent support (1·90 [1·38-2·62]; p<0·0001), good-quality social relationships (2·07 [1·35-3·18]; p=0·001), self-efficacy (1·49 [1·05-2·11]; p=0·03), and frequent exercise (2·96 [1·26-6·92]; p=0·01) were associated with sustained good mental health. Analyses accounting for parent depression severity were consistent, but frequent exercise only predicted better than expected mood-related mental health (ß=-0·22; p=0·0004) not behavioural mental health, whereas index parents' expression of positive emotions predicted better than expected behavioural mental health (ß=-0·16; p=0·01) not mood-related mental health. Multiple protective factors were required for offspring to be free of mental health problems (zero or one protective factor, 4% sustained good mental health; two protective factors, 10%; three protective factors, 13%, four protective factors, 38%; five protective factors, 48%). INTERPRETATION: Adolescent mental health problems are common, but not inevitable, even when parental depression is severe and recurrent. These findings suggest that prevention programmes will need to enhance multiple protective factors across different domains of functioning. FUNDING: Sir Jules Thorn Charitable Trust, Economic and Social Research Council.

Detecting recurrent major depressive disorder within primary care rapidly and reliably using short questionnaire measures.

BACKGROUND: Major depressive disorder (MDD) is often a chronic disorder with relapses usually detected and managed in primary care using a validated depression symptom questionnaire. However, for individuals with recurrent depression the choice of which questionnaire to use and whether a shorter measure could suffice is not established. AIM: To compare the nine-item Patient Health Questionnaire (PHQ-9), the Beck Depression Inventory, and the Hospital Anxiety and Depression Scale against shorter PHQ-derived measures for detecting episodes of DSM-IV major depression in primary care patients with recurrent MDD. DESIGN AND SETTING: Diagnostic accuracy study of adults with recurrent depression in primary care predominantly from Wales METHOD: Scores on each of the depression questionnaire measures were compared with the results of a semi-structured clinical diagnostic interview using Receiver Operating Characteristic curve analysis for 337 adults with recurrent MDD. RESULTS: Concurrent questionnaire and interview data were available for 272 participants. The one-month prevalence rate of depression was 22.2%. The area under the curve (AUC) and positive predictive value (PPV) at the derived optimal cut-off value for the three longer questionnaires were comparable (AUC = 0.86-0.90, PPV = 49.4-58.4%) but the AUC for the PHQ-9 was significantly greater than for the PHQ-2. However, by supplementing the PHQ-2 score with items on problems concentrating and feeling slowed down or restless, the AUC (0.91) and the PPV (55.3%) were comparable with those for the PHQ-9. CONCLUSION: A novel four-item PHQ-based questionnaire measure of depression performs equivalently to three longer depression questionnaires in identifying depression relapse in patients with recurrent MDD.

Investigating the genetic variation underlying episodicity in major depressive disorder: suggestive evidence for a bipolar contribution.

BACKGROUND: Highly recurrent major depressive disorder (MDD) has reportedly increased risk of shifting to bipolar disorder; high recurrence frequency has, therefore, featured as evidence of 'soft bipolarity'. We aimed to investigate the genetic underpinnings of total depressive episode count in recurrent MDD. METHODS: Our primary sample included 1966 MDD cases with negative family history of bipolar disorder from the RADIANT studies. Total episode count was adjusted for gender, age, MDD duration, study and center before being tested for association with genotype in two separate genome-wide analyses (GWAS), in the full set and in a subset of 1364 cases with positive family history of MDD (FH+). We also calculated polygenic scores from the Psychiatric Genomics Consortium MDD and bipolar disorder studies. RESULTS: Episodicity (especially intermediate episode counts) was an independent index of MDD familial aggregation, replicating previous reports. The GWAS produced no genome-wide significant findings. The strongest signals were detected in the full set at MAGI1 (p=5.1×10(-7)), previously associated with bipolar disorder, and in the FH+ subset at STIM1 (p=3.9×10(-6) after imputation), a calcium channel signaling gene. However, these findings failed to replicate in an independent Munich cohort. In the full set polygenic profile analyses, MDD polygenes predicted episodicity better than bipolar polygenes; however, in the FH+ subset, both polygenic scores performed similarly. LIMITATIONS: Episode count was self-reported and, therefore, subject to recall bias. CONCLUSIONS: Our findings lend preliminary support to the hypothesis that highly recurrent MDD with FH+ is part of a 'soft bipolar spectrum' but await replication in larger cohorts.