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 22 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 SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 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 and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).

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.

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.

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.

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.

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.

Common and rare variant analysis in early-onset bipolar disorder vulnerability.

Bipolar disorder is one of the most common and devastating psychiatric disorders whose mechanisms remain largely unknown. Despite a strong genetic contribution demonstrated by twin and adoption studies, a polygenic background influences this multifactorial and heterogeneous psychiatric disorder. To identify susceptibility genes on a severe and more familial sub-form of the disease, we conducted a genome-wide association study focused on 211 patients of French origin with an early age at onset and 1,719 controls, and then replicated our data on a German sample of 159 patients with early-onset bipolar disorder and 998 controls. Replication study and subsequent meta-analysis revealed two genes encoding proteins involved in phosphoinositide signalling pathway (PLEKHA5 and PLCXD3). We performed additional replication studies in two datasets from the WTCCC (764 patients and 2,938 controls) and the GAIN-TGen cohorts (1,524 patients and 1,436 controls) and found nominal P-values both in the PLCXD3 and PLEKHA5 loci with the WTCCC sample. In addition, we identified in the French cohort one affected individual with a deletion at the PLCXD3 locus and another one carrying a missense variation in PLCXD3 (p.R93H), both supporting a role of the phosphatidylinositol pathway in early-onset bipolar disorder vulnerability. Although the current nominally significant findings should be interpreted with caution and need replication in independent cohorts, this study supports the strategy to combine genetic approaches to determine the molecular mechanisms underlying bipolar disorder.

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.

Identifying gene-environment interactions in schizophrenia: contemporary challenges for integrated, large-scale investigations.

Recent years have seen considerable progress in epidemiological and molecular genetic research into environmental and genetic factors in schizophrenia, but methodological uncertainties remain with regard to validating environmental exposures, and the population risk conferred by individual molecular genetic variants is small. There are now also a limited number of studies that have investigated molecular genetic candidate gene-environment interactions (G × E), however, so far, thorough replication of findings is rare and G × E research still faces several conceptual and methodological challenges. In this article, we aim to review these recent developments and illustrate how integrated, large-scale investigations may overcome contemporary challenges in G × E research, drawing on the example of a large, international, multi-center study into the identification and translational application of G × E in schizophrenia. While such investigations are now well underway, new challenges emerge for G × E research from late-breaking evidence that genetic variation and environmental exposures are, to a significant degree, shared across a range of psychiatric disorders, with potential overlap in phenotype.

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.

Specific parental depression symptoms as risk markers for new-onset depression in high-risk offspring.

OBJECTIVE: To disaggregate the depression construct and investigate whether specific depression symptoms in parents with a history of recurrent depression are clinical risk markers for future depression in their high-risk offspring. Our hypothesis was that parental symptoms of the type that might impact offspring would most likely be of greatest importance. METHOD: Data were drawn from a longitudinal high-risk family study. Families were mainly recruited from primary care and included 337 parent-child dyads. Parents had a history of recurrent DSM-IV unipolar depression and were aged 26-55 years. Their offspring (197 female and 140 male) were aged 9-17 years. Three assessments were conducted between April 2007 and April 2011. Ninety-one percent of families (n = 305) provided full interview data at baseline and at least 1 follow-up, of which 291 were included in the primary analysis. The main outcome measure was new-onset DSM-IV mood disorder in the offspring, which was assessed using the Child and Adolescent Psychiatric Assessment. RESULTS: Of the 9 DSM-IV depression symptoms, parental change in appetite or weight, specifically loss of appetite or weight, most strongly predicted new-onset mood disorder (odds ratio [OR] = 4.47; 95% CI, 2.04-9.79; P < .001) and future depression symptoms in the offspring (ß = 0.12; B = 0.21; 95% CI, 0.00-0.42; P = .050). The cross-generational association was not accounted for by measures of parental depression severity (total depression symptom score, episode recurrence, age at onset, and past impairment or hospitalization) or other potential confounds (parent physical health, eating disorder, or medication). CONCLUSIONS: Findings from this study suggest that loss of appetite or weight in parents with a history of recurrent depression is a marker of risk for depression in their offspring. The findings highlight the importance of examining depression heterogeneity. The biological and environmental mechanisms underlying this finding require investigation.

Perinatal episodes across the mood disorder spectrum.

CONTEXT Affective disorders are common in women, with many episodes having an onset in pregnancy or during the postpartum period. OBJECTIVE To investigate the occurrence and timing of perinatal mood episodes in women with bipolar I disorder, bipolar II disorder, and recurrent major depression (RMD). SETTING AND PATIENTS Women were recruited in our ongoing research on the genetic and nongenetic determinants of major affective disorders. Participants were interviewed and case notes were reviewed. Best-estimate diagnoses were made according to DSM-IV criteria. The 1785 parous women identified included 1212 women with bipolar disorder (980 with type I and 232 with type II) and 573 with RMD. Data were available on 3017 live births. MAIN OUTCOME MEASURES We report the lifetime occurrence of perinatal mood episodes, the rates of perinatal episodes per pregnancy/postpartum period, and the timing of the onset of episodes in relation to delivery. RESULTS More than two-thirds of all diagnostic groups reported at least 1 lifetime episode of illness during pregnancy or the postpartum period. Women with bipolar I disorder reported an approximately 50% risk of a perinatal major affective episode per pregnancy/postpartum period. Risks were lower in women with RMD or bipolar II disorder, at approximately 40% per pregnancy/postpartum period. Mood episodes were significantly more common in the postpartum period in bipolar I disorder and RMD. Most perinatal episodes occurred within the first postpartum month, with mania or psychosis having an earlier onset than depression. CONCLUSIONS Although episodes of postpartum mood disorder are more common in bipolar I disorder and manic and psychotic presentations occur earlier in the postpartum period, perinatal episodes are highly prevalent across the mood disorder spectrum.

Missed opportunities: mental disorder in children of parents with depression.

BACKGROUND: Emerging evidence suggests that early intervention and prevention programmes for mental health problems in the offspring of parents with depression are important. Such programmes are difficult to implement if children with psychiatric disorder are not identified and are not accessing services, even if their parents are known to primary care. AIM: To investigate service use in children of parents who have recurrent depression, and factors that influence such contact. DESIGN AND SETTING: A total of 333 families were recruited, mainly through primary health care, in which at least one parent had received treatment for recurrent depression and had a child aged 9-17 years. METHOD: Psychiatric assessments of parents and children were completed using research diagnostic interviews. The service-use interview recorded current (in the 3 months prior to interview) and lifetime contact with health, educational, and social services due to concerns about the child's emotions or behaviour. RESULTS: Only 37% of children who met criteria for psychiatric disorder were in contact with any service at the time of interview. A third, who were suicidal or self-harming and had a psychiatric disorder at that time, were not in contact with any service. Lack of parental worry predicted lower service use, with higher rates in children with comorbidity and suicidality. CONCLUSION: Most children with a psychiatric disorder in this high-risk sample were not in contact with services. Improving ease of access to services, increasing parental and professional awareness that mental health problems can cluster in families, and improving links between adult and child services may help early detection and intervention strategies for the offspring of parents with depression.

Do parents know best? Parent-reported vs. child-reported depression symptoms as predictors of future child mood disorder in a high-risk sample.

BACKGROUND: Parents with depression are thought to be unreliable reporters of children's depression symptoms, but findings are contradictory and primarily focus on discrepancies between parent and child reports rather than on the predictive validity of informants. Using a sample of parents with recurrent depression, our analyses utilised data from a prospective high-risk longitudinal study (the Early Prediction of Adolescent Depression study) to investigate whether baseline parental reports of child depression symptoms predicted new onset mood disorder (NOMD) in children. METHODS: The sample included 287 parents with a history of recurrent depression and their adolescent offspring (aged 9-17 at baseline). Families were assessed at three time points. The Child and Adolescent Psychiatric assessment (parent and child versions) was used to assess the number of child depression symptoms (computed separately by informant at baseline) and NOMD at follow-up. All DSM-IV diagnoses were confirmed by two child psychiatrists. RESULTS: Parent reports of child depression symptoms at baseline significantly predicted NOMD in children. Secondary analyses stratifying the sample according to child age showed that, for younger children, parent reports were significantly better at predicting NOMD compared to child reports. For children aged 12 or older, there were no significant differences between parent and child reports in predicting NOMD. The pattern of association remained the same once we controlled for baseline levels of parental depression. LIMITATIONS: Not all parents were currently experiencing an episode of depression at the baseline assessments; the sample consisted predominantly of mothers, thus findings may not be applicable to fathers or families without a history of parental depression. CONCLUSIONS: In this high risk sample, child and parent ratings of depression predict new onset child mood disorder to a similar degree. Clinicians and researchers should give due consideration to parent ratings of their children's depression symptoms, regardless of whether the parent suffers with depression.

Permutation-based approaches do not adequately allow for linkage disequilibrium in gene-wide multi-locus association analysis.

Additional information about risk genes or risk pathways for diseases can be extracted from genome-wide association studies through analyses of groups of markers. The most commonly employed approaches involve combining individual marker data by adding the test statistics, or summing the logarithms of their P-values, and then using permutation testing to derive empirical P-values that allow for the statistical dependence of single-marker tests arising from linkage disequilibrium (LD). In the present study, we use simulated data to show that these approaches fail to reflect the structure of the sampling error, and the effect of this is to give undue weight to correlated markers. We show that the results obtained are internally inconsistent in the presence of strong LD, and are externally inconsistent with the results derived from multi-locus analysis. We also show that the results obtained from regression and multivariate Hotelling T(2) (H-T2) testing, but not those obtained from permutations, are consistent with the theoretically expected distributions, and that the H-T2 test has greater power to detect gene-wide associations in real datasets. Finally, we show that while the results from permutation testing can be made to approximate those from regression and multivariate Hotelling T(2) testing through aggressive LD pruning of markers, this comes at the cost of loss of information. We conclude that when conducting multi-locus analyses of sets of single-nucleotide polymorphisms, regression or multivariate Hotelling T(2) testing, which give equivalent results, are preferable to the other more commonly applied approaches.

Offspring of parents with recurrent depression: which features of parent depression index risk for offspring psychopathology?

BACKGROUND: Parental depression is associated with an increased risk of psychiatric disorder in offspring, although outcomes vary. At present relatively little is known about how differences in episode timing, severity, and course of recurrent depression relate to risk in children. The aim of this study was to consider the offspring of parents with recurrent depression and examine whether a recent episode of parental depression indexes risk for offspring psychopathology over and above these other parental depression features. METHODS: Three hundred and thirty seven recurrently depressed parents and their offspring (aged 9-17) were interviewed as part of an ongoing study, the 'Early Prediction of Adolescent Depression Study'. The Child and Adolescent Psychiatric Assessment was used to assess two child outcomes; presence of a DSM-IV psychiatric disorder and number of DSM-IV child-rated depression symptoms. RESULTS: Children whose parents had experienced a recent episode of depression reported significantly more depression symptoms, and odds of child psychiatric disorder were doubled relative to children whose parents had not experienced a recent episode of depression. Past severity of parental depression was also significantly associated with child depression symptoms. LIMITATIONS: Statistical analyses preclude causal conclusions pertaining to parental depression influences on offspring psychopathology; several features of parental depression were recalled retrospectively. CONCLUSIONS: This study suggests that particular features of parental depression, specifically past depression severity and presence of a recent episode, may be important indicators of risk for child psychiatric disorder and depressive symptoms.