[Show abstract][Hide abstract] ABSTRACT: Objectives
Darier disease is an autosomal dominant skin disorder caused by mutations in the ATPase, Ca++ transporting, cardiac muscle, slow twitch 2 (ATP2A2) gene and previously reported to cosegregate with bipolar disorder and schizophrenia in occasional pedigrees. It is, however, unknown whether these associations exist also in the general population, and the objective of this study was to examine this question.
We compared a national sample of individuals with Darier disease and their first-degree relatives with matched unexposed individuals from the general population and their first-degree relatives, respectively. To examine risks for bipolar disorder and schizophrenia, risk ratios and 95% confidence intervals (CIs) were estimated using conditional logistic regressions.
Individuals with Darier disease had a 4.3 times higher risk of being diagnosed with bipolar disorder (95% CI: 2.6–7.3) and a 2.3 times higher risk of being diagnosed with schizophrenia (95% CI: 1.1–5.2) than matched individuals from the general population. Relatives of individuals with Darier disease had a 1.6 times higher risk of having bipolar disorder (95% CI: 1.1–2.5) than relatives of matched individuals from the general population, but no increased risk of schizophrenia (risk ratio = 0.8, 95% CI: 0.4–1.8).
The association between Darier disease and bipolar disorder is manifest also in the population, and our data suggest that genetic variability within the ATP2A2 gene that causes Darier disease also confers susceptibility for bipolar disorder. The Darier-causing mutations merit additional attention in molecular genetic research on bipolar disorder.
[Show abstract][Hide abstract] ABSTRACT: Clinical, genetic and neuroimaging studies indicated strong evidence against traditional diagnostic separation of bipolar disorder from schizophrenia. In this study, we aimed to evaluate hypomanic symptoms and influence on general functioning among psychotic patients.
[Show abstract][Hide abstract] ABSTRACT: Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.
[Show abstract][Hide abstract] ABSTRACT: Background
Previous studies on the association between adiposity and mood disorder have produced
contradictory results, and few have used measurements other than body mass index (BMI).
We examined the association between probable major depression and several measurements
of adiposity: BMI, waist circumference (WC), waist-hip-ratio (WHR), and body fat
We conducted a cross-sectional study using baseline data on the sub-group of UK Biobank
participants who were assessed for mood disorder. Multivariate logistic regression models
were used, adjusting for potential confounders including: demographic and life-style factors,
comorbidity and psychotropic medication.
Of the 140,564 eligible participants, evidence of probable major depression was reported by
30,145 (21.5%). The fully adjusted odds ratios (OR) for obese participants were 1.16 (95%
confidence interval (CI) 1.12, 1.20) using BMI, 1.15 (95% CI 1.11, 1.19) using WC, 1.09
(95% CI 1.05, 1.13) using WHR and 1.18 (95% CI 1.12, 1.25) using BF% (all p < 0.001).
There was a significant interaction between adiposity and gender (p = 0.001). Overweight
women were at increased risk of depression with a dose response relationship across the
overweight (25.0-29.9 kg/m2
), obese I (30.0-34.9 kg/m2
), II (35.0-39.9 kg/m2
) and III (≥40.0
) categories; fully adjusted ORs 1.14, 1.20, 1.29 and 1.48, respectively (all p < 0.001).
In contrast, only obese III men had significantly increased risk of depression (OR 1.29, 95%
CI 1.08, 1.54, p = 0.006).
Adiposity was associated with probable major depression, irrespective of the measurement
used. The association was stronger in women than men. Physicians managing overweight and
obese women should be alert to this increased risk
[Show abstract][Hide abstract] ABSTRACT: Obesity has been shown to be associated with depression and it has been suggested that higher body mass index (BMI) increases the risk of depression and other common mental disorders. However, the causal relationship remains unclear and Mendelian randomisation, a form of instrumental variable analysis, has recently been employed to attempt to resolve this issue.
To investigate whether higher BMI increases the risk of major depression.
Two instrumental variable analyses were conducted to test the causal relationship between obesity and major depression in RADIANT, a large case-control study of major depression. We used a single nucleotide polymorphism (SNP) in FTO and a genetic risk score (GRS) based on 32 SNPs with well-established associations with BMI.
Linear regression analysis, as expected, showed that individuals carrying more risk alleles of FTO or having higher score of GRS had a higher BMI. Probit regression suggested that higher BMI is associated with increased risk of major depression. However, our two instrumental variable analyses did not support a causal relationship between higher BMI and major depression (FTO genotype: coefficient -0.03, 95% CI -0.18 to 0.13, P = 0.73; GRS: coefficient -0.02, 95% CI -0.11 to 0.07, P = 0.62).
Our instrumental variable analyses did not support a causal relationship between higher BMI and major depression. The positive associations of higher BMI with major depression in probit regression analyses might be explained by reverse causality and/or residual confounding.
The British journal of psychiatry: the journal of mental science 05/2014; · 6.62 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Psychiatric diagnosis is in the spotlight following the recent publication of DSM-5. In this article we consider both the benefits and limitations of diagnosis in psychiatry. The use of internationally recognised diagnoses, although insufficient alone, is part of a psychiatrist's professional responsibility to provide high-quality, evidence-based care for patients.
The British journal of psychiatry: the journal of mental science 02/2014; 204:93-5. · 6.62 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Identifying rare, highly penetrant risk mutations may be an important step in dissecting the molecular etiology of schizophrenia. We conducted a gene-based analysis of large (>100kb), rare copy number variants (CNVs) in the Wellcome Trust Case Control Consortium 2 (WTCCC2) schizophrenia sample of 1,564 cases and 1,748 controls all from Ireland, and further extended the analysis to include an additional 5,196 UK controls. We found association with duplications at chr20p12.2 (P=0.007) and evidence of replication in large independent European schizophrenia (P=0.052) and UK bipolar disorder case-control cohorts (P=0.047). A combined analysis of Irish/UK subjects including additional psychosis cases (schizophrenia and bipolar disorder) identified 22 carriers in 11,707 cases and 10 carriers in 21,204 controls (meta-analysis CMH P value=2x10(-4) (odds ratio (OR)=11.3, 95% CI=3.7, ∞)). Nineteen of the 22 cases and 8 of the 10 controls carried duplications starting at 9.68Mb with similar breakpoints across samples. By haplotype analysis and sequencing we identified a tandem ∼149kb duplication overlapping the gene p21 Protein-Activated Kinase 7 (PAK7, also called PAK5) which was in linkage disequilibrium with local haplotypes (P=2.5x10(-21)), indicative of a single ancestral duplication event. We confirmed the breakpoints in 8/8 carriers tested and found co-segregation of the duplication with illness in two additional family members of one of the affected probands. We demonstrate that PAK7 is developmentally co-expressed with another known psychosis risk gene (DISC1) suggesting a potential molecular mechanism involving aberrant synapse development and plasticity.
Human Molecular Genetics 01/2014; · 7.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Episodes of postpartum psychosis have been associated with first pregnancies in women with bipolar I disorder. It is unclear, however, if the effect extends to episodes at other times in relation to childbirth and to women with other mood disorders such as major depression and bipolar II disorder. This primiparity effect, which is also seen in other pregnancy related conditions such as pre-eclampsia, is a potentially important clue to the aetiology of childbirth related mood episodes.
Participants were interviewed and case notes reviewed. Best-estimate diagnoses were made according to DSM-IV criteria. Data on the occurrence of episodes in pregnancy and the postpartum were available on 3345 full term deliveries from 1667 participants, 934 with bipolar I disorder (BD-I), 278 with bipolar II disorder (BD-II) and 455 with recurrent major depression (RMD).
Onsets of psychosis/mania within 6 weeks of childbirth were overrepresented in primiparae (p=0.007) with BD-I. Although primiparity was not associated with perinatal bipolar depression, there was an association with the onset of depression within 6 weeks in women with RMD (p=0.035). Whilst women experiencing a postpartum episode were less likely to go on to have further children, this did not account for the association with primiparity.
Data were collected retrospectively. Information on pharmacological treatment was not available.
Primiparity is associated not only with postpartum psychosis/mania in BD-I, but also with postpartum depression in RMD. Psychosocial factors and biological differences between first and subsequent pregnancies may play a role and are candidates for examination in further studies.
Journal of affective disorders 01/2014; s 152–154:334–339. · 3.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Obesity is known to increase the risk of many diseases and reduce overall quality of life. This study examines the relationship with self-reported health (SRH) and happiness.
We conducted a cross-sectional study of the 163 066 UK Biobank participants who completed the happiness rating. The association between adiposity and SRH and happiness was examined using logistic regression. SRH was defined as good (excellent, good), or poor (fair, poor). Self-reported happiness was defined as happy (extremely, very, moderately) or unhappy (moderately, very, extremely).
Poor health was reported by 44 457 (27.3%) participants. The adjusted ORs for poor health were 3.86, 2.92, 2.60 and 6.41 for the highest, compared with lowest, deciles of Body Mass Index, waist circumference, waist to hip ratio and body fat percent, respectively. The associations were stronger in men (p<0.001). Overall, 7511 (4.6%) participants felt unhappy, and only class III obese participants were more likely to feel unhappy (adjusted OR 1.33, 95% CI 1.15 to 1.53, p<0.001) but the associations differed by sex (p<0.001). Among women, there was a significant association between unhappiness and all levels of obesity. By contrast, only class III obese men had significantly increased risk and overweight and class I obese men were less likely to be unhappy.
Obesity impacts adversely on happiness as well as health, but the association with unhappiness disappeared after adjustment for self-reported health, indicating this may be mediated by health. Compared with obese men, obese women are less likely to report poor health, but more likely to feel unhappy.
Journal of epidemiology and community health 12/2013; · 3.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The HCL-32 is a widely-used screening questionnaire for hypomania. We aimed to use a Rasch analysis approach to (i) evaluate the measurement properties, principally unidimensionality, of the HCL-32, and (ii) generate a score table to allow researchers to convert raw HCL-32 scores into an interval-level measurement which will be more appropriate for statistical analyses.
Subjects were part of the Bipolar Disorder Research Network (BDRN) study with DSM-IV bipolar disorder (n=389). Multidimensionality was assessed using the Rasch fit statistics and principle components analysis of the residuals (PCA). Item invariance (differential item functioning, DIF) was tested for gender, bipolar diagnosis and current mental state. Item estimates and reliabilities were calculated.
Three items (29, 30, 32) had unacceptable fit to the Rasch unidimensional model. Item 14 displayed significant DIF for gender and items 8 and 17 for current mental state. Item estimates confirmed that not all items measure hypomania equally.
This sample was recruited as part of a large ongoing genetic epidemiology study of bipolar disorder and may not be fully representative of the broader clinical population of individuals with bipolar disorder.
The HCL-32 is unidimensional in practice, but measurements may be further strengthened by the removal of four items. Re-scored linear measurements may be more appropriate for clinical research.
Journal of affective disorders 10/2013; · 3.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Large, rare chromosomal copy number variants (CNVs) have been shown to increase the risk for schizophrenia and other neuropsychiatric disorders including autism, attention-deficit hyperactivity disorder, learning difficulties, and epilepsy. Their role in bipolar disorder (BD) is less clear. There are no reports of an increase in large, rare CNVs in BD in general, but some have reported an increase in early-onset cases. We previously found that the rate of such CNVs in individuals with BD was not increased, even in early-onset cases. Our aim here was to examine the rate of large rare CNVs in BD in comparison with a new large independent reference sample from the same country.
We studied the CNVs in a case-control sample consisting of 1,650 BD cases (reported previously) and 10,259 reference individuals without a known psychiatric disorder who took part in the original Wellcome Trust Case Control Consortium (WTCCC) study. The 10,259 reference individuals were affected with six non-psychiatric disorders (coronary artery disease, types 1 and 2 diabetes, hypertension, Crohn's disease, and rheumatoid arthritis). Affymetrix 500K array genotyping data were used to call the CNVs.
The rate of CNVs > 100 kb was not statistically different between cases and controls. The rate of very large (defined as > 1 Mb) and rare (< 1%) CNVs was significantly lower in patients with BD compared with the reference group. CNV loci associated with schizophrenia were not enriched in BD and, in fact, cases of BD had the lowest number of such CNVs compared with any of the WTCCC cohorts; this finding held even for the early-onset BD cases.
Schizophrenia and BD differ with respect to CNV burden and association with specific CNVs. Our findings support the hypothesis that BD is etiologically distinct from schizophrenia with respect to large, rare CNVs and the accompanying associated neurodevelopmental abnormalities.
[Show abstract][Hide abstract] ABSTRACT: Objectives. Co-morbidity between depression and anxiety disorders is common. In this study we define a quantitative measure of anxiety by summating four anxiety items from the SCAN interview in a large collection of major depression (MDD) cases to identify genes contributing to this complex phenotype. Methods. A total of 1522 MDD cases dichotomised according to those with at least one anxiety item scored (n = 1080) and those without anxiety (n = 442) were analysed, and also compared to 1588 healthy controls at a genome-wide level, to identify genes that may contribute to anxiety in MDD. Results. For the quantitative trait, suggestive evidence of association was detected for two SNPs, and for the dichotomous anxiety present/absent ratings for three SNPs at genome-wide level. In the genome-wide analysis of MDD cases with co-morbid anxiety and healthy controls, two SNPs attained P values of < 5 × 10(-6). Analysing candidate genes, P values ≤ 0.0005 were found with three SNPs for the quantitative trait and three SNPs for the dichotomous trait. Conclusions. This study provides an initial genome-wide assessment of possible genetic contribution to anxiety in MDD. Although suggestive evidence of association was found for several SNPs, our findings suggest that there are no common variants strongly associated with anxious depression.
The World Journal of Biological Psychiatry 09/2013; · 3.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: TSPO mediated transport of cholesterol into the mitochondrion is a necessary step in steroid synthesis. The rs6971 polymorphism in the TSPO gene causes an amino acid substitution (Ala147Thr) within the transmembrane domain where the cholesterol-binding pocket is located, and has been shown to affect the steroidogenic pathway. We report a nominal association between this TSPO polymorphism and the diagnosis of Bipolar Disorder in both the genome-wide dataset of the Wellcome Trust Case-Control Consortium and the Psychiatric Genome-Wide Association Study Consortium Bipolar Disorder group (OR=1.11, p=0.007; OR=1.10, p=0.011, respectively). We propose that the amino acid substitution affects hypothalamic-pituitary-adrenal (HPA) regulation, and hence may predispose to Bipolar Disorder. This supports the hypothesis that HPA dysregulation has a causal role in Bipolar Disorder, and is not just a consequence of the disease.
[Show abstract][Hide abstract] ABSTRACT: Disruption in the parent-child relationship is a commonly hypothesized risk factor through which maternal depression may increase risk for offspring psychopathology. However, maternal depression is commonly accompanied by other psychopathology, including antisocial behaviour. Few studies have examined the role of co-occurring psychopathology in depressed mothers. Using a longitudinal study of offspring of mothers with recurrent depression, we aimed to test whether maternal warmth/hostility mediated links between maternal depression severity and child outcomes, and how far direct and indirect pathways were robust to controls for co-occurring maternal antisocial behaviour.
Mothers with a history of recurrent major depressive disorder and their adolescent offspring (9-17 years at baseline) were assessed three times between 2007 and 2010. Mothers completed questionnaires assessing their own depression severity and antisocial behaviour at Time 1 (T1). The parent-child relationship was assessed using parent-rated questionnaire and interviewer-rated 5-min speech sample at Time 2 (T2). Offspring symptoms of depression and disruptive behaviours were assessed using the Child and Adolescent Psychiatric Assessment at Time 3 (T3).
Maternal hostility and warmth, respectively, mediated the association between maternal depression severity and risk for offspring psychopathology. However, the effects were attenuated when maternal antisocial behaviour was included in the analysis. In tests of the full theoretical model, maternal antisocial behaviour predicted both maternal hostility and low warmth, maternal hostility predicted offspring disruptive behaviour disorder symptoms, but not depression, and maternal warmth was not associated with either child outcome.
Parenting interventions aimed at reducing hostility may be beneficial for preventing or reducing adolescent disruptive behaviours in offspring of depressed mothers, especially when depressed mothers report co-occurring antisocial behaviour.
Journal of Child Psychology and Psychiatry 06/2013; · 5.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Schizophrenia (SCZ) is a devastating psychiatric condition. Identifying the specific genetic variants and pathways that increase susceptibility to SCZ is critical to improve disease understanding and address the urgent need for new drug targets.
To identify SCZ susceptibility genes.
We integrated results from a meta-analysis of 18 genome-wide association studies (GWAS) involving 1,085,772 single-nucleotide polymorphisms (SNPs) and 6 databases that showed significant informativeness for SCZ. The 9380 most promising SNPs were then specifically genotyped in an independent family-based replication study that, after quality control, consisted of 8107 SNPs.
Linkage meta-analysis, brain transcriptome meta-analysis, candidate gene database, OMIM, relevant mouse studies, and expression quantitative trait locus databases.
We included 11,185 cases and 10,768 control subjects from 6 databases and, after quality control 6298 individuals (including 3286 cases) from 1811 nuclear families.
Case-control status for SCZ.
Replication results showed a highly significant enrichment of SNPs with small P values. Of the SNPs with replication values of P.01, the proportion of SNPs that had the same direction of effects as in the GWAS meta-analysis was 89% in the combined ancestry group (sign test, P < 2.20 x 10(-16) and 93% in subjects of European ancestry only (P < 2.20 < 10(-16)). Our results supported the major histocompatibility complex region showing a3.7-fold overall enrichment of replication values of P < .01 in subjects from European ancestry. We replicated SNPs in TCF4 (P = 2.53 x 10(-10)) and NOTCH4 (P = 3.16 x 10(-7)) that are among the most robust SCZ findings. More novel findings included POM121L2 (P = 3.51 x 10(-7)), AS3MT (P = 9.01 x 10(-7)), CNNM2 (P = 6.07 = 10(-7)), and NT5C2(P = 4.09 x 10(-7)). To explore the many small effects, we performed pathway analyses. The most significant pathways involved neuronal function (axonal guidance, neuronal systems, and L1 cell adhesion molecule interaction)and the immune system (antigen processing, cell adhesion molecules relevant to T cells, and translocation to immunological synapse).
We replicated novel SCZ disease genes and pathogenic pathways. Better understanding the molecular and biological mechanisms involved with schizophrenia may improve disease management and may identify new drug targets.
Archives of General Psychiatry 06/2013; 70(6):573-81. · 13.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: There is recent evidence of some degree of shared genetic susceptibility between adult schizophrenia and childhood attention-deficit hyperactivity disorder (ADHD) for rare chromosomal variants. AIMS: To determine whether there is overlap between common alleles conferring risk of schizophrenia in adults with those that do so for ADHD in children. METHOD: We used recently published Psychiatric Genome-wide Association Study (GWAS) Consortium (PGC) adult schizophrenia data to define alleles over-represented in people with schizophrenia and tested whether those alleles were more common in 727 children with ADHD than in 2067 controls. RESULTS: Schizophrenia risk alleles discriminated ADHD cases from controls (P = 1.04 × 10(-4), R(2) = 0.45%); stronger discrimination was given by alleles that were risk alleles for both adult schizophrenia and adult bipolar disorder (also derived from a PGC data-set) (P = 9.98 × 10(-6), R(2) = 0.59%). CONCLUSIONS: This increasing evidence for a small, but significant, shared genetic susceptibility between adult schizophrenia and childhood ADHD highlights the importance of research work across traditional diagnostic boundaries.
The British journal of psychiatry: the journal of mental science 05/2013; · 6.62 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVES: Women who experience postpartum psychosis (PP) seek guidance on further pregnancies and risk of illness; however, empirical data are limited. This study describes reproductive and mental health outcomes in women diagnosed with PP and examines clinical risk factors as predictors of further illness. METHODS: A retrospective cohort design was used; 116 women who experienced episodes of mania or depression with psychotic features within six weeks of childbirth were recruited. All subjects underwent clinical diagnostic interviews and medical case notes were reviewed. RESULTS: Only 33% of women had an antecedent history, of which 34% had bipolar disorder and 55% unipolar depression. Only 58% of those with PP in their first pregnancy had a subsequent pregnancy, and 18% of marriages ended following the PP episode. Clinical presentation at the time of initial episode did not influence the timing of the onset of symptoms, treatment, or recovery. Although 86% of patients received treatment within 30 days of onset, 26% of women reported ongoing symptoms at a year after delivery. The recurrence rate of PP was 54.4%; a longer duration of the index episode (p < 0.05) and longer latency between the index PP and next pregnancy predicted a subsequent PP. The rate of subsequent non-puerperal episodes was 69%, and all these episodes were bipolar. CONCLUSIONS: Postpartum psychosis is difficult to predict in women with no antecedent history and is associated with a high rate of subsequent puerperal and non-puerperal illness. Risk of further illness needs to be conveyed in order to allow fully informed decisions to be made regarding future pregnancies.