[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: 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.
British Journal of General Practice 01/2014; 64(618):e31-7. · 1.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Epidemiological and genetic data support the notion that schizophrenia and bipolar disorder share genetic risk factors. In our previous genome-wide association study, meta-analysis and follow-up (totaling as many as 18 206 cases and 42 536 controls), we identified four loci showing genome-wide significant association with schizophrenia. Here we consider a mixed schizophrenia and bipolar disorder (psychosis) phenotype (addition of 7469 bipolar disorder cases, 1535 schizophrenia cases, 333 other psychosis cases, 808 unaffected family members and 46 160 controls). Combined analysis reveals a novel variant at 16p11.2 showing genome-wide significant association (rs4583255[T]; odds ratio=1.08; P=6.6 × 10(-11)). The new variant is located within a 593-kb region that substantially increases risk of psychosis when duplicated. In line with the association of the duplication with reduced body mass index (BMI), rs4583255[T] is also associated with lower BMI (P=0.0039 in the public GIANT consortium data set; P=0.00047 in 22 651 additional Icelanders).Molecular Psychiatry advance online publication, 20 November 2012; doi:10.1038/mp.2012.157.
[Show abstract][Hide abstract] ABSTRACT: Bipolar disorder and schizophrenia are two often severe disorders with high heritabilities. Recent studies have demonstrated a large overlap of genetic risk loci between these disorders but diagnostic and molecular distinctions still remain. Here, we perform a combined genome-wide association study (GWAS) of 19 779 bipolar disorder (BP) and schizophrenia (SCZ) cases versus 19 423 controls, in addition to a direct comparison GWAS of 7129 SCZ cases versus 9252 BP cases. In our case-control analysis, we identify five previously identified regions reaching genome-wide significance (CACNA1C, IFI44L, MHC, TRANK1 and MAD1L1) and a novel locus near PIK3C2A. We create a polygenic risk score that is significantly different between BP and SCZ and show a significant correlation between a BP polygenic risk score and the clinical dimension of mania in SCZ patients. Our results indicate that first, combining diseases with similar genetic risk profiles improves power to detect shared risk loci and second, that future direct comparisons of BP and SCZ are likely to identify loci with significant differential effects. Identifying these loci should aid in the fundamental understanding of how these diseases differ biologically. These findings also indicate that combining clinical symptom dimensions and polygenic signatures could provide additional information that may someday be used clinically.Molecular Psychiatry advance online publication, 26 November 2013; doi:10.1038/mp.2013.138.
[Show abstract][Hide abstract] ABSTRACT: A number of large, rare copy number variants (CNVs) are deleterious for neurodevelopmental disorders, but large, rare, protective CNVs have not been reported for such phenotypes. Here we show in a CNV analysis of 47 005 individuals, the largest CNV analysis of schizophrenia to date, that large duplications (1.5–3.0 Mb) at 22q11.2—the reciprocal of the well-known, risk-inducing deletion of this locus—are substantially less common in schizophrenia cases than in the general population (0.014% vs 0.085%, OR=0.17, P=0.00086). 22q11.2 duplications represent the first putative protective mutation for schizophrenia.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
Episode count was self-reported and, therefore, subject to recall bias.
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.
Journal of affective disorders 10/2013; · 3.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.
[Show abstract][Hide abstract] ABSTRACT: To assess the comorbidity rates of alcohol use disorders (AUDs) in bipolar disorder (BD) and to explore possible sources of heterogeneity.
Studies were identified through database searches. Meta-analytic techniques were employed to aggregate data on lifetime comorbidity and to explore possible sources of heterogeneity. Funnel plots were used to detect publication bias.
In clinical studies, AUDs affected more than one in three subjects with BD. Significant heterogeneity was found, which was largely explained by the geographical location of study populations and gender ratio of participants. AUDs affected more than one in five women and two in five men.
AUDs are highly prevalent in BD. Our study revealed a substantial heterogeneity across studies. Further research including control groups is needed. Patients with BD should be assessed for current and previous AUDs.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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 (β = 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).
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.
The Journal of Clinical Psychiatry 09/2013; 74(9):925-931. · 5.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17–29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn’s disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: An association between bipolar disorder and cognitive impairment has repeatedly been described, even for euthymic patients. Findings are inconsistent both across primary studies and previous meta-analyses. This study reanalysed 31 primary data sets as a single large sample (N = 2876) to provide a more definitive view. METHOD: Individual patient and control data were obtained from original authors for 11 measures from four common neuropsychological tests: California or Rey Verbal Learning Task (VLT), Trail Making Test (TMT), Digit Span and/or Wisconsin Card Sorting Task. RESULTS: Impairments were found for all 11 test-measures in the bipolar group after controlling for age, IQ and gender (Ps ≤ 0.001, E.S. = 0.26-0.63). Residual mood symptoms confound this result but cannot account for the effect sizes found. Impairments also seem unrelated to drug treatment. Some test-measures were weakly correlated with illness severity measures suggesting that some impairments may track illness progression. CONCLUSION: This reanalysis supports VLT, Digit Span and TMT as robust measures of cognitive impairments in bipolar disorder patients. The heterogeneity of some test results explains previous differences in meta-analyses. Better controlling for confounds suggests deficits may be smaller than previously reported but should be tracked longitudinally across illness progression and treatment.
[Show abstract][Hide abstract] ABSTRACT: The Schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC) highlighted 81 single-nucleotide polymorphisms (SNPs) with moderate evidence for association to schizophrenia. After follow-up in independent samples, seven loci attained genome-wide significance (GWS), but multi-locus tests suggested some SNPs that did not do so represented true associations. We tested 78 of the 81 SNPs in 2640 individuals with a clinical diagnosis of schizophrenia attending a clozapine clinic (CLOZUK), 2504 cases with a research diagnosis of bipolar disorder, and 2878 controls. In CLOZUK, we obtained significant replication to the PGC-associated allele for no fewer than 37 (47%) of the SNPs, including many prior GWS major histocompatibility complex (MHC) SNPs as well as 3/6 non-MHC SNPs for which we had data that were reported as GWS by the PGC. After combining the new schizophrenia data with those of the PGC, variants at three loci (ITIH3/4, CACNA1C and SDCCAG8) that had not previously been GWS in schizophrenia attained that level of support. In bipolar disorder, we also obtained significant evidence for association for 21% of the alleles that had been associated with schizophrenia in the PGC. Our study independently confirms association to three loci previously reported to be GWS in schizophrenia, and identifies the first GWS evidence in schizophrenia for a further three loci. Given the number of independent replications and the power of our sample, we estimate 98% (confidence interval (CI) 78–100%) of the original set of 78 SNPs represent true associations. We also provide strong evidence for overlap in genetic risk between schizophrenia and bipolar disorder.
[Show abstract][Hide abstract] ABSTRACT: 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.
Archives of general psychiatry 12/2012; · 12.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Although usually thought of as external environmental stressors, a significant heritable component has been reported for measures of stressful life events (SLEs) in twin studies. Method We examined the variance in SLEs captured by common genetic variants from a genome-wide association study (GWAS) of 2578 individuals. Genome-wide complex trait analysis (GCTA) was used to estimate the phenotypic variance tagged by single nucleotide polymorphisms (SNPs). We also performed a GWAS on the number of SLEs, and looked at correlations between siblings. RESULTS: A significant proportion of variance in SLEs was captured by SNPs (30%, p = 0.04). When events were divided into those considered to be dependent or independent, an equal amount of variance was explained for both. This 'heritability' was in part confounded by personality measures of neuroticism and psychoticism. A GWAS for the total number of SLEs revealed one SNP that reached genome-wide significance (p = 4 × 10-8), although this association was not replicated in separate samples. Using available sibling data for 744 individuals, we also found a significant positive correlation of R 2 = 0.08 in SLEs (p = 0.03). CONCLUSIONS: These results provide independent validation from molecular data for the heritability of reporting environmental measures, and show that this heritability is in part due to both common variants and the confounding effect of personality.
Psychological Medicine 12/2012; · 5.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals. We also identified, using conditional analyses, five independent signals within previously known loci. The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3). Notably, they included candidate genes whose products are involved in innate host defense, including interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C) and nuclear factor (NF)-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense.
[Show abstract][Hide abstract] ABSTRACT: We have conducted a genotyping study using a custom Illumina Infinium HD genotyping array, the ImmunoChip, in a new UK sample of 1218 bipolar disorder (BD) cases and 2913 controls that have not been used in any studies previously reported independently or in meta-analyses. The ImmunoChip was designed before the publication of the Psychiatric Genome-Wide Association Study Consortium Bipolar Disorder Working Group (PGC-BD) meta-analysis data. As such 3106 single-nucleotide polymorphisms (SNPs) with a P-value <1 × 10(-3) from the BD meta-analysis by Ferreira et al. were genotyped. We report support for two of the three most strongly associated chromosomal regions in the Ferreira study, CACNA1C (rs1006737, P=4.09 × 10(-4)) and 15q14 (rs2172835, P=0.043) but not ANK3 (rs10994336, P=0.912). We have combined our ImmunoChip data (569 quasi-independent SNPs from the 3016 SNPs genotyped) with the recently published PGC-BD meta-analysis data, using either the PGC-BD combined discovery and replication data where available or just the discovery data where the SNP was not typed in a replication sample in PGC-BD. Our data provide support for two regions, at ODZ4 and CACNA1C, with prior evidence for genome-wide significant (GWS) association in PGC-BD meta-analysis. In addition, the combined analysis shows two novel GWS associations. First, rs7296288 (P=8.97 × 10(-9), odds ratio (OR)=0.9), an intergenic polymorphism on chromosome 12 located between RHEBL1 and DHH. Second, rs3818253 (P=3.88 × 10(-8), OR=1.16), an intronic SNP on chromosome 20q11.2 in the gene TRPC4AP, which lies in a high linkage disequilibrium region along with the genes GSS and MYH7B.Molecular Psychiatry advance online publication, 16 October 2012; doi:10.1038/mp.2012.142.
[Show abstract][Hide abstract] ABSTRACT: 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.
To investigate service use in children of parents who have recurrent depression, and factors that influence such contact.
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.
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.
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.
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.
British Journal of General Practice 07/2012; 62(600):e487-93. · 1.83 Impact Factor