[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: We conducted a combined genome-wide association study (GWAS) of 7,481 individuals with bipolar disorder (cases) and 9,250 controls as part of the Psychiatric GWAS Consortium. Our replication study tested 34 SNPs in 4,496 independent cases with bipolar disorder and 42,422 independent controls and found that 18 of 34 SNPs had P < 0.05, with 31 of 34 SNPs having signals with the same direction of effect (P = 3.8 × 10(-7)). An analysis of all 11,974 bipolar disorder cases and 51,792 controls confirmed genome-wide significant evidence of association for CACNA1C and identified a new intronic variant in ODZ4. We identified a pathway comprised of subunits of calcium channels enriched in bipolar disorder association intervals. Finally, a combined GWAS analysis of schizophrenia and bipolar disorder yielded strong association evidence for SNPs in CACNA1C and in the region of NEK4-ITIH1-ITIH3-ITIH4. Our replication results imply that increasing sample sizes in bipolar disorder will confirm many additional loci.
[Show abstract][Hide abstract] ABSTRACT: Aims To investigate binge drinking trends using unrelated singletons from the GENESiS sample, aged 20–60 years.Methods The GENESiS study is a questionnaire study based in the UK and includes measures on various mental health items as well as measures of alcohol consumption. Alcohol data from 20 062 subjects were analysed with respect to binge/heavy drinking behaviour as defined by the Office for National Statistics, UK.Results The average number of units of alcohol per week consumed was 16 for men and 8 for women. Female binge drinking (more than 6 units per drinking session) was found to be very comparable to male binge drinking (more than 8 units per drinking session) with 15% of males reporting binge drinking compared with 18% of females. Binge drinking was found to be most prevalent amongst males and females in their twenties (33% of males vs 38% of females).Conclusions This study revealed that, for both men and women, there was evidence of substantial numbers drinking heavily and in a binge drinking pattern, particularly in young adults.
No preview · Article · Jul 2009 · Journal of Substance Use
[Show abstract][Hide abstract] ABSTRACT: Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N ≤ 71,225 European ancestry, N ≤ 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10(-24)), CYP1A2 (P = 1 × 10(-23)), FGF5 (P = 1 × 10(-21)), SH2B3 (P = 3 × 10(-18)), MTHFR (P = 2 × 10(-13)), c10orf107 (P = 1 × 10(-9)), ZNF652 (P = 5 × 10(-9)) and PLCD3 (P = 1 × 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.
[Show abstract][Hide abstract] ABSTRACT: To identify susceptibility loci for bipolar disorder, we tested 1.8 million variants in 4,387 cases and 6,209 controls and identified a region of strong association (rs10994336, P = 9.1 x 10(-9)) in ANK3 (ankyrin G). We also found further support for the previously reported CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel; combined P = 7.0 x 10(-8), rs1006737). Our results suggest that ion channelopathies may be involved in the pathogenesis of bipolar disorder.
[Show abstract][Hide abstract] ABSTRACT: Few studies have examined the rates of physical disorders in those with recurrent depression.
To examine self-reported physical disorders in people with recurrent depression compared with a psychiatrically healthy control group.
As part of a genetic case-control association study, 1546 participants with recurrent depression and 884 controls were interviewed about lifetime ever treatment for 16 different physical health disorders.
The cases group had a significantly higher frequency of 14 physical disorders and more obesity than the control group. After controlling for age, gender, body mass index (BMI) and multiple testing, those in the cases group had significantly higher rates of gastric ulcer, rhinitis/hay fever, osteoarthritis, thyroid disease, hypertension and asthma.
People with recurrent depression show high rates of many common physical disorders. Although this can be partly explained by BMI, shared aetiological pathways such as dysfunction of the hypothalamic-pituitary axis may have a role.
No preview · Article · Jun 2008 · The British Journal of Psychiatry
[Show abstract][Hide abstract] ABSTRACT: The Antipsychotic Non-Neurological Side-Effects Rating Scale (ANNSERS) was developed to provide a comprehensive measure for rating non-neurological adverse drug reactions (ADRs) to antipsychotics. Although there were already available measures that adequately rated specific non-neurological ADRs, such as sexual side effects, a need was identified for a scale that comprehensively rated the full range of non-neurological ADRs commonly seen across the spectrum of first and second generation antipsychotic drugs, including metabolic and autonomic ADRs. This article reports on work to establish the interrater reliability of an early version and a later, more comprehensive version of the ANNSERS (versions 1 and 2, v1 and v2, respectively). The measures were administered in London centres to patients treated with clozapine. Trained clinicians rated the patients simultaneously and independently. Interrater reliability on the scores was calculated using the kappa coefficient method. The results (mean kappa coefficients of 0.77 and 0.72, respectively) indicate that substantial interrater reliability was achieved for both versions. Items for which the main basis for rating was laboratory investigations rather than patient interview were largely excluded from this study, and kappas were also not calculated for items with a low frequency (less than 10%) of endorsement. Samples of patients on other antipsychotics would be required to reliably calculate kappa coefficients for these items. In conclusion, the ANNSERS represents a clinically applicable research innovation, with good interrater reliability on clinician judged items, which is now available for the comprehensive assessment of non-neurological ADRs to antipsychotics, to aid the processes of clinical audit, research and drug discovery.
No preview · Article · Jun 2008 · Journal of Psychopharmacology
[Show abstract][Hide abstract] ABSTRACT: Sexual dysfunction and raised prolactin are common adverse effects of many anti-psychotics. Aripiprazole is an atypical anti-psychotic associated with a reduction in prolactin level in anti-psychotic-induced hyperprolactinemia. Our hypothesis was that switching from another anti-psychotic to aripiprazole would be associated with a reduction in sexual dysfunction. An open label switch to aripiprazole was offered to 27 subjects with inadequate therapeutic response or intolerance to another anti-psychotic, who were followed up for 26 weeks. Serial clinical ratings included the Anti-psychotic Non-Neurological Side-Effects Rating Scale (ANNSERS), and the Sexual Functioning Questionnaire. Our primary analysis point was week 12. In both sexes, there was a significant reduction in prolactin by week 12 (P = 0.003), accompanied by a significant improvement in libido (P = 0.028). In males, both erectile and ejaculatory difficulties were also significantly reduced (P = 0.04 and P = 0.017, respectively). In females, menstrual dysfunction was also significantly reduced at week 12 (P = 0.04). By week 26, the changes in all of the above remained significant, and were accompanied by a significant increase in satisfaction in overall sexual functioning (P = 0.007), despite the fact that 54.5% of subjects at were also taking their original antipsychotic. There was also a significant decrease in the total ANNSERS score (P < 0.001) and a significant improvement in all other measures of psychopathology (PANSS, CGI-S/I, GAF-S/D, and QoL). We conclude that switching to aripiprazole or the addition of aripiprazole to another antipsychotic regime is associated with a reduction in sexual dysfunction.
No preview · Article · May 2008 · Journal of Psychopharmacology
[Show abstract][Hide abstract] ABSTRACT: A number of scales are used to estimate the severity of depression. However, differences between self-report and clinician rating, multi-dimensionality and different weighting of individual symptoms in summed scores may affect the validity of measurement. In this study we examined and integrated the psychometric properties of three commonly used rating scales.
The 17-item Hamilton Depression Rating Scale (HAMD-17), the Montgomery-Asberg Depression Rating Scale (MADRS) and the Beck Depression Inventory (BDI) were administered to 660 adult patients with unipolar depression in a multi-centre pharmacogenetic study. Item response theory (IRT) and factor analysis were used to evaluate their psychometric properties and estimate true depression severity, as well as to group items and derive factor scores.
The MADRS and the BDI provide internally consistent but mutually distinct estimates of depression severity. The HAMD-17 is not internally consistent and contains several items less suitable for out-patients. Factor analyses indicated a dominant depression factor. A model comprising three dimensions, namely 'observed mood and anxiety', 'cognitive' and 'neurovegetative', provided a more detailed description of depression severity.
The MADRS and the BDI can be recommended as complementary measures of depression severity. The three factor scores are proposed for external validation.
Full-text · Article · Mar 2008 · Psychological Medicine
[Show abstract][Hide abstract] ABSTRACT: We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.
[Show abstract][Hide abstract] ABSTRACT: The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods - recursive partitioning and regression - to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; P combined = 2.01 × 10 -19 and 2.35 × 10 -13, respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes.
[Show abstract][Hide abstract] ABSTRACT: There is increasing evidence that genome-wide association (GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study (using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined 2,000 individuals for each of 7 major diseases and a shared set of 3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 10-7: 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals (including 58 loci with single-point P values between 10-5 and 5 10-7) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research.
[Show abstract][Hide abstract] ABSTRACT: Evidence indicates the genetic susceptibility to depression and anxiety is both overlapping and dimensional. In the current study, a quantitative phenotype had been created from several depression and anxiety-related measures in order to index this common genetic susceptibility (G). This has been studied in 119 sibships comprising 312 individuals, selected for extreme scores on G, from a community-based sample of 34,371 individuals. In a pathway based candidate gene study, we examined five microsatellite markers located within or nearby to five serotonin system genes (5HT2C, 5HT1D, 5HT1B, TPH1, and MAOB). Statistical analysis, carried out using QTDT, gave a significant association with a microsatellite downstream of TPH1. Further analysis included a life-events composite as a co-variable, this lead to a stronger association of TPH1. To our knowledge, this is the first study to report an association of the 3' end of TPH1 with continuous measures of depression and anxiety.
No preview · Article · May 2005 · American Journal of Medical Genetics Part B Neuropsychiatric Genetics
[Show abstract][Hide abstract] ABSTRACT: Questionnaire-based dimensional measures are often employed in epidemiological studies to predict the presence of psychiatric disorders. The present study sought to determine how accurately 4 dimensional mental health measures, the 12-item General Health Questionnaire (GHQ-12), Neuroticism (EPQ-N), the high positive affect and anxious arousal scales from the Mood and Anxiety Symptoms Questionnaire (MASQ-HPA and MASQ-AA) and a composite of all 4, predicted psychiatric caseness as diagnosed by the University of Michigan Composite International Diagnostic Interview (UM-CIDI). Community subjects were recruited through general practitioners; those who agreed to participate were sent a questionnaire containing the above measures. Subsequently, the UM-CIDI was administered by telephone to 469 subjects consisting of sibling pairs who scored most discordantly or concordantly on a composite index of the 4 measures. Logistic Regression and Receiver Operating Characteristic (ROC) curve analyses were carried out to assess the predictive accuracy of the dimensional measures on UM-CIDI diagnosis. A total of 179 subjects, 62 men and 117 women with an average age of 42 years, were diagnosed with at least one of the following psychiatric disorders: depression, dysthymia, generalized anxiety disorder (GAD), social phobia, agoraphobia and panic attack. The six disorders showed high comorbidity. EPQ-N and the Composite Index were found to be very strong and accurate predictors of psychiatric caseness; they were however unable to differentiate between specific disorders. The results from the present study therefore validated the four mental health measures as being predictive of psychiatric caseness.
Preview · Article · May 2005 · Twin Research and Human Genetics
[Show abstract][Hide abstract] ABSTRACT: Previous studies have shown fatigue and depression/anxiety to be highly associated with each other. The present study seeks to differentiate between fatigue and depression/anxiety and to investigate the familiality/heritability of fatigue using sib-pairs.
The GENESiS study is a questionnaire study based in the United Kingdom that includes a five-item fatigue scale and four mental health measures (GHQ-12, EPQ-N, MASQ-AA, MASQ-HPA). Fatigue data from 10,444 sibling pairs were analysed using multivariate methods and model fitting techniques to investigate the familiality/heritability of fatigue and its relationship with the other mental health measures and physical health items.
Fatigue correlated highly with GHQ-12 (r=0.62, p<0.001). A principal components analysis of the fatigue scale and the GHQ-12 revealed one main component which correlated highly with mental health items, and a smaller second component which correlated modestly with physical health items. Fatigue showed a modest sibling correlation (0.09, p<0.001), and multivariate modelling revealed evidence for familial effects on fatigue that were independent of the mental health measures.
Fatigue showed a strong relationship with both physical illness and mental health measures. Fatigue is modestly familial and at least part of this familial factor is not shared with mental health measures.
Full-text · Article · Mar 2005 · Social Psychiatry and Psychiatric Epidemiology
[Show abstract][Hide abstract] ABSTRACT: There is considerable evidence to suggest that the genetic vulnerabilities to depression and anxiety substantially overlap and quantitatively act to alter risk to both disorders. Continuous scales can be used to index this shared liability and are a complementary approach to the use of clinical phenotypes in the genetic analysis of depression and anxiety. The aim of this study (Genetic and Environmental Nature of Emotional States in Siblings) was to identify genetic variants for the liability to depression and anxiety after the application of quantitative genetic methodology to a large community-based sample (n = 34,371), using four well-validated questionnaires of depression and anxiety. Genetic model fitting was performed on 2658 unselected sibships, which provided evidence for a single common familial factor that accounted for a substantial proportion of the genetic variances and covariances of the four scales. Using the parameter estimates from this model, a composite index of liability (G) was constructed. This index was then used to select a smaller--but statistically powerful--sample for DNA collection (757 individuals, 297 sibships). These individuals were genotyped with more than 400 microsatellite markers. After the data were checked and cleaned, linkage analysis was performed on G and the personality scale of neuroticism using the regression-based linkage program MERLIN-REGRESS. The results indicated two potential quantitative trait loci (QTL): one on chromosome 1p (LOD 2.2) around 64 cM (43-70 cM) near marker D1S2892 and another on chromosome 6p (LOD 2.7) around 47 cM (34-63 cM) near marker D6S1610. Further exploratory sex-specific analyses suggested that these QTLs might have sex-limited effects.
Full-text · Article · Nov 2004 · Human Molecular Genetics
[Show abstract][Hide abstract] ABSTRACT: Familial risk for depression results from both biological and social influences. These may also be associated with other characteristics, including alcohol use, smoking, and body mass index (BMI), and with environmental risks such as social problems, life events, and educational level, all of which may be associated with depression in offspring. The authors examined the links between (1) parental familial vulnerability to depression and (2) the role of associated parental characteristics on severe adolescent depressive symptoms. Third, the authors explored the influence of family environment variables. Fourth, the authors sought interactions between parental familial vulnerability and family environment.
Questionnaires were obtained from 1,294 parents of 1,818 adolescent offspring.
The odds of severe adolescent depressive symptoms increased by a factor of 1.5 per standard deviation increase in parental familial vulnerability to depression (odds ratio [OR] = 1.50). Parental BMI (OR = 1.05) and educational level (OR = 2.60) had significant influences independent of parental vulnerability. Analyses indicated a significant interaction such that those with high parental familial vulnerability, whose parents also had no qualifications, had a threefold risk of severe depressive symptoms.
Adolescents with a family history of depression whose parents also lack qualifications may be a target for intervention.
Full-text · Article · Apr 2004 · Journal of the American Academy of Child & Adolescent Psychiatry