Genome-wide analysis of over 106 000 individuals identifies 9 neuroticism-associated loci.

Neuroticism is a personality trait of fundamental importance for psychological well-being and public health. It is strongly associated with major depressive disorder (MDD) and several other psychiatric conditions. Although neuroticism is heritable, attempts to identify the alleles involved in previous studies have been limited by relatively small sample sizes. Here we report a combined meta-analysis of genome-wide association study (GWAS) of neuroticism that includes 91 370 participants from the UK Biobank cohort, 6659 participants from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and 8687 participants from a QIMR (Queensland Institute of Medical Research) Berghofer Medical Research Institute (QIMR) cohort. All participants were assessed using the same neuroticism instrument, the Eysenck Personality Questionnaire-Revised (EPQ-R-S) Short Form's Neuroticism scale. We found a single-nucleotide polymorphism-based heritability estimate for neuroticism of ∼15% (s.e.=0.7%). Meta-analysis identified nine novel loci associated with neuroticism. The strongest evidence for association was at a locus on chromosome 8 (P=1.5 × 10(-15)) spanning 4 Mb and containing at least 36 genes. Other associated loci included interesting candidate genes on chromosome 1 (GRIK3 (glutamate receptor ionotropic kainate 3)), chromosome 4 (KLHL2 (Kelch-like protein 2)), chromosome 17 (CRHR1 (corticotropin-releasing hormone receptor 1) and MAPT (microtubule-associated protein Tau)) and on chromosome 18 (CELF4 (CUGBP elav-like family member 4)). We found no evidence for genetic differences in the common allelic architecture of neuroticism by sex. By comparing our findings with those of the Psychiatric Genetics Consortia, we identified a strong genetic correlation between neuroticism and MDD and a less strong but significant genetic correlation with schizophrenia, although not with bipolar disorder. Polygenic risk scores derived from the primary UK Biobank sample captured ∼1% of the variance in neuroticism in the GS:SFHS and QIMR samples, although most of the genome-wide significant alleles identified within a UK Biobank-only GWAS of neuroticism were not independently replicated within these cohorts. The identification of nine novel neuroticism-associated loci will drive forward future work on the neurobiology of neuroticism and related phenotypes.

Osteoarthritis and the rule of halves.

BACKGROUND: Symptomatic osteoarthritis poses a major challenge to primary health care but no studies have related accessing primary care ('detection'), receiving recommended treatments ('treatment'), and achieving adequate control ('control'). OBJECTIVE: To provide estimates of detection, treatment, and control within a single population adapting the approach used to determine a Rule of Halves for other long-term conditions. SETTING: General population. PARTICIPANTS: 400 adults aged 50+ years with prevalent symptomatic knee osteoarthritis. DESIGN: Prospective cohort with baseline questionnaire, clinical assessment, and plain radiographs, and questionnaire follow-up at 18 and 36 months and linkage to primary care medical records. OUTCOME MEASURES: 'Detection' was defined as at least one musculoskeletal knee-related GP consultation between baseline and 36 months. 'Treatment' was self-reported use of at least one recommended treatment or physiotherapy/hospital specialist referral for their knee problem at all three measurement points. Pain was 'controlled' if characteristic pain intensity <5 out of 10 on at least two occasions. RESULTS: In 221 cases (55.3%; 95%CI: 50.4, 60.1) there was evidence that the current problem had been detected in general practice. Of those detected, 164 (74.2% (68.4, 80.0)) were receiving one or more of the recommended treatments at all three measurement points. Of those detected and treated, 45 (27.4% (20.5, 34.3)) had symptoms under control on at least two occasions. Using narrower definitions resulted in substantially lower estimates. CONCLUSION: Osteoarthritis care does not conform to a Rule of Halves. Symptom control is low among those accessing health care and receiving treatment.

Exploring the genetic susceptibility of chronic widespread pain: the tender points in genetic association studies.

Chronic widespread pain (CWP) is a prevalent disorder associated with a low pain threshold and increased levels of psychological distress. Evidence indicates that there is a genetic component to CWP syndromes and pain sensitivity. Here we have identified and reviewed the current literature on genetic association (GA) studies of CWP and pain sensitivity by searching MEDLINE and EMBASE between January 1990 and May 2007. Of the 18 candidate genes studied to date, no definitive susceptibility genes have been identified. This review highlights the key issues for consideration when interpreting the findings from existing studies and in designing future studies to ensure robust and comparable findings in this field. Well-designed GA studies are essential if the genetic component to CWP aetiology is to be fully determined.

Restorative sleep predicts the resolution of chronic widespread pain: results from the EPIFUND study.

OBJECTIVES: Poor sleep is associated with chronic widespread pain (CWP). Conversely, good-quality sleep may play a role in the resolution of pain symptoms. Sleep is a multidimensional construct, comprising a number of diverse components. The aims of the current study were to examine the hypotheses that: (i) good sleep quality would predict the resolution of CWP, (ii) restorative sleep would predict the resolution of CWP and (iii) that these relationships would be independent of confounding psychological factors. METHODS: Subjects in a population-based prospective study completed a pain questionnaire at baseline from which subjects with CWP were identified. Baseline sleep was measured using the Estimation of Sleep Problems Scale which measures sleep onset, maintenance, early wakening and restorative sleep. The questionnaire also contained scales examining psychosocial status. Subjects were followed up 15 months later and pain status was assessed. RESULTS: A total of 1061 subjects reported CWP at baseline of whom 679 (75% of eligible subjects) responded at follow-up. Of those, a total of 300 (44%) no longer satisfied criteria for CWP. Univariate analysis revealed that three of the four sleep components were associated with the resolution of CWP: rapid sleep onset, odds ratio (OR) = 1.7, 95% CI 1.2, 2.5; absence of early wakening, OR = 1.6, 95% CI 1.1, 2.4; and restorative sleep, OR = 2.7, 95% CI 1.5, 4.8. After adjusting for the effect of psychosocial factors, which may have confounded the relationship, only restorative sleep (OR = 2.0, 95% CI 1.02, 3.8) was associated. CONCLUSIONS: Self-reported restorative sleep was independently associated with the resolution of CWP and return to musculoskeletal health.

Discussing prognosis with patients with osteoarthritis: a cross-sectional survey in general practice.

Osteoarthritis is a leading cause of chronic pain and disability and one of the most common conditions diagnosed and managed in primary care. Despite the evidence that patients would value discussions about the course of osteoarthritis to help them make informed treatment decisions and plan for the future, little is known of GPs' practice of, or views regarding, discussing prognosis with these patients. A cross-sectional postal survey asked 2500 randomly selected UK GPs their views on discussing prognosis with patients with osteoarthritis and potential barriers or facilitators to such discussions. They were also asked if prognostic discussions were part of their current practice and what indicators they considered important in assessing the prognosis associated with osteoarthritis. Of 768 respondents (response rate 30.7 %), the majority felt it necessary to discuss prognosis with osteoarthritis patients (n = 738, 96.1 %), but only two thirds reported that it was part of their routine practice (n = 498, 64.8 %). Most respondents found predicting the course of osteoarthritis (n = 703, 91.8 %) and determining the prognosis of patients difficult (n = 589, 76.7 %). Obesity, level of physical disability and pain severity were considered the most important prognostic indicators in osteoarthritis. Although GPs consider prognostic discussions necessary for patients with osteoarthritis, few prioritise these discussions. Lack of time and perceived difficulties in predicting the disease course and determining prognosis for patients with osteoarthritis may be barriers to engaging in prognostic discussions. Further research is required to identify ways to assist GPs making prognostic predictions for patients with osteoarthritis and facilitate engagement in these discussions.

Cognitive function and lifetime features of depression and bipolar disorder in a large population sample: Cross-sectional study of 143,828 UK Biobank participants.

BACKGROUND: This study investigated differences in cognitive performance between middle-aged adults with and without a lifetime history of mood disorder features, adjusting for a range of potential confounders. METHODS: Cross-sectional analysis of baseline data from the UK Biobank cohort. Adults aged 40-69 (n=143,828) were assessed using measures of reasoning, reaction time and memory. Self-reported data on lifetime features of major depression and bipolar disorder were used to construct groups for comparison against controls. Regression models examined the association between mood disorder classification and cognitive performance, adjusting for sociodemographic, lifestyle and clinical confounders. RESULTS: Inverse associations between lifetime history of bipolar or severe recurrent depression features and cognitive performance were attenuated or reversed after adjusting for confounders, including psychotropic medication use and current depressive symptoms. Participants with a lifetime history of single episode or moderate recurrent depression features outperformed controls to a small (but statistically significant) degree, independent of adjustment for confounders. There was a significant interaction between use of psychotropic medication and lifetime mood disorder features, with reduced cognitive performance observed in participants taking psychotropic medication. CONCLUSIONS: In this general population sample of adults in middle age, lifetime features of recurrent depression or bipolar disorder were only associated with cognitive impairment within unadjusted analyses. These findings underscore the importance of adjusting for potential confounders when investigating mood disorder-related cognitive function.

Cryptococcal meningitis associated with steroid therapy.

Two patients on prolonged steroid therapy developed meningitis due to Cryptococcus neoformans. The first responded satisfactorily to treatment with amphotericin B, both initially and again following relapse. The second died shortly after treatment was begun. Pathogenicity studies suggest that the strain isolated from the fatal case was the more virulent. Cryptococcal meningitis probably occurs more often in Britain than is generally appreciated, and this possibility should be remembered when investigating patients with obscure forms of meningitis; if not, then the correct diagnosis may not be made. Attention is drawn to the increasing number of recently reported cases of this disease which have been associated with long-term steroid therapy.

Premorbid psychosocial factors are associated with poor health-related quality of life in subjects with new onset of chronic widespread pain - results from the EPIFUND study.

Chronic widespread pain (CWP) is associated with poor health-related quality of life (HRQoL). It is unclear whether pain itself is the cause of poor HRQoL or other factors play a role. We hypothesised that new onset of CWP was associated with poor physical and mental HRQoL but that psychosocial risk markers for CWP onset would explain this relationship. A prospective population-based survey measured pain and psychosocial status at baseline. Subjects free of CWP at baseline were followed up 15 months later, when pain status, threatening life events and HRQoL (SF-12) were assessed. The risk associated with the new onset of CWP and reporting poor SF12-MCS and SF12-PCS was quantified using multinomial logistic regression (relative risk ratios (RRRs) with 95% confidence intervals (95% CI)), adjusted for age and gender. 3000 subjects (77%) free of CWP at baseline participated at follow-up. 2650 subjects (88%) provided full SF-12 and pain data and formed the cohort for this analysis. 9.4% of subjects (n=248) reported new CWP. New CWP was associated with an increased risk of having the poorest SF12-MCS (RRR=2.3; 95% CI 1.6-3.2) and SF12-PCS (RRR=8.0; 95% CI 5.4-11.8) scores. After adjusting for baseline psychosocial status, the relationship between CWP onset and SF12-MCS was attenuated (RRR=1.2; 95% CI 0.8-1.8), although the association with SF12-PCS remained (RRR=4.8% CI 3.1-7.47). New onset of CWP is associated with poor mental and physical HRQoL. However, the relationship with mental HRQoL is explained by psychosocial risk markers.

Psychosocial risk markers for new onset irritable bowel syndrome--results of a large prospective population-based study.

Irritable bowel syndrome (IBS) affects up to 22% of the general population. Its aetiology remains unclear. Previously reported cross-sectional associations with psychological distress and depression are not fully understood. We hypothesised that psychosocial factors, particularly those associated with somatisation, would act as risk markers for the onset of IBS. We conducted a community-based prospective study of subjects, aged 25-65 years, randomly selected from the registers of three primary care practices. Responses to a detailed questionnaire allowed subjects' IBS status to be classified using a modified version of the Rome II criteria. The questionnaire also included validated psychosocial instruments. Subjects free of IBS at baseline and eligible for follow-up 15 months later formed the cohort for this analysis (n=3732). An adjusted participation rate of 71% (n=2456) was achieved at follow-up. 3.5% (n=86) of subjects developed IBS. After adjustment for age, gender and baseline abdominal pain status, high levels of illness behaviour (odds ratio (OR)=5.2; 95% confidence interval (95% CI) 2.5-11.0), anxiety (OR=2.0; 95% CI 0.98-4.1), sleep problems (OR=1.6; 95% CI 0.8-3.2), and somatic symptoms (OR=1.6; 95% CI 0.8-2.9) were found to be independent predictors of IBS onset. This study has demonstrated that psychosocial factors indicative of the process of somatisation are independent risk markers for the development of IBS in a group of subjects previously free of IBS. Similar relationships are observed in other "functional" disorders, further supporting the hypothesis that they have similar aetiologies.

The role of psychosocial factors in predicting the onset of chronic widespread pain: results from a prospective population-based study.

OBJECTIVE: Chronic widespread pain (CWP) is strongly associated with psychosocial distress both in a clinical setting and in the community. The aim of this study was to determine the contribution of measures of psychosocial distress, health-seeking behaviour, sleep problems and traumatic life events to the development of new cases of CWP in the community. METHODS: In a population-based prospective study, 3171 adults aged 25-65 yrs free of CWP were followed-up 15 months later to identify those with new CWP. Baseline data were available on their scores from a number of psychological scales including Illness Attitude Scales (IAS), Somatic Symptom Checklist (SSC), Hospital Anxiety & Depression Scale, Sleep Problems Scale, and Life Events Inventory. RESULTS: 324 subjects [10%, 95% confidence interval (CI) 9.2, 11.3] developed new CWP at follow-up. After adjustment for age and sex, three factors independently predicted the development of CWP: scoring three or more on the SSC [odds ratio (OR) 1.8, 95% CI 1.1, 3.1], scoring eight or more on the Illness Behaviour subscale of the IAS (OR 3.3, 95% CI 2.3, 4.8), and nine or more on the Sleep Problem Scale (OR 2.7, 95% CI 1.6, 3.2). Subjects exposed to all three factors were at 12 times the odds of new CWP than those with low scores on all scales. CONCLUSION: Subjects are at substantial increased odds of developing CWP if they display features of somatization, health-seeking behaviour and poor sleep. Psychosocial distress has a strong aetiological influence on CWP.