Barbara I. Nicholl

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

&NA; 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.

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.

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

Abstract 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.

Prevalence and Characteristics of Probable Major Depression and Bipolar Disorder within UK Biobank: Cross-Sectional Study of 172,751 Participants

Objectives UK Biobank is a landmark cohort of over 500,000 participants which will be used to investigate genetic and non-genetic risk factors for a wide range of adverse health outcomes. This is the first study to systematically assess the prevalence and validity of proposed criteria for probable mood disorders within the cohort (major depression and bipolar disorder). Methods This was a descriptive epidemiological study of 172,751 individuals assessed for a lifetime history of mood disorder in relation to a range of demographic, social, lifestyle, personality and health-related factors. The main outcomes were prevalence of a probable lifetime (single) episode of major depression, probable recurrent major depressive disorder (moderate), probable recurrent major depressive disorder (severe), probable bipolar disorder and no history of mood disorder (comparison group). Outcomes were compared on age, gender, ethnicity, socioeconomic status, educational attainment, functioning, self-reported health status, current depressive symptoms, neuroticism score, smoking status and alcohol use. Results Prevalence rates for probable single lifetime episode of major depression (6.4%), probable recurrent major depression (moderate) (12.2%), probable recurrent major depression (severe) (7.2%) and probable bipolar disorder (1.3%) were comparable to those found in other population studies. The proposed diagnostic criteria have promising validity, with a gradient in evidence from no mood disorder through major depression and probable bipolar disorder in terms of gender distribution, socioeconomic status, self-reported health rating, current depressive symptoms and smoking. Significance The validity of our proposed criteria for probable major depression and probable bipolar disorder within this cohort are supported by these cross-sectional analyses. Our findings are likely to prove useful as a framework for a wide range of future genetic and non-genetic studies.

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.

Genetic variation in the hypothalamic–pituitary–adrenal stress axis influences susceptibility to musculoskeletal pain: results from the EPIFUND study

Objectives To determine if genetic variation in genes in the hypothalamic–pituitary–adrenal (HPA) axis, the primary stress response system, influences susceptibility to developing musculoskeletal pain. Methods Pain and comorbidity data was collected at three time points in a prospective population-based cohort study. Pairwise tagging single nucleotide polymorphisms (SNPs) were selected and genotyped for seven genes. Genetic association analysis was carried out using zero-inflated negative binomial regression to test for association between SNPs and the maximum number of pain sites across the three time points in participants reporting pain, reported as proportional changes with 95% CIs. SNPs were also tested for association with chronic widespread pain (CWP) using logistic regression reporting odds ratios and 95% CI. Results A total of 75 SNPs were successfully genotyped in 994 participants including 164 cases with persistent CWP and 172 pain-free controls. Multiple SNPs in SERPINA6 were associated with the maximum number of pain sites; for example, each copy of the T allele of rs941601 was associated with having 16% (proportional change=1.16, 95% CI 1.04 to 1.28, p=0.006) more pain sites compared to participants with the CC genotype. SERPINA6 gene SNPs were also associated with CWP. Significant associations between the maximum number of pain sites and SNPs in the CRHBP and POMC genes were also observed and a SNP in MC2R was also associated with CWP. Associations between SNPs and comorbidity of poor sleep quality and depression explained some of the associations observed. Conclusions Genetic variation in HPA axis genes was associated with musculoskeletal pain; however, some of the associations were explained by comorbidities. Replication of these findings is required in independent cohorts.

Chronic widespread pain predicts physical inactivity: results from the prospective EPIFUND study.

This study tested the hypothesis that chronic widespread pain (CWP) would predict low levels of physical activity (PA). Pain status and PA levels were ascertained at baseline and 32 months in community subjects. Three PA questions were used: “in comparison with others your own age, is your PA “the same” (referent), “more‐much more” or “less‐much less””, and “during the past month on average how many days/week have you taken exercise that has (i) lasted at least 20 min? and (ii) made you sweat?: “4–7” (referent), “1–3” or “none””. Multinomial logistic regression models quantified the relationship between baseline CWP and PA at follow‐up (relative risk ratios (RRR) (95% confidence intervals)). Two thousands one hundred and eighty‐two subjects participated and provided complete pain and PA information at both timepoints. CWP was reported by 18% (n = 429) of participants at baseline. Compared to subjects who were free of CWP at baseline, those with CWP had an increased odds of reporting “less‐much less” PA at follow‐up (RRR = 4.5 (3.2–6.2)). This relationship remained after adjustment for confounders (RRR = 1.9 (1.3–2.9)). A similar association was observed with exercise that lasted at least 20 min (RRR = 1.9 (1.3–2.8)). The current study suggests that low self‐reported levels of physical activity are a consequence of having CWP.

Genetic variation in neuroendocrine genes associates with somatic symptoms in the general population: Results from the EPIFUND study

Objective Functional somatic syndromes commonly occur together, share a genetic component and are associated with numerous somatic symptoms. This study aimed to determine if genetic variation in two neuroendocrine systems, the serotoninergic system and the hypothalamic-pituitary-adrenal (HPA) axis, was associated with the number of reported somatic symptoms. Methods This population-based cohort study (Epidemiology of Functional Disorders) recruited participants from three primary care registers in the northwest of England. Somatic symptoms, anxiety, depression, and pain were assessed using the Somatic Symptoms Checklist, Hospital Anxiety and Depression scales, and body manikins, respectively, via a postal questionnaire. Tag Single Nucleotide Polymorphisms (SNPs) (r2>0.8) were selected for serotoninergic system genes (TPH2, SLC6A4 and HTR2A) and HPA axis genes (CRH, CRHR1, CRHBP, MC2R, POMC, NR3C1, and SERPINA6) and genotyped using Sequenom technology. Negative binomial regression was used to test for association between SNPs and the number of somatic symptoms. Stepwise-regression was used to identify independent effects and adjustments were made for anxiety, depression, and pain. Results A total of 967 subjects were successfully genotyped for 143 (87%) SNPs. Multiple SNP associations with the number of somatic symptoms were observed in HTR2A and SERPINA6 as well as two SNPs in TPH2. Stepwise regression identified two effects in HTR2A and a single effect in TPH2 which were independent of anxiety, depression, and pain. A single effect was also identified in SERPINA6 but was no longer significant when adjusted for pain. Conclusion This study finds association of SNPs in HTR2A, SERPINA6, and TPH2 with somatic symptoms implicating them as potentially important in the shared genetic component to functional somatic syndromes, although replication is required.

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.

Association of HTR2A polymorphisms with chronic widespread pain and the extent of musculoskeletal pain: Results from two population-based cohorts

OBJECTIVE The aim of the current study was to investigate whether genetic variation in genes across the serotoninergic system is associated with chronic widespread pain (CWP) and the number of pain sites reported. METHODS A discovery cohort, with pain data at 3 time points, was used to investigate genetic associations with 2 phenotypes: 1) CWP (at ≥ 2 time points; n = 164) compared with pain-free controls (at 3 time points; n = 172), and 2) the maximum number of pain sites reported at any 1 of the 3 time points (range of sites 0-29; n = 989). A cohort of 2,285 men for whom a DNA sample and pain data were available (including 203 CWP cases and 929 controls) was used for validation. Pairwise tagging (r(2) > 0.8) single-nucleotide polymorphisms (SNPs) were genotyped. Logistic and zero-inflated negative binomial regression analyses were used to test for SNP associations with CWP and the number of pain sites, respectively. RESULTS SNPs in HTR2A were associated with both pain phenotypes in the discovery cohort, and a number of these SNP associations were replicated in the validation cohort, some of which were attenuated after adjustment for depression. There was an increased likelihood of having CWP in subjects with 1 or 2 copies of the T allele of rs12584920 (odds ratio [OR] 1.64, 95% confidence interval [95% CI] 1.01-2.60 [P = 0.03] in the discovery cohort, and OR 1.46, 95% CI 1.07-2.00 [P = 0.018] in the validation cohort). A similar association was observed between rs17289394 and the maximum number of pain sites reported in both cohorts. Results from a meta-analysis of the data from the 2 cohorts further strengthened these findings. CONCLUSION The findings of this study support the role of HTR2A in the genetic predisposition to musculoskeletal pain.