Chris Power

A genome-wide association meta-analysis identifies new childhood obesity loci

Multiple genetic variants have been associated with adult obesity and a few with severe obesity in childhood; however, less progress has been made in establishing genetic influences on common early-onset obesity. We performed a North American, Australian and European collaborative meta-analysis of 14 studies consisting of 5,530 cases (≥95th percentile of body mass index (BMI)) and 8,318 controls (<50th percentile of BMI) of European ancestry. Taking forward the eight newly discovered signals yielding association with P < 5 × 10−6 in nine independent data sets (2,818 cases and 4,083 controls), we observed two loci that yielded genome-wide significant combined P values near OLFM4 at 13q14 (rs9568856; P = 1.82 × 10−9; odds ratio (OR) = 1.22) and within HOXB5 at 17q21 (rs9299; P = 3.54 × 10−9; OR = 1.14). Both loci continued to show association when two extreme childhood obesity cohorts were included (2,214 cases and 2,674 controls). These two loci also yielded directionally consistent associations in a previous meta-analysis of adult BMI.

Does the influence of childhood adversity on psychopathology persist across the lifecourse? A 45-year prospective epidemiologic study

PURPOSEnProspective evidence about whether the association of childhood adversity and psychopathology attenuates across the lifecourse and whether effects on mid-life psychopathology are mediated through adolescent and early adulthood psychopathology is limited.nnnMETHODSnData were from the 1958 British Birth Cohort, a 45-year study of 98% of births in 1 week in 1958 in England, Scotland, and Wales. Outcomes included International Statistical Classification of Diseases (ICD-10) diagnoses for affective and anxiety disorders at 45 years and psychopathology at 16 years and 23 years. Multiple multi-informant measures of childhood adversity were available at 7, 11, and 16 years, with additional retrospective measures of parental sexual and physical abuse at 45 years. Analyses were determined on the basis of N = 9377; 59% of the surviving sample.nnnRESULTSnAfter adjustment for socioeconomic covariates, childhood adversities were associated with adolescent, early adulthood, and mid-life psychopathology: most associations did not attenuate with age. Mid-life associations were significantly fully or partially mediated by early adulthood psychopathology: cumulative adversity, illness, sexual abuse, and physical abuse remained significantly associated with mid-life psychopathology.nnnCONCLUSIONSnThe findings confirm the importance of preventing exposure to adversity and suggest that effects of adversity on mid-life psychopathology may operate through psychopathology in early adulthood. Future research is needed to examine other intermediary factors which may explain these associations.

Does financial hardship account for elevated psychological distress in lone mothers

Lone mothers have been shown to have higher levels of psychological distress than married mothers, but it is not clear how this difference arises. Using data from the 1958 British birth cohort followed to age 33, we investigated alternative explanations for the excess distress of lone mothers. Logistic regression models were used to estimate odds ratios for distress (measured using the Malaise Inventory) in lone vs married mothers. Odds ratios were adjusted to assess the contribution of explanatory factors. At age 33, psychological distress was greater among lone than married mothers (OR 2.59, 95% CI 1.97, 3.41). The odds ratio decreased to 1.43 (95% CI 1.02, 2.01) after adjustment for all explanatory factors (prior psychological distress, age of youngest child and number of children in the household, and contemporary measures of financial hardship, employment, and social support). Attenuation of the odds ratio was most marked after taking account of financial hardship. Psychological distress was greater among divorced mothers than never married mothers, though not significantly (OR = 1.70, 95% CI 0.88, 3.28). This difference was not explained by the factors examined, and was not due to the immediate distress associated with a recent divorce. Elevated psychological distress of lone mothers appears to be related to financial hardship, while other explanations, including social support and selection, have a more modest impact. Not all of the elevated psychological distress among lone mothers was accounted for, particularly among divorced lone mothers.

Life-time socio-economic position and cortisol patterns in mid-life.

The influence of adversity over long periods of the life-span on adult cortisol metabolism is not established. We assess whether morning cortisol levels are associated with socio-economic position (SEP) from birth to mid-adulthood, and if so, whether the association is due primarily to SEP in childhood, adulthood or both. Data are from 6335 participants in the 1958 British birth cohort, with salivary cortisol samples collected at 45 yr. Two saliva samples were obtained on the same day: 45 min post-waking (t1) and 3 h later (t2). Median t1 and t2 cortisol values were 18.80 and 7.10 nmol/l for men; 19.60 and 6.60 nmol/l for women. Three outcomes were constructed: (1) extreme t1 cortisol (top and bottom 5%), (2) area-under-curve (AUC), and (3) abnormal t1-t2 pattern. All three outcomes were associated with lifetime SEP but the relative contribution of childhood and adulthood SEP varied by outcome measure. Our results suggest that the impact of less advantaged SEP over a lifetime would lead to an approximate doubling of the proportion of extreme post-waking cortisol levels for both sexes; an 8% and 10% increase, respectively for females and males in AUC, and an increased risk of having an abnormal cortisol pattern of 60% and 91%. SEP differences were independent of time of waking and sample collection, and in most instances, remained after adjustment for smoking and body mas index (BMI). Thus, our study provides evidence for effects of chronic adversity on cortisol in mid-adult life.

25-Hydroxyvitamin D and pre-clinical alterations in inflammatory and hemostatic markers: a cross sectional analysis in the 1958 British birth cohort.

Background Vitamin D deficiency has been suggested as a cardiovascular risk factor, but little is known about underlying mechanisms or associations with inflammatory or hemostatic markers. Our aim was to investigate the association between 25-hydroxyvitamin D [25(OH)D, a measure for vitamin D status] concentrations with pre-clinical variations in markers of inflammation and hemostasis. Methodology/Principal Findings Serum concentrations of 25(OH)D, C-reactive protein (CRP), fibrinogen, D-dimer, tissue plasminogen activator (tPA) antigen, and von Willebrand factor (vWF) were measured in a large population based study of British whites (aged 45y). Participants for the current investigation were restricted to individuals free of drug treated cardiovascular disease (nu200a=u200a6538). Adjusted for sex and month, 25(OH)D was inversely associated with all outcomes (p≤0.015 for all), but associations with CRP, fibrinogen, and vWF were explained by adiposity. Association with tPA persisted after full adjustment (body mass index, waist circumference, physical activity, TV watching, smoking, alcohol consumption, social class, sex, and month), and average concentrations were 18.44% (95% CI 8.13, 28.75) lower for 25(OH)D ≥75 nmol/l compared to <25 nmol/l. D-dimer concentrations were lower for participants with 25(OH)D 50–90nmol/l compared to others (quadratic term pu200a=u200a0.01). We also examined seasonal variation in hemostatic and inflammatory markers, and evaluated 25(OH)D contribution to the observed patterns using mediation models. TPA concentrations varied by season (pu200a=u200a0.02), and much of this pattern was related to fluctuations in 25(OH)D concentrations (p≤0.001). Some evidence of a seasonal variation was observed also for fibrinogen, D-dimer and vWF (p<0.05 for all), with 25(OH)D mediating some of the pattern for fibrinogen and D-dimer, but not vWF. Conclusions Current vitamin D status was associated with tPA concentrations, and to a lesser degree with fibrinogen and D-dimer, suggesting that vitamin D status/intake may be important for maintaining antithrombotic homeostasis.

Comparative analysis of genome-wide association studies signals for lipids, diabetes, and coronary heart disease: Cardiovascular Biomarker Genetics Collaboration

Aims To evaluate the associations of emergent genome-wide-association study-derived coronary heart disease (CHD)-associated single nucleotide polymorphisms (SNPs) with established and emerging risk factors, and the association of genome-wide-association study-derived lipid-associated SNPs with other risk factors and CHD events. Methods and results Using two case–control studies, three cross-sectional, and seven prospective studies with up to 25 000 individuals and 5794 CHD events we evaluated associations of 34 genome-wide-association study-identified SNPs with CHD risk and 16 CHD-associated risk factors or biomarkers. The Ch9p21 SNPs rs1333049 (OR 1.17; 95% confidence limits 1.11–1.24) and rs10757274 (OR 1.17; 1.09–1.26), MIA3 rs17465637 (OR 1.10; 1.04–1.15), Ch2q36 rs2943634 (OR 1.08; 1.03–1.14), APC rs383830 (OR 1.10; 1.02, 1.18), MTHFD1L rs6922269 (OR 1.10; 1.03, 1.16), CXCL12 rs501120 (OR 1.12; 1.04, 1.20), and SMAD3 rs17228212 (OR 1.11; 1.05, 1.17) were all associated with CHD risk, but not with the CHD biomarkers and risk factors measured. Among the 20 blood lipid-related SNPs, LPL rs17411031 was associated with a lower risk of CHD (OR 0.91; 0.84–0.97), an increase in Apolipoprotein AI and HDL-cholesterol, and reduced triglycerides. SORT1 rs599839 was associated with CHD risk (OR 1.20; 1.15–1.26) as well as total- and LDL-cholesterol, and apolipoprotein B. ANGPTL3 rs12042319 was associated with CHD risk (OR 1.11; 1.03, 1.19), total- and LDL-cholesterol, triglycerides, and interleukin-6. Conclusion Several SNPs predicting CHD events appear to involve pathways not currently indexed by the established or emerging risk factors; others involved changes in blood lipids including triglycerides or HDL-cholesterol as well as LDL-cholesterol. The overlapping association of SNPs with multiple risk factors and biomarkers supports the existence of shared points of regulation for these phenotypes.

Repeated exposure to socioeconomic disadvantage and health selection as life course pathways to mid-life depressive and anxiety disorders

BackgroundSocioeconomic position (SEP) in childhood and adulthood influences the risk of adult psychiatric disorder. This paper investigates first how cumulative childhood manual SEP influences the risk for mid-life depressive and anxiety disorders and secondly the effects of health selection based on psychological disorder in childhood and psychological distress in early adulthood on mid-life social position.Methods9,377 participants of the 1958 Birth Cohort were followed up at 45xa0years with the Revised Clinical Interview Schedule to measure depressive and anxiety disorders. SEP was measured by Registrar General Social Class in childhood (ages 7, 11 and 16xa0years) and adulthood (ages 23, 33 and 42xa0years). Internalising and externalising disorders were also measured in childhood.ResultsCumulative manual SEP in childhood was weakly associated with increased risk of mid-life disorder. Childhood internalising and externalising disorders were associated with less upward social mobility and manual adult social position. Psychological disorder on three occasions in childhood was associated with manual adult occupational status (ORxa0=xa03.33, 95% CI 2.63–4.21) even after adjusting for childhood SEP and malaise score at 42xa0years.ConclusionsBoth social causation and health selection contribute to the association of childhood socioeconomic disadvantage and mid-life depressive and anxiety disorders. Tackling accumulation of disadvantage and understanding and treating childhood psychological disorders and their educational and occupational consequences could reduce the risk of mid-life psychiatric disorders.

Investigating the possible causal association of smoking with depression and anxiety using Mendelian randomisation meta-analysis: the CARTA consortium

Objectives To investigate whether associations of smoking with depression and anxiety are likely to be causal, using a Mendelian randomisation approach. Design Mendelian randomisation meta-analyses using a genetic variant (rs16969968/rs1051730) as a proxy for smoking heaviness, and observational meta-analyses of the associations of smoking status and smoking heaviness with depression, anxiety and psychological distress. Participants Current, former and never smokers of European ancestry aged ≥16u2005years from 25 studies in the Consortium for Causal Analysis Research in Tobacco and Alcohol (CARTA). Primary outcome measures Binary definitions of depression, anxiety and psychological distress assessed by clinical interview, symptom scales or self-reported recall of clinician diagnosis. Results The analytic sample included up to 58u2005176 never smokers, 37u2005428 former smokers and 32u2005028 current smokers (total N=127u2005632). In observational analyses, current smokers had 1.85 times greater odds of depression (95% CI 1.65 to 2.07), 1.71 times greater odds of anxiety (95% CI 1.54 to 1.90) and 1.69 times greater odds of psychological distress (95% CI 1.56 to 1.83) than never smokers. Former smokers also had greater odds of depression, anxiety and psychological distress than never smokers. There was evidence for positive associations of smoking heaviness with depression, anxiety and psychological distress (ORs per cigarette per day: 1.03 (95% CI 1.02 to 1.04), 1.03 (95% CI 1.02 to 1.04) and 1.02 (95% CI 1.02 to 1.03) respectively). In Mendelian randomisation analyses, there was no strong evidence that the minor allele of rs16969968/rs1051730 was associated with depression (OR=1.00, 95% CI 0.95 to 1.05), anxiety (OR=1.02, 95% CI 0.97 to 1.07) or psychological distress (OR=1.02, 95% CI 0.98 to 1.06) in current smokers. Results were similar for former smokers. Conclusions Findings from Mendelian randomisation analyses do not support a causal role of smoking heaviness in the development of depression and anxiety.

Social support at age 33: the influence of gender, employment status and social class.

This paper investigates the conceptualisation and operationalisation of social support and its relationship to gender, employment status and social class. Clarification of these relationships is sought in order to better understand associations between social support and health. We used data from the 33-year survey of the 1958 British birth cohort study. Individual items and subscales of practical and emotional support were examined. In general, men had lower support than women and social classes IV and V had lower support than classes I and II. Emotional support, either from personal (for example, from friends or family), or combined with organisational sources of support (such as from a church or a financial institution), showed consistent gender and social class patterns. This suggests that emotional support is a robust concept across socio-demographic groups. Less consistent trends were found for practical support, in that socio-demographic trends depended on how practical support was measured. In particular, it depended on whether both personal and organisational sources of support were examined. Gender differences in social support were large and might therefore be expected to contribute to gender differences in health, whereas social class differences in social support were modest, suggesting a minor explanatory role for this factor in accounting for inequalities in health.

Effects of Socioeconomic Position on Inflammatory and Hemostatic Markers: A Life-Course Analysis in the 1958 British Birth Cohort

The cumulative effects of socioeconomic position (SEP) on cardiovascular disease have been described, but the pathways are unclear. In this study, the authors examined the effects of life-course SEP on inflammatory and hemostatic markers: fibrinogen, C-reactive protein, von Willebrand factor antigen, and tissue plasminogen activator antigen. Data from the 1958 British birth cohort, including data on persons who underwent a biomedical follow-up in 2002-2004, were used. Social class was determined at three stages of respondents lives: childhood (birth), early adulthood (age 23 years), and midlife (age 42 years). A cumulative indicator score of SEP was calculated that ranged from 0 (always in the highest social class) to 9 (always in the lowest social class). In men and women, associations were observed between cumulative indicator score and fibrinogen (p < 0.001), C-reactive protein (p < 0.001), von Willebrand factor antigen (p < or = 0.05), and tissue plasminogen activator antigen (p < 0.001 only in women). The trends in fibrinogen and C-reactive protein remained after adjustment for body mass index, smoking, and physical activity. However, the trends became nonsignificant for von Willebrand factor antigen and tissue plasminogen activator antigen in women. Risk exposure related to SEP accumulates across the life course and contributes to raised levels of fibrinogen and C-reactive protein, while childhood SEP influences hemostatic markers more than does adult SEP.