Stress-sensitive neurosignalling in depression : an integrated network biology approach to candidate gene selection for genetic association analysis

Genetic risk for depressive disorders is poorly understood despite consistent suggestions of a high heritable component. Most genetic studies have focused on risk associated with single variants, a strategy which has so far only yielded small (often non-replicable) risks for depressive disorders. In this paper we argue that more substantial risks are likely to emerge from genetic variants acting in synergy within and across larger neurobiological systems (polygenic risk factors). We show how knowledge of major integrated neurobiological systems provides a robust basis for defining and testing theoretically defensible polygenic risk factors. We do this by describing the architecture of the overall stress response. Maladaptation via impaired stress responsiveness is central to the aetiology of depression and anxiety and provides a framework for a systems biology approach to candidate gene selection. We propose principles for identifying genes and gene networks within the neurosystems involved in the stress response and for defining polygenic risk factors based on the neurobiology of stress-related behaviour. We conclude that knowledge of the neurobiology of the stress response system is likely to play a central role in future efforts to improve genetic prediction of depression and related disorders

Early diet quality in a longitudinal study of Australian children: associations with nutrition and body mass index later in childhood and adolescence

Obesity has origins extending to antenatal and early postnatal periods; however, the relationship between early postnatal diet and subsequent obesity is not well defined. The aims of this study were to determine whether early childhood dietary quality was associated with (a) infant and adolescent nutrition and (b) body mass index (BMI) in childhood and adolescence. The degree to which early nutrition and growth factors determine BMI throughout childhood and adolescence was also explored. This research was conducted using the Raine Study, a longitudinal survey of Australian children assessed from mid-gestation to 17 years of age. A dietary quality index, the Raine Eating Assessment in Toddler score, was assigned to 2562 participants to assess early nutrition. Linear regression determined that breastfeeding was associated with dietary quality at 1–3 years. Dietary elements at 14 years of age were related to earlier dietary quality. There were no consistent associations between early diet and BMI at 3, 5, 8, 10, 14 or 17 years. In contrast, birth weight and infant weight gain were significantly associated with BMI at these ages. This study suggests that early dietary patterns are associated with aspects of diet in adolescence, likely reflecting the influence of maternal reporting. Birth weight and early growth appear to be more important determinants of adolescent BMI than early diet and nutrition. While optimizing early diet by maternal nutritional education has potential to influence later nutrition, interventions focussing on early weight gain may have a greater impact on the obesity epidemic

DNA methylation of the IGF2/H19 imprinting control region and adiposity distribution in young adults

BACKGROUND: The insulin-like growth factor 2 (IGF2) and H19 imprinted genes control growth and body composition. Adverse in-utero environments have been associated with obesity-related diseases and linked with altered DNA methylation at the IGF2/H19 locus. Postnatally, methylation at the IGF2/H19 imprinting control region (ICR) has been linked with cerebellum weight. We aimed to investigate whether decreased IGF2/H19 ICR methylation is associated with decreased birth and childhood anthropometry and increased contemporaneous adiposity. DNA methylation in peripheral blood (n = 315) at 17 years old was measured at 12 cytosine-phosphate-guanine sites (CpGs), analysed as Sequenom MassARRAY EpiTYPER units within the IGF2/H19 ICR. Birth size, childhood head circumference (HC) at six time-points and anthropometry at age 17 years were measured. DNA methylation was investigated for its association with anthropometry using linear regression. RESULTS: The principal component of IGF2/H19 ICR DNA methylation (representing mean methylation across all CpG units) positively correlated with skin fold thickness (at four CpG units) (P-values between 0.04 to 0.001) and subcutaneous adiposity (P = 0.023) at age 17, but not with weight, height, BMI, waist circumference or visceral adiposity. IGF2/H19 methylation did not associate with birth weight, length or HC, but CpG unit 13 to 14 methylation was negatively associated with HC between 1 and 10 years. β-coefficients of four out of five remaining CpG units also estimated lower methylation with increasing childhood HC. CONCLUSIONS: As greater IGF2/H19 methylation was associated with greater subcutaneous fat measures, but not overall, visceral or central adiposity, we hypothesize that obesogenic pressures in youth result in excess fat being preferentially stored in peripheral fat depots via the IGF2/H19 domain. Secondly, as IGF2/H19 methylation was not associated with birth size but negatively with early childhood HC, we hypothesize that the HC may be a more sensitive marker of early life programming of the IGF axis and of fetal physiology than birth size. To verify this, investigations of the dynamics of IGF2/H19 methylation and expression from birth to adolescence are required

Tracking of vitamin D status from childhood to early adulthood and its association with peak bone mass

Background: To our knowledge, there are few longitudinal studies of vitamin D status from childhood to early adulthood, and it is uncertain whether vitamin D predicts peak bone mass in young adults. Objectives: The purpose of this longitudinal study was to evaluate the long-term stability of vitamin D status from ages 6 to 20 y in healthy individuals and to study associations between serum 25-hydroxyvitamin D [25(OH)D] at different developmental stages and bone mass measured at age 20 y. Design: Participants were offspring of the Western Australian Pregnancy Cohort (Raine) study. Serum 25(OH)D was assessed at ages 6, 14, 17, and 20 y, and whole-body bone mineral content (BMC) and bone mineral density (BMD) were measured at age 20 y through the use of dual-energy X-ray absorptiometry (DXA). Our analysis included 821 participants (385 females) who had ≥3 serum 25(OH)D measures and DXA data. We used latent class growth analysis and identified 4 vitamin D status trajectories: consistently lower (n = 259), decreasing (n = 125), increasing (n = 138), and consistently higher (n = 299). Results: There were significant correlations between serum 25(OH)D concentrations at different time points in both sexes (r = 0.346–0.560, P \u3c 0.001), with stronger correlations at adjacent time points. In males, but not in females, serum 25(OH)D at ages 6, 17, and 20 y was positively associated with total-body BMC and BMD at age 20 y [covariate-adjusted increments of 40.7–53.9 g and 14.7–18.6 mg/cm2, respectively, per 25 nmol/L 25(OH)D]; when 25(OH)D at all 4 ages was included in the same model, the concentration at age 6 y remained significant. Males in the “consistently higher” trajectory had 3.2–3.4% higher total body BMC and BMD than those who were in the “consistently lower” trajectory, accounting for age and anthropometric and lifestyle factors. Conclusions: Within both sexes, there are moderate associations between vitamin D status measured in prepuberty, adolescence, and early adulthood. Vitamin D status in childhood is a significant predictor of peak bone mass in male but not female subjects

A life course approach to the relationship between fetal growth and hypothalamic-pituitary-adrenal axis function

CONTEXT: Human and animal studies suggest that hypothalamic-pituitary-adrenal axis (HPA-A) function may be programmed in utero; however, these findings are inconsistent. Given the powerful metabolic actions of cortisol, it is important to clarify the influence of early life on adult HPA-A function. OBJECTIVE: To determine the relationship between fetal growth and HPA-A stress response to a psychosocial stressor in young adults. DESIGN: Multigenerational, prospective cohort study (the Raine Study) conducted between 1989 and 1991. SETTING: King Edward Memorial Hospital, Perth, Western Australia, Australia. PARTICIPANTS: A total of 917 participants aged 18 years from Gen2 of the Raine Study. MAIN OUTCOME MEASURES: Measures of hypothalamic-pituitary-adrenal axis function before and after exposure to the Trier Social Stress Test. RESULTS: In fully adjusted models, an inverse linear relationship was observed between birthweight and plasma measures of (1) baseline cortisol (β = -0.90%, 95% CI: -1.73 to -0.07; P = 0.03); (2) peak cortisol (β = -0.78%, 95% CI -1.51 to -0.06; P = 0.03); (3) area under the curve with respect to ground (β = -0.89%, 95% CI -1.60 to -0.18; P = 0.01); and (4) adrenal sensitivity (β = -1.02, 95% CI: -1.85 to -0.18; P = 0.02). Similar results were demonstrated for percent optimal birthweight. No consistent quadratic relationships were identified. No associations were found between measures of fetal adiposity and HPA-A function at age 18 years, or fetal growth and HPA-A response pattern. Removal of anticipatory responders from the models substantially attenuated the observed relationships. CONCLUSION: We observed an inverse linear relationship between fetal growth and HPA-A function at age 18 years. This differs from the inverse parabolic relationship (inverted U curve) reported in adults of advanced age. Altered adrenal sensitivity may underlie this relationship

Dual energy X-ray absorptiometry compared with anthropometry in relation to cardio-metabolic risk factors in a young adult population: Is the ‘Gold Standard’ tarnished?

Background and Aims: Assessment of adiposity using dual energy x-ray absorptiometry (DXA) has been considered more advantageous in comparison to anthropometryfor predicting cardio-metabolic risk in the older population, by virtue of its ability to distinguish total and regional fat. Nonetheless, there is increasing uncertainty regarding the relative superiority of DXA and little comparative data exist in young adults. This study aimed to identify which measure of adiposity determined by either DXA or anthropometry is optimal within a range of cardio-metabolic risk factors in young adults. Methods and Results: 1138 adults aged 20 years were assessed by DXA and standard anthropometry from the Western Australian Pregnancy Cohort (Raine) Study. Cross-sectional linear regression analyses were performed. Waist to height ratio was superior to any DXA measure with HDL-C. BMI was the superior model in relation to blood pressure than any DXA measure. Midriff fat mass (DXA) and waist circumference were comparable in relation to glucose. For all the other cardio-metabolic variables, anthropometricand DXA measures were comparable. DXA midriff fat mass compared with BMI or waist hip ratio was the superior measure for triglycerides, insulin and HOMA-IR. Conclusion: Although midriff fat mass (measured by DXA) was the superior measure with insulin sensitivity and triglycerides, the anthropometricmeasures were better or equal with various DXA measures for majority of the cardio-metabolic risk factors. Our findings suggest, clinical anthropometry is generally as useful as DXA in the evaluation of the individual cardio-metabolic risk factors in young adults

Role of the TCF4 gene intronic variant in normal variation of corneal endothelium

PURPOSE: To identify early features of Fuchs endothelial dystrophy (FED) in carriers of the rs613872(G) transcription factor 4 gene (TCF4) aged 20 to 21 years. METHODS: Prospective cohort study of people aged 20 to 21 years previously enrolled in the Western Australia Pregnancy (Raine) Cohort. Specular microscopy was performed using a noncontact specular microscopy (EM-3000; Tomey, Nagoya, Japan). Individual genotype data were extracted from the genome-wide Illumina 660 Quad Array. Analysis of the association between the rs613872 risk allele in TCF4 and specular microscopic measurements was conducted. RESULTS: Association between the rs613872 risk allele and corneal endothelial cell density (CD) as well as the coefficient of variation in cell shape was the main outcome measure. Genotype and specular microscopic data were available for a total of 445 participants (46% women). The median CD was 2851 and 2850 cells per square millimeter in the right and left eyes, respectively. No significant differences between intereye variability in endothelial CD were seen (right eye to left eye correlation = 0.64); however, a significant difference in variability of endothelial CD between men and women was observed (male: OD, 2839 ± 124 cells/mm and OS, 2845 ± 124 cells/mm vs. female: OD, 2838 ± 134 cells/mm and OS, 2842 ± 132 cells/mm; OD, P = 0.0013 and OS, P = 0.0016). Eleven individuals were homozygous for the rs613872 risk allele. We found no association between rs613872 genotype and CD or coefficient of variation. One of 11 homozygous GG individuals was found to have a gutta in 1 sample field on specular microscopy, whereas 2 of 297 TT individuals also had a gutta each in 1 sample field. CONCLUSIONS: We were unable to detect an association between TCF4 rs613872 genotype and the variation in corneal endothelial CD or variation in cell morphology in a healthy young adult population. Copyrigh

Prenatal stress and risk of behavioral morbidity from age 2 to 14 years: The influence of the number, type, and timing of stressful life events

The maternal experience of stressful events during pregnancy has been associated with a number of adverse consequences for behavioral development in offspring, but the measurement and interpretation of prenatal stress varies among reported studies. The Raine Study recruited 2900 pregnancies and recorded life stress events experienced by 18 and 34 weeks’ gestation along with numerous sociodemographic data. The mother’s exposure to life stress events was further documented when the children were followed-up in conjunction with behavioral assessments at ages 2, 5, 8, 10, and 14 years using the Child Behavior Checklist. The maternal experience of multiple stressful events during pregnancy was associated with subsequent behavioral problems for offspring. Independent (e.g., death of a relative, job loss) and dependent stress events (e.g., financial problems, marital problems) were both significantly associated with a greater incidence of mental health morbidity between age 2 and 14 years. Exposure to stressful events in the first 18 weeks of pregnancy showed similar associations with subsequent total and externalizing morbidity to events reported at 34 weeks of gestation. These results were independent of postnatal stress exposure. Improved support for women with chronic stress exposure during pregnancy may improve the mental health of their offspring in later life