Child maltreatment and substances use throughout adolescence and adulthood: Data from a Brazilian Birth Cohort.

BACKGROUND: Child maltreatment has been associated with substance use later in life, but few studies have used repeated measures. OBJECTIVE: To assess the association between child maltreatment and use of psychoactive substances from adolescence to early adulthood, and whether this differs by sex. PARTICIPANTS AND SETTING: 3641 participants from the 1993 Pelotas Birth Cohort, Brazil. METHODS: Child maltreatment (psychological, physical and sexual abuse, and physical neglect) was assessed up to age 15 and use of psychoactive substances (smoking, harmful use of alcohol and use of illicit drugs) was assessed at ages 15, 18, and 22 years. Associations between child maltreatment and use of substances at each time point were analyzed using logistic regression, adjusted for confounders. RESULTS: Overall, child maltreatment was associated with substance use, and the strength of the associations decreased over time. E.g., the association between psychological abuse and harmful use of alcohol was OR 2.17 (95%CI 1.80, 2.62; p-value < 0.001) at 15 years, OR 1.61 (95%CI 1.31, 1.97; p-value < 0.001) at 18 years, and OR1.55 (95%CI 1.22, 1.96; p-value < 0.001) at 22 years. When sex differences were evident, stronger associations were observed among females. E.g., the association between physical abuse and smoking at 15 years was OR 3.49 (95%CI 2.17, 5.62) in females and OR 0.87 (95%CI 0.30, 2.52) in males (p-value for sex interaction = 0.041). CONCLUSIONS: Child maltreatment was associated with psychoactive substance in adolescence and early adulthood. Strategies to prevent use of substances could benefit those who suffered maltreatment in childhood.

Sex differences in systemic metabolites at four life stages: cohort study with repeated metabolomics.

BACKGROUND: Males experience higher rates of coronary heart disease (CHD) than females, but the circulating traits underpinning this difference are poorly understood. We examined sex differences in systemic metabolites measured at four life stages, spanning childhood to middle adulthood. METHODS: Data were from the Avon Longitudinal Study of Parents and Children (7727 offspring, 49% male; and 6500 parents, 29% male). Proton nuclear magnetic resonance (1H-NMR) spectroscopy from a targeted metabolomics platform was performed on EDTA-plasma or serum samples to quantify 229 systemic metabolites (including lipoprotein-subclass-specific lipids, pre-glycaemic factors, and inflammatory glycoprotein acetyls). Metabolites were measured in the same offspring once in childhood (mean age 8 years), twice in adolescence (16 years and 18 years) and once in early adulthood (25 years), and in their parents once in middle adulthood (50 years). Linear regression models estimated differences in metabolites for males versus females on each occasion (serial cross-sectional associations). RESULTS: At 8 years, total lipids in very-low-density lipoproteins (VLDL) were lower in males; levels were higher in males at 16 years and higher still by 18 years and 50 years (among parents) for medium-or-larger subclasses. Larger sex differences at older ages were most pronounced for VLDL triglycerides-males had 0.19 standard deviations (SD) (95% CI = 0.12, 0.26) higher at 18 years, 0.50 SD (95% CI = 0.42, 0.57) higher at 25 years, and 0.62 SD (95% CI = 0.55, 0.68) higher at 50 years. Low-density lipoprotein (LDL) cholesterol, apolipoprotein-B, and glycoprotein acetyls were generally lower in males across ages. The direction and magnitude of effects were largely unchanged when adjusting for body mass index measured at the time of metabolite assessment on each occasion. CONCLUSIONS: Our results suggest that males begin to have higher VLDL triglyceride levels in adolescence, with larger sex differences at older ages. Sex differences in other CHD-relevant metabolites, including LDL cholesterol, show the opposite pattern with age, with higher levels among females. Such life course trends may inform causal analyses with clinical endpoints in specifying traits which underpin higher age-adjusted CHD rates commonly seen among males.

The genetic architecture of sporadic and multiple consecutive miscarriage.

Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10-8, odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10-8, OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10-9, OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10-8, OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.

Changes in six domains of cognitive function with reproductive and chronological ageing and sex hormones: a longitudinal study in 2411 UK mid-life women.

BACKGROUND: There may be changes in cognitive function in women going through the menopause. The current evidence remains unclear, however, whether these changes occur over and above those of general ageing. We aimed to evaluate the potential impact of the menopause (assessed by reproductive age and hormone levels) on cognitive function in women in mid-life accounting for the underlying effects of ageing. METHODS: The study was based on the follow up of women originally enrolled in pregnancy in a birth cohort when resident in the South West of England, UK between 1991 and 1992. Using up to three repeated measurements in 2411 women (mean age 51 at first assessment), we modelled changes in six cognitive function domains: immediate and delayed verbal episodic memory, working memory, processing speed, verbal intelligence and verbal fluency. The exposures of interest were reproductive age measured as years relative to the final menstrual period (FMP), chronological age and reproductive hormones (follicle-stimulating hormone (FSH), luteinizing hormone (LH) and anti-Müllerian hormone (AMH)). RESULTS: Processing speed (- 0.21 (95% CI - 0.36 to - 0.06) standard deviation (SD) difference per 10 years since FMP), immediate verbal episodic memory (- 0.15 (95% CI - 0.35 to 0.06)) and delayed verbal episodic memory (- 0.17 (95% CI - 0.37 to 0.03)) declined with reproductive age. Reproductive hormones were not robustly associated with processing speed, but FSH and LH were both negatively associated with immediate (- 0.08 (95% CI - 0.13 to - 0.02) SD difference per SD difference in hormone level) and delayed verbal episodic memory (- 0.08 (95% CI - 0.13 to - 0.03)). There was little consistent evidence of cognitive function declining with menopause in other cognitive domains. CONCLUSIONS: Of the cognitive domains tested only verbal episodic memory declined both in relation to age since the menopause and in conjunction with the reproductive hormones that reflect the menopause. This decline was independent of normal ageing and suggests that the menopause is associated with a mild impact on this specific domain of cognitive function.

A comparison of the associations between adiposity and lipids in Malawi and the United Kingdom.

BACKGROUND: The prevalence of excess adiposity, as measured by elevated body mass index (BMI) and waist-hip ratio (WHR), is increasing in sub-Saharan African (SSA) populations. This could add a considerable burden of cardiovascular and metabolic diseases for which these populations are currently ill-prepared. Evidence from white, European origin populations shows that higher adiposity leads to an adverse lipid profile; whether these associations are similar in all SSA populations requires further exploration. This study compared the association of BMI and WHR with lipid profile in urban Malawi with a contemporary cohort with contrasting socioeconomic, demographic, and ethnic characteristics in the United Kingdom (UK). METHODS: We used data from 1248 adolescents (mean 18.7 years) and 2277 Malawian adults (mean 49.8 years), all urban-dwelling, and from 3201 adolescents (mean 17.8 years) and 6323 adults (mean 49.7 years) resident in the UK. Adiposity measures and fasting lipids were assessed in both settings, and the associations of BMI and WHR with total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) were assessed by sex and age groups in both studies. RESULTS: Malawian female adults were more adipose and had more adverse lipid profiles than their UK counterparts. In contrast, Malawian adolescent and adult males were leaner and had more favourable lipid profiles than in the UK. Higher BMI and WHR were associated with increased TC, LDL-C and TG and reduced HDL-C in both settings. The magnitude of the associations of BMI and WHR with lipids was mostly similar or slightly weaker in the Malawian compared with the UK cohort in both adolescents and adults. One exception was the stronger association between increasing adiposity and elevated TC and LDL-C in Malawian compared to UK men. CONCLUSIONS: Malawian adult women have greater adiposity and more adverse lipid profiles compared with their UK counterparts. Similar associations of adiposity with adverse lipid profiles were observed for Malawian and UK adults in most age and sex groups studied. Sustained efforts are urgently needed to address the excess adiposity and adverse lipid profiles in Malawi to mitigate a future epidemic of cardio-metabolic disease among the poorest populations.

Genomic analysis of male puberty timing highlights shared genetic basis with hair colour and lifespan.

The timing of puberty is highly variable and is associated with long-term health outcomes. To date, understanding of the genetic control of puberty timing is based largely on studies in women. Here, we report a multi-trait genome-wide association study for male puberty timing with an effective sample size of 205,354 men. We find moderately strong genomic correlation in puberty timing between sexes (rg = 0.68) and identify 76 independent signals for male puberty timing. Implicated mechanisms include an unexpected link between puberty timing and natural hair colour, possibly reflecting common effects of pituitary hormones on puberty and pigmentation. Earlier male puberty timing is genetically correlated with several adverse health outcomes and Mendelian randomization analyses show a genetic association between male puberty timing and shorter lifespan. These findings highlight the relationships between puberty timing and health outcomes, and demonstrate the value of genetic studies of puberty timing in both sexes.

Adiposity, depression and anxiety: interrelationship and possible mediators.

OBJECTIVES: To explore the association between adiposity, major depressive disorder and generalized anxiety disorder, and to assess the role of inflammation, diet quality and physical activity in this association. METHODS: We used data from 2,977 individuals from the 1993 Pelotas Cohort (Brazil) who attended the 18- and 22-year follow-ups. We assessed general obesity using body mass index, fat mass index, and abdominal obesity using waist circumference. Major Depressive Disorder and generalized anxiety disorder were assessed using the mini-international neuropsychiatric interview. C-reactive protein and interleukin-6 (IL-6) levels were used as a measure of inflammation; diet quality was estimated using the revised diet quality index, and physical activity was assessed by the International physical activity questionnaire (IPAQ, min/day). The association between adiposity and major depressive disorder and generalized anxiety disorder was assessed using logistic regression, and the natural indirect effect via the mediators was estimated using G-computation. RESULTS: General obesity assessed by body mass index (OR: 2.3; 95% CI:1.13; 4.85), fat mass index (OR: 2.6; 95%CI: 1.37; 4.83), and abdominal obesity (OR: 2.5; 95%CI: 1.18; 5.39) were associated with higher odds of major depressive disorder, whereas major depressive disorder was only associated with obesity assessed by body mass index (OR=1.9; 95% CI: 1.09; 3.46). Obesity and generalized anxiety disorder were not associated. C-reactive protein, diet quality and physical activity did not mediate the effect of obesity on major depressive disorder, and C-reactive protein mediated about 25% of the effect of major depressive disorder on adiposity. CONCLUSIONS: Depression, but not generalized anxiety disorder, is associated with adiposity in both directions, with a stronger evidence for the direction obesity-depression. Inflammation explains part of the effect of major depressive disorder on obesity but not the other way around. Further research should explore other mechanisms that could be involved in the association between obesity and depression.

Mental disorders and suicide risk in emerging adulthood: the 1993 Pelotas birth cohort.

OBJECTIVE: To assess the prevalence of some mental disorders and suicide risk, and the association between them in youths. METHODS: Data from the 1993 Pelotas Birth Cohort (Brazil) was used. The prevalence of mental disorders at 22 years [major depressive disorder (MDD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), attention-deficit/ hyperactivity disorder (ADHD), bipolar disorders type 1 and 2 (BD1; BD2), post-traumatic stress disorder (PTSD), and antisocial personality disorder (APD)] and of suicide risk were assessed using the Mini International Neuropsychiatric Interview (n = 3,781). Comorbidity between disorders was also assessed. Association of each mental disorder and the number of disorders with suicide risk was assessed using Poisson regression. RESULTS: The prevalence of any mental disorder was 19.1% (95%CI 17.8-20.3), and GAD was the most prevalent (10.4%; 95%CI 9.5-11.4). The prevalence of current suicide risk was 8.8% (95%CI 5.9-9.7). All disorders (except APD) and the suicide risk were higher among women. Mental disorders were associated with a higher suicide risk, with the highest risks being observed for MDD (RR = 5.6; 95%CI 4.1-7.8) and PTSD (RR = 5.0; 95%CI 3.9-6.3). The higher the number of co-occurring mental disorders, the higher the risk of suicide. CONCLUSIONS: Our findings showed that about 20% of the youths had at least one mental disorder. However, this prevalence is underestimated since other relevant mental disorders were not assessed. Mental disorders were associated with higher suicide risk, especially the comorbidity between them.

Sex and area differences in the association between adiposity and lipid profile in Malawi.

BACKGROUND: Evidence from high-income countries shows that higher adiposity results in an adverse lipid profile, but it is unclear whether this association is similar in Sub-Saharan African (SSA) populations. This study aimed to assess the association between total and central adiposity measures and lipid profile in Malawi, exploring differences by sex and area of residence (rural/urban). METHODS: In this cross-sectional study, data from 12 096 rural and 12 847 urban Malawian residents were used. The associations of body mass index (BMI) and waist to hip ratio (WHR) with fasting lipids (total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C) and triglycerides (TG)) were assessed by area and sex. RESULTS: After adjusting for potential confounders, higher BMI and WHR were linearly associated with increased TC, LDL-C and TG and reduced HDL-C. BMI was more strongly related to fasting lipids than was WHR. The associations of adiposity with adverse lipid profile were stronger in rural compared with urban residents. For instance, one SD increase in BMI was associated with 0.23 mmol/L (95% CI 0.19 to 0.26) increase in TC in rural women and 0.13 mmol/L (95% CI 0.11 to 0.15) in urban women. Sex differences in the associations between adiposity and lipids were less evident. CONCLUSIONS: The consistent associations observed of higher adiposity with adverse lipid profiles in men and women living in rural and urban areas of Malawi highlight the emerging adverse cardio-metabolic epidemic in this poor population. Our findings underline the potential utility of BMI in estimating cardiovascular risk and highlight the need for greater investment to understand the long-term health outcomes of obesity and adverse lipid profiles and the extent to which lifestyle changes and treatments effectively prevent and modify adverse cardio-metabolic outcomes.

Genome-wide association study of anti-Müllerian hormone levels in pre-menopausal women of late reproductive age and relationship with genetic determinants of reproductive lifespan.

Anti-Müllerian hormone (AMH) is required for sexual differentiation in the fetus, and in adult females AMH is produced by growing ovarian follicles. Consequently, AMH levels are correlated with ovarian reserve, declining towards menopause when the oocyte pool is exhausted. A previous genome-wide association study identified three genetic variants in and around the AMH gene that explained 25% of variation in AMH levels in adolescent males but did not identify any genetic associations reaching genome-wide significance in adolescent females. To explore the role of genetic variation in determining AMH levels in women of late reproductive age, we carried out a genome-wide meta-analysis in 3344 pre-menopausal women from five cohorts (median age 44-48 years at blood draw). A single genetic variant, rs16991615, previously associated with age at menopause, reached genome-wide significance at P = 3.48 × 10-10, with a per allele difference in age-adjusted inverse normal AMH of 0.26 standard deviations (SD) (95% confidence interval (CI) [0.18,0.34]). We investigated whether genetic determinants of female reproductive lifespan were more generally associated with pre-menopausal AMH levels. Genetically-predicted age at menarche had no robust association but genetically-predicted age at menopause was associated with lower AMH levels by 0.18 SD (95% CI [0.14,0.21]) in age-adjusted inverse normal AMH per one-year earlier age at menopause. Our findings provide genetic support for the well-established use of AMH as a marker of ovarian reserve.

Mental disorders and suicide risk in emerging adulthood: the 1993 Pelotas birth cohort

ABSTRACT OBJECTIVE To assess the prevalence of some mental disorders and suicide risk, and the association between them in youths. METHODS Data from the 1993 Pelotas Birth Cohort (Brazil) was used. The prevalence of mental disorders at 22 years [major depressive disorder (MDD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), attention-deficit/ hyperactivity disorder (ADHD), bipolar disorders type 1 and 2 (BD1; BD2), post-traumatic stress disorder (PTSD), and antisocial personality disorder (APD)] and of suicide risk were assessed using the Mini International Neuropsychiatric Interview (n = 3,781). Comorbidity between disorders was also assessed. Association of each mental disorder and the number of disorders with suicide risk was assessed using Poisson regression. RESULTS The prevalence of any mental disorder was 19.1% (95%CI 17.8-20.3), and GAD was the most prevalent (10.4%; 95%CI 9.5-11.4). The prevalence of current suicide risk was 8.8% (95%CI 5.9-9.7). All disorders (except APD) and the suicide risk were higher among women. Mental disorders were associated with a higher suicide risk, with the highest risks being observed for MDD (RR = 5.6; 95%CI 4.1-7.8) and PTSD (RR = 5.0; 95%CI 3.9-6.3). The higher the number of co-occurring mental disorders, the higher the risk of suicide. CONCLUSIONS Our findings showed that about 20% of the youths had at least one mental disorder. However, this prevalence is underestimated since other relevant mental disorders were not assessed. Mental disorders were associated with higher suicide risk, especially the comorbidity between them.

Adverse Childhood Experiences (ACEs) and Adiposity in Adolescents: A Cross-Cohort Comparison.

OBJECTIVE: This study aimed to assess the association between adverse childhood experiences (ACEs) and adiposity in adolescents from two cohorts in different socioeconomic contexts. METHODS: Data from the Avon Longitudinal Study of Parents and Children (ALSPAC, United Kingdom) and the 1993 Pelotas Cohort (Brazil) were used. Six ACEs were assessed in both cohorts up to age 15. At 15 years, body mass index (BMI) and waist circumference (WC) were measured, and at 18 years, BMI, fat mass index, and android fat percentage were assessed. RESULTS: Few associations were observed between ACEs and adiposity at 15 years, and they were not consistent across cohorts. For adiposity at age 15 in ALSPAC, physical abuse had a positive association with WC, and domestic violence had a positive association with both WC and BMI. A dose-response relationship between the ACE score and both WC and BMI at 15 years was observed in ALSPAC. In the 1993 Pelotas Cohort, the associations found in crude analysis were no longer evident after adjustment. CONCLUSIONS: This study found some evidence of an association between an ACE score and adiposity in adolescence in a United Kingdom cohort but no evidence of association in a Brazilian cohort. Residual confounding or context-specific relationships could explain the different pattern of associations.