Environmental risk factors for schizophrenia and bipolar disorder from childhood to diagnosis: a Swedish nested case-control study.

BACKGROUND: Shared genetic risk between schizophrenia (SCZ) and bipolar disorder (BD) is well-established, yet the extent to which they share environmental risk factors remains unclear. We compare the associations between environmental exposures during childhood/prior to disorder onset with the risk of developing SCZ and BD. METHODS: We conducted a Swedish register-based nested case-control study using 4184 SCZ cases and 18 681 BD cases diagnosed 1988-2013. Cases were matched to five controls by birth year, birth region, and sex. Conditional logistic regression was used to estimate incidence rate ratios (IRR) for SCZ and BD for each exposure (severe childhood infections, adverse childhood experiences (ACEs), substance use disorders (SUDs), urban birth/longest residence). RESULTS: All SUD types were associated with very high risk (IRR 4.9-25.5), and all forms of ACEs with higher risk (IRR 1.5-4.3) for both disorders. In the mutually adjusted models, ACEs demonstrated slightly higher risk for BD (SCZ IRR 1.30, 1.19-1.42; BD IRR 1.49, 1.44-1.55), while for SUD, risk was higher for SCZ (SCZ IRR 9.43, 8.15-10.92; BD IRR 5.50, 5.15-5.88). Infections were associated with increased risk of BD (IRR 1.21, 1.17-1.26) but not SCZ. Urban birth and urban longest residence were associated with higher risk of SCZ (IRR 1.19, 1.03-1.37), while only the combination of urban birth and rural longest residence showed higher risk for BD (IRR 1.24, 1.13-1.35). CONCLUSIONS: There were both shared and unique environmental risk factors: SUDs and ACEs were risk factors for both disorders, while infections were more strongly associated with BD and urbanicity with SCZ.

Migration and risk of schizophrenia and bipolar disorder: A Swedish national study.

OBJECTIVE: Prior studies report increased risk of schizophrenia (SCZ) in migrants relative to the native-born population; however, few have investigated bipolar disorder (BD) and migrant characteristics which may influence risk. We aimed to examine the risk of SCZ and BD in migrants and their children relative to those of Swedish ancestry, and whether risk varied by age at migration, region of origin, sex, and parental migrant status. METHODS: We conducted a nested case-control study using 5539 SCZ cases and 20,577 BD cases diagnosed 1988-2013, individually matched to five population-based controls by birth year and sex. Conditional logistic regression was used to evaluate the risk of SCZ and BD by migrant status, region of origin and age at migration, with models stratified by sex. RESULTS: First-generation migrants had increased risk of SCZ and decreased risk of BD. There was a distinct pattern of risk for SCZ by age at migration. Childhood migrants from all regions had increased risk of SCZ, particularly those from Africa. In contrast, risk for BD declined with age at migration, with increased risk only in Nordic child migrants. SCZ and BD diagnoses were decreased in adult migrants, elevated in second-generation migrants (with risk differing by number of migrant parents and greater for those with migrant fathers) and higher in male migrants (vs. female). CONCLUSIONS: Age at migration, sex, and region of origin affect risk of SCZ and BD. Further research is required to determine how migration-related factors influence disease etiology and the receipt of these diagnoses.

Impact of Early-Life Factors on Risk for Schizophrenia and Bipolar Disorder.

BACKGROUND AND HYPOTHESIS: Schizophrenia (SCZ) and bipolar disorder (BD) have shared genetic risk and clinical symptoms, yet the extent to which environmental risk factors are shared is not well known. We aimed to examine the associations of early-life environmental exposures with the risk of SCZ and BD. STUDY DESIGN: We conducted a Swedish register-based nested case-control study using 4184 SCZ and 18 681 BD cases diagnosed 1988-2013, individually matched to 5 population-based controls by birth year, sex and birthplace. Conditional logistic regression was used to evaluate the risk of SCZ and BD by seasonality, severe prenatal infections, and perinatal factors. STUDY RESULTS: Seasonality had similar patterns of risk for both disorders: Higher risk for births November-December; lower risk April-June. Experiencing any perinatal factor was associated with a significantly higher risk of SCZ (incidence rate ratio [IRR] 1.19, 95%CI 1.11-1.63) and to a lesser extent BD (IRR 1.08, 95%CI 1.05-1.12). Prenatal infections were only associated with a greater risk of SCZ (IRR 1.30, 95%CI 1.04-1.63). In the mutually adjusted model, only perinatal factors were associated with outcomes. Several perinatal factors were associated with both disorders, but estimates were significantly higher for SCZ for low birth weight, low APGAR, and high parity. Congenital malformations were only associated with risk of SCZ, and jaundice with BD. CONCLUSIONS: Adverse perinatal factors and winter birth were the risk factors for both disorders, while severe prenatal infections were only risk a factor for SCZ. Early-life exposures were associated with a higher risk of both disorders, but may play a larger role in the development of SCZ than BD.

Anti-cancer therapy is associated with long-term epigenomic changes in childhood cancer survivors.

BACKGROUND: Childhood cancer survivors (CCS) exhibit significantly increased chronic diseases and premature death. Abnormalities in DNA methylation are associated with development of chronic diseases and reduced life expectancy. We investigated the hypothesis that anti-cancer treatments are associated with long-term DNA methylation changes that could be key drivers of adverse late health effects. METHODS: Genome-wide DNA methylation was assessed using MethylationEPIC arrays in paired samples (before/after therapy) from 32 childhood cancer patients. Separately, methylation was determined in 32 samples from different adult CCS (mean 22-years post-diagnosis) and compared with cancer-free controls (n = 284). RESULTS: Widespread DNA methylation changes were identified post-treatment in childhood cancer patients, including 146 differentially methylated regions (DMRs), which were consistently altered in the 32 post-treatment samples. Analysis of adult CCS identified matching methylation changes at 107/146 of the DMRs, suggesting potential long-term retention of post-therapy changes. Adult survivors also exhibited epigenetic age acceleration, independent of DMR methylation. Furthermore, altered methylation at the DUSP6 DMR was significantly associated with early mortality, suggesting altered methylation may be prognostic for some late adverse health effects in CCS. CONCLUSIONS: These novel methylation changes could serve as biomarkers for assessing normal cell toxicity in ongoing treatments and predicting long-term health outcomes in CCS.

Impact of In Utero Folate Exposure on DNA Methylation and Its Potential Relevance for Later-Life Health-Evidence from Mouse Models Translated to Human Cohorts.

SCOPE: Persistent DNA methylation changes may mediate effects of early-life exposures on later-life health. Human lifespan is challenging for prospective studies, therefore data from longitudinal studies are limited. Projecting data from mouse models of early-life exposure to human studies offers a tool to address this challenge. METHODS AND RESULTS: C57BL/6J mice were fed low/normal folate diets before and during pregnancy and lactation. Genome-wide promoter methylation was measured in male offspring livers at 17.5 days gestation and 28 weeks. Eight promoters were concurrently hypermethylated by folate depletion in fetuses and adults (>1.10 fold-change; p < 0.05). Processes/pathways potentially influenced by global changes, and function of these eight genes, suggest neurocognitive effects. Human observational and randomized controlled trial data were interrogated for translation. Methylation at birth was inversely associated with maternal plasma folate in six genes (-1.15% to -0.16% per nmol L-1 ; p < 0.05), while maternal folic acid supplementation was associated with differential methylation of four genes in adulthood. Three CpGs were persistently hypermethylated with lower maternal folate (p = 0.04). CONCLUSION: Some persistent folate-induced methylation changes in mice are mirrored in humans. This demonstrates utility of mouse data in identifying human loci for interrogation as biomarkers of later-life health.

Environmental Risk Factors for Schizophrenia and Bipolar Disorder and Their Relationship to Genetic Risk: Current Knowledge and Future Directions.

Schizophrenia (SZ) and bipolar disorder (BD) are severe psychiatric disorders which result from complex interplay between genetic and environmental factors. It is well-established that they are highly heritable disorders, and considerable progress has been made identifying their shared and distinct genetic risk factors. However, the 15-40% of risk that is derived from environmental sources is less definitively known. Environmental factors that have been repeatedly investigated and often associated with SZ include: obstetric complications, infections, winter or spring birth, migration, urban living, childhood adversity, and cannabis use. There is evidence that childhood adversity and some types of infections are also associated with BD. Evidence for other risk factors in BD is weaker due to fewer studies and often smaller sample sizes. Relatively few environmental exposures have ever been examined for SZ or BD, and additional ones likely remain to be discovered. A complete picture of how genetic and environmental risk factors confer risk for these disorders requires an understanding of how they interact. Early gene-by-environment interaction studies for both SZ and BD often involved candidate genes and were underpowered. Larger samples with genome-wide data and polygenic risk scores now offer enhanced prospects to reveal genetic interactions with environmental exposures that contribute to risk for these disorders. Overall, although some environmental risk factors have been identified for SZ, few have been for BD, and the extent to which these account for the total risk from environmental sources remains unknown. For both disorders, interactions between genetic and environmental risk factors are also not well understood and merit further investigation. Questions remain regarding the mechanisms by which risk factors exert their effects, and the ways in which environmental factors differ by sex. Concurrent investigations of environmental and genetic risk factors in SZ and BD are needed as we work toward a more comprehensive understanding of the ways in which these disorders arise.

Mediterranean diet and the hallmarks of ageing.

Ageing is a multifactorial process associated with reduced function and increased risk of morbidity and mortality. Recently, nine cellular and molecular hallmarks of ageing have been identified, which characterise the ageing process, and collectively, may be key determinants of the ageing trajectory. These include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intercellular communication. Healthier dietary patterns reduce the risk of age-related diseases and increase longevity and may influence positively one or more of these hallmarks. The Mediterranean dietary pattern (MedDiet) is a plant-based eating pattern that was typical of countries such as Greece, Spain, and Italy pre-globalisation of the food system and which is associated with better health during ageing. Here we review the potential effects of a MedDiet on each of the nine hallmarks of ageing, and provide evidence that the MedDiet as a whole, or individual elements of this dietary pattern, may influence each hallmark positively-effects which may contribute to the beneficial effects of this dietary pattern on age-related disease risk and longevity. We also highlight potential avenues for future research.

The Biological and Social Determinants of Childhood Obesity: Comparison of 2 Cohorts 50 Years Apart.

OBJECTIVE: To determine whether the same relationships between early-life risk factors and socioeconomic status (SES) with childhood body mass index (BMI) are observed in a modern cohort (2000) compared with a historic cohort (1947). STUDY DESIGN: The relationships between early-life factors and SES with childhood BMI were examined in 2 prospective birth cohorts from the same region, born 50 years apart: 711 children in the 1947 Newcastle Thousand Families Study (NTFS) and 475 from the 2000 Gateshead Millennium Study (GMS). The associations between birth weight, breastfeeding, rapid infancy growth (0-12 months), early-life adversity (0-12 months), and parental SES (birth and childhood) with childhood BMI z-scores and whether overweight/obese (BMI >91st percentile using UK 1990 reference) aged 9 years were examined using linear regression, path analyses, and logistic regression. RESULTS: In the NTFS, the most advantaged children were taller than the least (+0.91 height z-score, P = .001), whereas in GMS they had lower odds of overweight/obese than the least (0.35 [95% CI 0.14-0.86]). Rapid infancy growth was associated with increased BMI z-scores in both cohorts, and with increased likelihood of overweight/obese in GMS. CONCLUSIONS: This study suggests that children exposed to socioeconomic disadvantage or who have rapid infancy growth in modern environments are now at lower risk of growth restriction but greater risk of overweight.

DNA methylation patterns of LINE-1 and Alu for pre-symptomatic dementia in type 2 diabetes.

The identification of early markers of dementia is important for higher-risk populations such as those with type 2 diabetes (T2D). Retrotransposons, including long interspersed nuclear element 1 (LINE-1) and Alu, comprise ~40% of the human genome. Although dysregulation of these retrotransposons can induce aberrant gene regulation and genomic instability, their role in the development of pre-symptomatic dementia (PSD) among T2D patients is unknown. Here, we examined locus-specific changes in LINE-1 and Alu methylation in PSD and the potential to offset these changes via supplementation with folate and vitamin B12. We interrogated DNA methylation patterns corresponding to 22,352 probes for LINE-1 and Alu elements using publicly-available Illumina Infinium 450K methylation datasets from i) an 18-month prospective study in 28 T2D patients (GSE62003) and ii) an intervention study in which 44 individuals were supplemented with folic acid (400 µg/day) and vitamin B12 (500 µg/day) over two years (GSE74548). We identified 714 differentially methylated positions (DMP) mapping to retrotransposons in T2D patients who developed PSD in comparison to those who did not (PFDR < 0.05), comprised of 2.4% (228 probes) of all LINE-1 probes and 3.8% (486 probes) of all Alu probes. These loci were enriched in genes with functions related to Alzheimer's disease and cognitive decline, including GNB5, GNG7 and PKN3 (p < 0.05). In older individuals supplemented with folate/vitamin B12, 85 (11.9%) PSD retrotransposon loci showed significant changes in methylation (p < 0.05): participants with the MTHFR CC genotype predominantly showed hypermethylation at these loci, while hypomethylation was observed more frequently in those with the TT genotype. In T2D patients, LINE-1 and Alu elements are differentially methylated in PSD in a locus-specific manner and may offer clinical utility in monitoring risk of dementia. Further work is required to examine the potential for dietary supplementation in lowering the risk of PSD.

It's No Has Bean: A Review of the Effects of White Kidney Bean Extract on Body Composition and Metabolic Health.

The rising prevalence of overweight and obesity is a global concern, increasing the risk of numerous non-communicable diseases and reducing quality of life. A healthy diet and exercise remain the cornerstone treatments for obesity. However, adherence rates can be low and the effectiveness of these interventions is often less than anticipated, due to compensatory changes in other aspects of the energy balance equation. Whilst some alternative weight-loss therapies are available, these strategies are often associated with side effects and are expensive. An alternative or adjunct to traditional weight-loss approaches may be the use of bioactive compounds extracted from food sources, which can be incorporated into habitual diet with a low cost and minimal burden. One product which has attracted attention in this regard is white kidney bean extract (WKBE), which has been suggested to inhibit the enzyme α-amylase, limiting carbohydrate digestion and absorption with small but potentially meaningful attendant beneficial effects on body weight and metabolic health. In this review, drawing evidence from both human and animal studies, we discuss the current evidence around the effects of WKBE on body composition and metabolic health. In addition, we discuss evidence on the safety of this supplement and explore potential directions for future research.

Alzheimer's disease pathogenesis: Is there a role for folate?

Epigenetic modifications, including changes in DNA methylation, have been implicated in a wide range of diseases including neurological diseases such as Alzheimer's. The role of dietary folate in providing methyl groups required for maintenance and modulation of DNA methylation makes it a nutrient of interest in Alzheimer's. Late onset Alzheimer's disease is the most common form of dementia and at present its aetiology is largely undetermined. From epidemiological studies, the interactions between folate, B-vitamins and homocysteine as well as the long latency period has led to difficulties in interpretation of the data, thus current evidence exploring the role of dietary folate in Alzheimer's is contradictory and unresolved. Therefore, examining the effects at a molecular level and exploring potential epigenetic mechanisms could increase our understanding of the disease and aetiology. The aim of this review is to examine the role that folate could play in Alzheimer's disease neuropathology and will focus on the effects of folate on DNA methylation which link to disease pathology, initiation and progression.