An evolutionary timeline of the oxytocin signaling pathway.

Oxytocin is a neuropeptide associated with both psychological and somatic processes like parturition and social bonding. Although oxytocin homologs have been identified in many species, the evolutionary timeline of the entire oxytocin signaling gene pathway has yet to be described. Using protein sequence similarity searches, microsynteny, and phylostratigraphy, we assigned the genes supporting the oxytocin pathway to different phylostrata based on when we found they likely arose in evolution. We show that the majority (64%) of genes in the pathway are 'modern'. Most of the modern genes evolved around the emergence of vertebrates or jawed vertebrates (540 - 530 million years ago, 'mya'), including OXTR, OXT and CD38. Of those, 45% were under positive selection at some point during vertebrate evolution. We also found that 18% of the genes in the oxytocin pathway are 'ancient', meaning their emergence dates back to cellular organisms and opisthokonta (3500-1100 mya). The remaining genes (18%) that evolved after ancient and before modern genes were classified as 'medium-aged'. Functional analyses revealed that, in humans, medium-aged oxytocin pathway genes are highly expressed in contractile organs, while modern genes in the oxytocin pathway are primarily expressed in the brain and muscle tissue.

Association between gestational levels of toxic metals and essential elements and cerebral palsy in children.

Introduction: Cerebral palsy (CP) is the most common motor disability in childhood, but its causes are only partly known. Early-life exposure to toxic metals and inadequate or excess amounts of essential elements can adversely affect brain and nervous system development. However, little is still known about these as perinatal risk factors for CP. This study aims to investigate the associations between second trimester maternal blood levels of toxic metals, essential elements, and mixtures thereof, with CP diagnoses in children. Methods: In a large, population-based prospective birth cohort (The Norwegian Mother, Father, and Child Cohort Study), children with CP diagnoses were identified through The Norwegian Patient Registry and Cerebral Palsy Registry of Norway. One hundred forty-four children with CP and 1,082 controls were included. The relationship between maternal blood concentrations of five toxic metals and six essential elements and CP diagnoses were investigated using mixture approaches: elastic net with stability selection to identify important metals/elements in the mixture in relation to CP; then logistic regressions of the selected metals/elements to estimate odds ratio (OR) of CP and two-way interactions among metals/elements and with child sex and maternal education. Finally, the joint effects of the mixtures on CP diagnoses were estimated using quantile-based g-computation analyses. Results: The essential elements manganese and copper, as well as the toxic metal Hg, were the most important in relation to CP. Elevated maternal levels of copper (OR = 1.40) and manganese (OR = 1.20) were associated with increased risk of CP, while Hg levels were, counterintuitively, inversely related to CP. Metal/element interactions that were associated with CP were observed, and that sex and maternal education influenced the relationships between metals/elements and CP. In the joint mixture approach no significant association between the mixture of metals/elements and CP (OR = 1.00, 95% CI = [0.67, 1.50]) was identified. Conclusion: Using mixture approaches, elevated levels of copper and manganese measured in maternal blood during the second trimester could be related to increased risk of CP in children. The inverse associations between maternal Hg and CP could reflect Hg as a marker of maternal fish intake and thus nutrients beneficial for foetal brain development.

Brain-based gene expression of putative risk genes for anorexia nervosa.

The etiology of anorexia nervosa (AN) remains elusive. Recent genome-wide association studies identified the first genes liked to AN which reached genome-wide significance, although our understanding of how these genes confer risk remains preliminary. Here, we leverage the Allen Human Brain Atlas to characterize the spatially distributed gene expression patterns of genes linked to AN in the non-disordered human brain, developing whole-brain maps of AN gene expression. We found that genes associated with AN are most expressed in the brain, relative to all other body tissue types, and demonstrate gene-specific expression patterns which extend to cerebellar, temporal and basal ganglia structures in particular. fMRI meta-analyses reveal that AN gene expression maps correspond with functional brain activity involved in processing and anticipating appetitive and aversive cues. Findings offer novel insights around putative mechanisms through which genes associated with AN may confer risk.

The oxytocin signalling gene pathway contributes to the association between loneliness and cardiometabolic health.

Increasing evidence has shown adverse effects of loneliness on cardiometabolic health. The neuromodulator and hormone oxytocin has traditionally been linked with social cognition and behaviour. However, recent implications of the oxytocin system in energy metabolism and the overrepresentation of metabolic issues in psychiatric illness suggests that oxytocin may represent a mechanism bridging mental and somatic traits. To clarify the role of the oxytocin signalling system in the link between cardiometabolic risk factors and loneliness, we calculated the contribution of single nucleotide polymorphisms (SNPs) in the oxytocin signalling pathway gene-set (154 genes) to the polygenic architecture of loneliness and body mass index (BMI). We investigated the associations of these oxytocin signalling pathway polygenic scores with body composition measured using body magnetic resonance imaging (MRI), bone mineral density (BMD), haematological markers, and blood pressure in a sample of just under half a million adults from the UK Biobank (BMD subsample n = 274,457; body MRI subsample n = 9796). Our analysis revealed significant associations of the oxytocin signalling pathway polygenic score for BMI with abdominal subcutaneous fat tissue, HDL cholesterol, lipoprotein(a), triglycerides, and BMD. We also found an association between the oxytocin signalling pathway polygenic score for loneliness and apolipoprotein A1, the major protein component of HDL. Altogether, these results provide additional evidence for the oxytocin signalling pathway's role in energy metabolism, lipid homoeostasis, and bone density, and support oxytocin's complex pleiotropic effects.

Adipose tissue distribution from body MRI is associated with cross-sectional and longitudinal brain age in adults.

There is an intimate body-brain connection in ageing, and obesity is a key risk factor for poor cardiometabolic health and neurodegenerative conditions. Although research has demonstrated deleterious effects of obesity on brain structure and function, the majority of studies have used conventional measures such as waist-to-hip ratio, waist circumference, and body mass index. While sensitive to gross features of body composition, such global anthropometric features fail to describe regional differences in body fat distribution and composition. The sample consisted of baseline brain magnetic resonance imaging (MRI) acquired from 790 healthy participants aged 18-94 years (mean ± standard deviation (SD) at baseline: 46.8 ± 16.3), and follow-up brain MRI collected from 272 of those individuals (two time-points with 19.7 months interval, on average (min = 9.8, max = 35.6). Of the 790 included participants, cross-sectional body MRI data was available from a subgroup of 286 participants, with age range 19-86 (mean = 57.6, SD = 15.6). Adopting a mixed cross-sectional and longitudinal design, we investigated cross-sectional body magnetic resonance imaging measures of adipose tissue distribution in relation to longitudinal brain structure using MRI-based morphometry (T1) and diffusion tensor imaging (DTI). We estimated tissue-specific brain age at two time points and performed Bayesian multilevel modelling to investigate the associations between adipose measures at follow-up and brain age gap (BAG) - the difference between actual age and the prediction of the brain's biological age - at baseline and follow-up. We also tested for interactions between BAG and both time and age on each adipose measure. The results showed credible associations between T1-based BAG and liver fat, muscle fat infiltration (MFI), and weight-to-muscle ratio (WMR), indicating older-appearing brains in people with higher measures of adipose tissue. Longitudinal evidence supported interaction effects between time and MFI and WMR on T1-based BAG, indicating accelerated ageing over the course of the study period in people with higher measures of adipose tissue. The results show that specific measures of fat distribution are associated with brain ageing and that different compartments of adipose tissue may be differentially linked with increased brain ageing, with potential to identify key processes involved in age-related transdiagnostic disease processes.

Oxytocin-pathway polygenic scores for severe mental disorders and metabolic phenotypes in the UK Biobank.

Oxytocin is a neuromodulator and hormone that is typically associated with social cognition and behavior. In light of its purported effects on social cognition and behavior, research has investigated its potential as a treatment for psychiatric illnesses characterized by social dysfunction, such as schizophrenia and bipolar disorder. While the results of these trials have been mixed, more recent evidence suggests that the oxytocin system is also linked with cardiometabolic conditions for which individuals with severe mental disorders are at a higher risk for developing. To investigate whether the oxytocin system has a pleiotropic effect on the etiology of severe mental illness and cardiometabolic conditions, we explored oxytocin's role in the shared genetic liability of schizophrenia, bipolar disorder, type-2 diabetes, and several phenotypes linked with cardiovascular disease and type 2 diabetes risk using a polygenic pathway-specific approach. Analysis of a large sample with about 480,000 individuals (UK Biobank) revealed statistically significant associations across the range of phenotypes analyzed. By comparing these effects to those of polygenic scores calculated from 100 random gene sets, we also demonstrated the specificity of many of these significant results. Altogether, our results suggest that the shared effect of oxytocin-system dysfunction could help partially explain the co-occurrence of social and cardiometabolic dysfunction in severe mental illnesses.

Prominent health problems, socioeconomic deprivation, and higher brain age in lonely and isolated individuals: A population-based study.

Loneliness is linked to increased risk for Alzheimer's disease, but little is known about factors potentially contributing to adverse brain health in lonely individuals. In this study, we used data from 24,867 UK Biobank participants to investigate risk factors related to loneliness and estimated brain age based on neuroimaging data. The results showed that on average, individuals who self-reported loneliness on a single yes/no item scored higher on neuroticism, depression, social isolation, and socioeconomic deprivation, performed less physical activity, and had higher BMI compared to individuals who did not report loneliness. In line with studies pointing to a genetic overlap of loneliness with neuroticism and depression, permutation feature importance ranked these factors as the most important for classifying lonely vs. not lonely individuals (ROC AUC = 0.83). While strongly linked to loneliness, neuroticism and depression were not associated with brain age estimates. Conversely, objective social isolation showed a main effect on brain age, and individuals reporting both loneliness and social isolation showed higher brain age relative to controls - as part of a prominent risk profile with elevated scores on socioeconomic deprivation and unhealthy lifestyle behaviours, in addition to neuroticism and depression. While longitudinal studies are required to determine causality, this finding may indicate that the combination of social isolation and a genetic predisposition for loneliness involves a risk for adverse brain health. Importantly, the results underline the complexity in associations between loneliness and adverse health outcomes, where observed risks likely depend on a combination of interlinked variables including genetic as well as social, behavioural, physical, and socioeconomic factors.

Population-based body-brain mapping links brain morphology with anthropometrics and body composition.

Understanding complex body-brain processes and the interplay between adipose tissue and brain health is important for understanding comorbidity between psychiatric and cardiometabolic disorders. We investigated associations between brain structure and anthropometric and body composition measures using brain magnetic resonance imaging (MRI; n = 24,728) and body MRI (n = 4973) of generally healthy participants in the UK Biobank. We derived regional and global measures of brain morphometry using FreeSurfer and tested their association with (i) anthropometric measures, and (ii) adipose and muscle tissue measured from body MRI. We identified several significant associations with small effect sizes. Anthropometric measures showed negative, nonlinear, associations with cerebellar/cortical gray matter, and brain stem structures, and positive associations with ventricular volumes. Subcortical structures exhibited mixed effect directionality, with strongest positive association for accumbens. Adipose tissue measures, including liver fat and muscle fat infiltration, were negatively associated with cortical/cerebellum structures, while total thigh muscle volume was positively associated with brain stem and accumbens. Regional investigations of cortical area, thickness, and volume indicated widespread and largely negative associations with anthropometric and adipose tissue measures, with an opposite pattern for thigh muscle volume. Self-reported diabetes, hypertension, or hypercholesterolemia were associated with brain structure. The findings provide new insight into physiological body-brain associations suggestive of shared mechanisms between cardiometabolic risk factors and brain health. Whereas the causality needs to be determined, the observed patterns of body-brain relationships provide a foundation for understanding the underlying mechanisms linking psychiatric disorders with obesity and cardiovascular disease, with potential for the development of new prevention strategies.

Polygenic overlap and shared genetic loci between loneliness, severe mental disorders, and cardiovascular disease risk factors suggest shared molecular mechanisms.

Clinical and epidemiological evidence suggest that loneliness is associated with severe mental disorders (SMDs) and increases the risk of cardiovascular disease (CVD). However, the mechanisms underlying the relationship between loneliness, SMDs, and CVD risk factors remain unknown. Here we explored overlapping genetic architecture and genetic loci shared between SMDs, loneliness, and CVD risk factors. We analyzed large independent genome-wide association study data on schizophrenia (SCZ), bipolar disorder (BD), major depression (MD), loneliness and CVD risk factors using bivariate causal mixture mode (MiXeR), which estimates the total amount of shared variants, and conditional false discovery rate to evaluate overlap in specific loci. We observed substantial genetic overlap between SMDs, loneliness and CVD risk factors, beyond genetic correlation. We identified 149 loci jointly associated with loneliness and SMDs (MD n = 67, SCZ n = 54, and BD n = 28), and 55 distinct loci jointly associated with loneliness and CVD risk factors. A total of 153 novel loneliness loci were found. Most of the shared loci possessed concordant effect directions, suggesting that genetic risk for loneliness may increase the risk of both SMDs and CVD. Functional analyses of the shared loci implicated biological processes related to the brain, metabolic processes, chromatin and immune system. Altogether, the study revealed polygenic overlap between loneliness, SMDs and CVD risk factors, providing new insights into their shared genetic architecture and common genetic mechanisms.

Heart rate variability is associated with disease severity in psychosis spectrum disorders.

While a growing literature links cardiac autonomic dysregulation to a variety of psychiatric disorders, the relationship between cardiac autonomic functioning and specific symptoms in schizophrenia (SZ) and bipolar disorder (BD) remains elusive. Thus, we investigated heart rate variability (HRV), a proxy for vagal activity, as a biological marker for symptom severity in patients with SZ and BD. HRV was calculated in 35 patients with SZ and 52 patients with BD, as well as in 149 healthy controls. In the patient groups, symptom severity and function were measured by the Positive and Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning (GAF) scale. Results showed that HRV was significantly lower in both clinical groups compared to the healthy controls, with no significant HRV differences between patient groups. PANSS general psychopathology scores, GAF symptom scores, and GAF function scores showed statistically significant associations with HRV across groups. These results suggest that disease severity is associated with autonomic dysfunction and that HRV may provide a potential biomarker of disease severity in SZ and BD.

Improving the precision of intranasal oxytocin research.

The neuropeptide oxytocin has been popularized for its role in social behaviour and nominated as a candidate treatment for several psychiatric illnesses due to promising preclinical results. However, these results so far have failed to reliably translate from animal models to human research. In response, there have been justified calls to improve intranasal oxytocin delivery methodology in terms of verifying that intranasal administration increases central levels of oxytocin. Nonetheless, improved methodology needs to be coupled with a robust theory of the role of oxytocin in behaviour and physiology to ask meaningful research questions. Moreover, stringent methodology based on robust theory may yield interesting results, but such findings will have limited utility if they are not reproducible. We outline how the precision of intranasal oxytocin research can be improved by the complementary consideration of methodology, theory and reproducibility.

Associations of loneliness and social isolation with cardiovascular and metabolic health: a systematic review and meta-analysis protocol.

BACKGROUND: A growing number of studies suggest that social isolation and loneliness are associated with premature mortality and are more prevalent among people with mental illness than in the general population, outlining many potential paths to disease still to be elucidated. The purpose of this meta-analysis is to examine the relationship between loneliness, social isolation, and established cardiovascular/metabolic risk factors and disorders, especially in severe mental illness, and to account for potential heterogeneity in the literature. METHODS/DESIGN: Studies that report measures of loneliness and/or social isolation along with cardiovascular/metabolic risk factors will be identified. PubMed, EMBASE (through Ovid SP), Scopus, and PsycINFO (through Ovid SP) will be searched, along with citation lists of retrieved articles and the Cochrane Database of Systematic Reviews. Grey literature will be searched using Google Scholar. Data will be extracted from eligible studies for a random effects meta-analysis. For each study, a summary effect size, heterogeneity, risk of bias, publication bias, and the effect of categorical and continuous moderator variables will be determined. DISCUSSION: This proposed systematic review and meta-analysis will identify and synthesise evidence to determine if there is an association between loneliness, social isolation, and cardiovascular/metabolic risk factors, with a special focus on severe mental illnesses. The results will help determine links and promising avenues of further research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018111911.