Abstract
Sex differences in the human brain are of interest for many reasons: for example, there are sex differences in the observed prevalence of psychiatric disorders and in some psychological ...traits that brain differences might help to explain. We report the largest single-sample study of structural and functional sex differences in the human brain (2750 female, 2466 male participants; mean age 61.7 years, range 44-77 years). Males had higher raw volumes, raw surface areas, and white matter fractional anisotropy; females had higher raw cortical thickness and higher white matter tract complexity. There was considerable distributional overlap between the sexes. Subregional differences were not fully attributable to differences in total volume, total surface area, mean cortical thickness, or height. There was generally greater male variance across the raw structural measures. Functional connectome organization showed stronger connectivity for males in unimodal sensorimotor cortices, and stronger connectivity for females in the default mode network. This large-scale study provides a foundation for attempts to understand the causes and consequences of sex differences in adult brain structure and function.
AbstractBackgroundSchizophrenia is a neurodevelopmental disorder with many genetic variants of individually small effect contributing to phenotypic variation. Lower cortical thickness (CT), surface ...area, and cortical volume have been demonstrated in people with schizophrenia. Furthermore, a range of obstetric complications (e.g., lower birth weight) are consistently associated with an increased risk for schizophrenia. We investigated whether a high polygenic risk score for schizophrenia (PGRS-SCZ) is associated with CT, surface area, and cortical volume in UK Biobank, a population-based sample, and tested for interactions with birth weight. MethodsData were available for 2864 participants ( nmale/ nfemale = 1382/1482; mean age = 62.35 years, SD = 7.40). Linear mixed models were used to test for associations among PGRS-SCZ and cortical volume, surface area, and CT and between PGRS-SCZ and birth weight. Interaction effects of these variables on cortical structure were also tested. ResultsWe found a significant negative association between PGRS-SCZ and global CT; a higher PGRS-SCZ was associated with lower CT across the whole brain. We also report a significant negative association between PGRS-SCZ and insular lobe CT. PGRS-SCZ was not associated with birth weight and no PGRS-SCZ × birth weight interactions were found. ConclusionsThese results suggest that individual differences in CT are partly influenced by genetic variants and are most likely not due to factors downstream of disease onset. This approach may help to elucidate the genetic pathophysiology of schizophrenia. Further investigation in case-control and high-risk samples could help identify any localized effects of PGRS-SCZ, and other potential schizophrenia risk factors, on CT as symptoms develop.
Abstract There are established differences in cortical thickness (CT) in schizophrenia (SCZ) and bipolar (BD) patients when compared to healthy controls (HC). However, it is unknown to what extent ...environmental or genetic risk factors impact on CT in these populations. We have investigated the effect of Environmental Risk Scores (ERS) and Polygenic Risk Scores for SCZ (PGRS-SCZ) on CT. Structural MRI scans were acquired at 3T for patients with SCZ or BD (n = 57) and controls (n = 41). Cortical reconstructions were generated in FreeSurfer (v5.3). The ERS was created by determining exposure to cannabis use, childhood adverse events, migration, urbanicity and obstetric complications. The PGRS-SCZ were generated, for a subset of the sample (Patients = 43, HC = 32), based on the latest PGC GWAS findings. ANCOVAs were used to test the hypotheses that ERS and PGRS-SCZ relate to CT globally, and in frontal and temporal lobes. An increase in ERS was negatively associated with CT within temporal lobe for patients. A higher PGRS-SCZ was also related to global cortical thinning for patients. ERS effects remained significant when including PGRS-SCZ as a fixed effect. No relationship which survived FDR correction was found for ERS and PGRS-SCZ in controls. Environmental risk for SCZ was related to localised cortical thinning in patients with SCZ and BD, while increased PGRS-SCZ was associated with global cortical thinning. Genetic and environmental risk factors for SCZ appear therefore to have differential effects. This provides a mechanistic means by which different risk factors may contribute to the development of SCZ and BD.
It is now accepted that Schizophrenia, a neurodevelopmental disorder which affects around 1% of the population, is influenced by both genetic and environmental risk factors. Schizophrenia is ...evidenced as being heritable with twin-heritability estimates of around 80%. Recently, the disorder has been demonstrated to be polygenic in nature; many genetic variants with individually small effects contribute to the overall phenotypic variation. Furthermore, cannabis use, adverse events, urbanicity, obstetric complications and migration, are five environmental risk factors that have been evidenced as being associated with an increased risk of developing the disorder. Abnormalities in brain structure are also well evidenced in individuals with schizophrenia, in particular, reduced cortical thickness, volume and surface area have been linked to those with schizophrenia when compared to healthy controls. It has been posited that these cortical alterations may predate disorder onset, for example, disruptions in brain development may be a function of experiencing schizophrenia-associated genetic and environmental risk factors. However, the link between genes, environment and brain structure within schizophrenia remains unclear. In this thesis, we aimed to examine whether genetic and environmental risk factors for schizophrenia directly impact cortical brain structure. Methods and Results The current aims were assessed using measures of cortical thickness, volume and surface area, as defined by FreeSurfer, in three separate studies. Firstly, ANCOVA models were applied to a case-control sample, the Scottish Family Mental Health (SFMH) study, ncontrols/npatients = 41/58) to determine whether PolyGenic Risk Scores for Schizophrenia (PGRS-SCZ) are associated with lower cortical thickness both globally and within regions of interest (frontal and temporal lobes) as well as to examine whether the effects of experiencing an accumulation of the five environmental risk factors (outlined above) is associated with greater cortical thinning (Chapter Two). The results indicated that an increased PGRS-SCZ was related to lower, global cortical thickness in the whole sample and not a result of group differences. With regards to environmental effects, the more environmental risk factors experienced, the lower the cortical thickness, this was specific to the temporal lobe. Secondly, to further investigate the link between environmental risk factors of schizophrenia, we focused on birth weight as a proxy for obstetric complications (Chapter Three). Linear mixed effects regression (LME) models were used to assess whether birth weight was associated with cortical thickness, surface area and volume in a UK Biobank (UKB) sample (n = 1,680). We then applied Mendelian Randomisation (MR) to determine if birth weight-associated genetic variants were causally related to cortical structure. The results in this chapter suggested that higher weight at birth was associated with larger cortical volumes and surface area, both globally and in several cortical sub-regions. In contrast, a negative association was found between birth weight and cortical thickness in the lateral occipital parcel. MR analysis suggested a causal link of birth weight, as indexed by genetic variants, and insular lobe cortical volume as well as surface area globally, in the insular lobe and in middle temporal, medial orbitofrontal and inferior frontal gyrus parcels. Lastly, we tested whether the same association between PGRS-SCZ and cortical thickness (outlined in Chapter Two) could be replicated within a subset of UKB (Chapter Four). For this, we again utilised LME models using the second genetic data release of UKB (n = 2,864). We tested this globally, lobarly and within 27 bilateral cortical parcels for each of these parameters. We found a higher PGRS-SCZ to be associated with lower global cortical volume and thickness as well as insular lobe cortical thickness. To further test potential environmental influences (as outlined in Chapter Three) on these effects, we used a liner regression model to test for a relationship between PGRS-SCZ and birth weight as well as LME models to test for interactional effects. No relationship was found between PGRS-SCZ and birth weight nor were there any significant interactions found between PGRS-SCZ and birth weight on cortical structure Conclusion Together, these studies highlight the fact that both genetic and environmental risk factors for schizophrenia may, indeed, directly but differentially impact cortical brain structure. This information may help us to further understand the progression of the disorder but also, by identifying and addressing these risk factors early, we may be able to minimise the impact that the disorder can have on cortical brain structure; particularly in relation to potentially modifiable factors, such as birth weight. We also highlight the importance of using large samples and replications in order to examine such relationships.
Induced pluripotent stem cells (iPSCs) and their differentiated neurons (iPSC-neurons) are a widely used cellular model in the research of the central nervous system. However, it is unknown how well ...they capture age-associated processes, particularly given that pluripotent cells are only present during the earliest stages of mammalian development. Epigenetic clocks utilize coordinated age-associated changes in DNA methylation to make predictions that correlate strongly with chronological age. It has been shown that the induction of pluripotency rejuvenates predicted epigenetic age. As existing clocks are not optimized for the study of brain development, we developed the fetal brain clock (FBC), a bespoke epigenetic clock trained in human prenatal brain samples in order to investigate more precisely the epigenetic age of iPSCs and iPSC-neurons. The FBC was tested in two independent validation cohorts across a total of 194 samples, confirming that the FBC outperforms other established epigenetic clocks in fetal brain cohorts. We applied the FBC to DNA methylation data from iPSCs and embryonic stem cells and their derived neuronal precursor cells and neurons, finding that these cell types are epigenetically characterized as having an early fetal age. Furthermore, while differentiation from iPSCs to neurons significantly increases epigenetic age, iPSC-neurons are still predicted as being fetal. Together our findings reiterate the need to better understand the limitations of existing epigenetic clocks for answering biological research questions and highlight a limitation of iPSC-neurons as a cellular model of age-related diseases.
Human DNA methylation data have been used to develop biomarkers of ageing, referred to as 'epigenetic clocks', which have been widely used to identify differences between chronological age and ...biological age in health and disease including neurodegeneration, dementia and other brain phenotypes. Existing DNA methylation clocks have been shown to be highly accurate in blood but are less precise when used in older samples or in tissue types not included in training the model, including brain. We aimed to develop a novel epigenetic clock that performs optimally in human cortex tissue and has the potential to identify phenotypes associated with biological ageing in the brain. We generated an extensive dataset of human cortex DNA methylation data spanning the life course (n = 1397, ages = 1 to 108 years). This dataset was split into 'training' and 'testing' samples (training: n = 1047; testing: n = 350). DNA methylation age estimators were derived using a transformed version of chronological age on DNA methylation at specific sites using elastic net regression, a supervised machine learning method. The cortical clock was subsequently validated in a novel independent human cortex dataset (n = 1221, ages = 41 to 104 years) and tested for specificity in a large whole blood dataset (n = 1175, ages = 28 to 98 years). We identified a set of 347 DNA methylation sites that, in combination, optimally predict age in the human cortex. The sum of DNA methylation levels at these sites weighted by their regression coefficients provide the cortical DNA methylation clock age estimate. The novel clock dramatically outperformed previously reported clocks in additional cortical datasets. Our findings suggest that previous associations between predicted DNA methylation age and neurodegenerative phenotypes might represent false positives resulting from clocks not robustly calibrated to the tissue being tested and for phenotypes that become manifest in older ages. The age distribution and tissue type of samples included in training datasets need to be considered when building and applying epigenetic clock algorithms to human epidemiological or disease cohorts.
The pancreatic beta cell is unique in its response to nutrient by increased fuel oxidation. Recent studies have demonstrated that oxygen consumption rate (OCR) may be a valuable predictor of islet ...quality and long term nutrient responsiveness. To date, high-throughput and user-friendly assays for islet respiration are lacking. The aim of this study was to develop such an assay and to examine bioenergetic efficiency of rodent and human islets.
The XF24 respirometer platform was adapted to islets by the development of a 24-well plate specifically designed to confine islets. The islet plate generated data with low inter-well variability and enabled stable measurement of oxygen consumption for hours. The F1F0 ATP synthase blocker oligomycin was used to assess uncoupling while rotenone together with myxothiazol/antimycin was used to measure the level of non-mitochondrial respiration. The use of oligomycin in islets was validated by reversing its effect in the presence of the uncoupler FCCP. Respiratory leak averaged to 59% and 49% of basal OCR in islets from C57Bl6/J and FVB/N mice, respectively. In comparison, respiratory leak of INS-1 cells and C2C12 myotubes was measured to 38% and 23% respectively. Islets from a cohort of human donors showed a respiratory leak of 38%, significantly lower than mouse islets.
The assay for islet respiration presented here provides a novel tool that can be used to study islet mitochondrial function in a relatively high-throughput manner. The data obtained in this study shows that rodent islets are less bioenergetically efficient than human islets as well as INS1 cells.
Carbonate lithologies tend to have highly heterogeneous and tortuous pore systems that are created and/or modified by diagenetic and tectonic processes following deposition. The correlation between ...porosity and permeability in carbonate lithologies is often poor as a result of their heterogeneous and complex pore systems. To effectively predict permeability, it is necessary to understand the processes that modify pore systems and quantify the impact of these modifications on permeability. Using outcrop exposures of normal fault zones hosted in carbonate lithologies on the Maltese Islands, this study documents the evolution of textures in contrasting carbonate lithofacies (wackestones, packstones and pack/grainstones) across two normal fault zones of varying displacement (c. 10 and 100 m). The pore system modifications associated with these textural changes are quantified using image analysis and point count methods, while porosity and permeability are measured across the studied fault zones using core plug porosimetry and permeametry techniques.
The fault related processes that occur within the fault zones are controlled by the primary lithofacies and to a lesser extent the fault displacement. Aggrading neomorphism is observed within the damage zones in the grain supported lithofacies and is postdated by fracturing. In the micrite supported lithofacies in the same damage zones, aggrading neomorphism is absent, but fracturing is prevalent. In the fault core, brecciation occurs in both lithofacies within the 10 and 100 m displacement fault zones, while cataclasis is only active in the grain supported lithofacies in the higher displacement fault zone. The mineralogical and textural compositions of the primary lithofacies dictate the processes that occur in the fault zones. These processes variably modify the pore systems and hence control the temporal evolution of permeability in the fault zones. Such observations can help understand reservoir quality distribution around fault zones in the subsurface reservoirs.
•Two categories of fault processes are active in carbonate hosted fault zones.•Porosity occlusion processes, e.g. aggrading neomorphism, reduce permeability.•Porosity creation processes, e.g. fracturing and dissolution, enhance permeability.•The processes active are dependent on the lithofacies and the fault displacement.•These processes control the spatial and temporal evolution of permeability.
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