Genetics of Environmental Sensitivity and its Moderating Effects on Mental Health Outcomes

PhDAccording to differential susceptibility theories, individuals vary in the extent to which they are impacted by the quality of their environment, with some individuals identified as generally more sensitive than others making them more susceptible to develop psychopathology in adverse contexts but also more likely to benefit from positive environmental contexts such as psychological interventions. Such individual differences in environmental sensitivity are hypothesised to have a genetic basis. This thesis had three main objectives: first, to examine the heritability of environmental sensitivity; second, to identify the molecular genetic variants associated with environmental sensitivity; third, to examine the moderating effects of genetic sensitivity on the impact of negative and positive environmental contexts on mental health. First a new measure of environmental sensitivity was developed for use with children. Applying this measure, the heritability of environmental sensitivity was estimated via twin modelling and its molecular genetic basis was explored using candidate genes, genome-wide data, gene-based analyses and polygenic scoring. Longitudinal mixed effect regression models were used to examine polygenic score-by-environment interactions involved in predicting psychopathology and treatment response. The samples for all studies comprised of children and adolescents (N= 1,000-2,800). The results indicated that environmental sensitivity is heritable (47%, CI = 30-53) and genetically correlated with neuroticism, extraversion, depression and anxiety. Candidate gene and GWAS failed to identify molecular genetic factors that were significantly associated with sensitivity, but polygenic scores of personality, depression and wellbeing predicted variations in sensitivity (~ 3%). Genetic sensitivity was found to moderate the outcomes of environmental exposures, with more sensitive children at higher risk of psychological distress in response to poor quality childhood psychosocial environment, but lower risk of distress later in life. High genetic sensitivity was associated with better response to more individualised type of treatment.Queen Mary University of Londo

Genome-wide DNA methylation profiling identifies convergent molecular signatures associated with idiopathic and syndromic autism in post-mortem human brain tissue

Autism spectrum disorder (ASD) encompasses a collection of complex neuropsychiatric disorders characterized by deficits in social functioning, communication and repetitive behaviour. Building on recent studies supporting a role for developmentally moderated regulatory genomic variation in the molecular aetiology of ASD, we quantified genome-wide patterns of DNA methylation in 223 post-mortem tissues samples isolated from three brain regions [prefrontal cortex, temporal cortex and cerebellum (CB)] dissected from 43 ASD patients and 38 non-psychiatric control donors.We identified widespread differences in DNA methylation associated with idiopathic ASD (iASD), with consistent signals in both cortical regions that were distinct to those observed in the CB. Individuals carrying a duplication on chromosome 15q (dup15q), representing a genetically defined subtype of ASD, were characterized by striking differences in DNA methylation across a discrete domain spanning an imprinted gene cluster within the duplicated region. In addition to the dramatic cis-effects on DNA methylation observed in dup15q carriers, we identified convergent methylomic signatures associated with both iASD and dup15q, reflecting the findings from previous studies of gene expression and H3K27ac. Cortical co-methylation network analysis identified a number of co-methylated modules significantly associated with ASD that are enriched for genomic regions annotated to genes involved in the immune system, synaptic signalling and neuronal regulation. Our study represents the first systematic analysis of DNA methylation associated with ASD across multiple brain regions, providing novel evidence for convergent molecular signatures associated with both idiopathic and syndromic autism

Investigation of the Redox Chemistry of Anthraquinone Derivatives Using Density Functional Theory

Application of density functional calculations to compute electrochemical properties such as redox windows, effect of substitution by electron donating and electron withdrawing groups on redox windows, and solvation free energies for ∼50 anthraquinone (AQ) derivatives are presented because of their potential as anolytes in all-organic redox flow batteries. Computations suggest that lithium ions can increase (by ∼0.4 V) the reduction potential of anthraquinone due to the lithium ion pairing by forming a Lewis base–Lewis acid complex. To design new redox active species, the substitution by electron donating groups is essential to improve the reduction window of AQ with adequate oxidative stability. For instance, a complete methylation of AQ can improve its reduction window by ∼0.4 V. The quantum chemical studies of the ∼50 AQ derivatives are used to derive a relationship that connects the computed LUMO energy and the reduction potential that can be applied as a descriptor for screening thousands of AQ derivatives. Our computations also suggest that incorporating oxy-methyl dioxolane substituents in the AQ framework can increase its interaction with nonaqueous solvent and improve its solubility. Thermochemical calculations for likely bond breaking decomposition reactions of unsubstituted AQ anions suggest that the dianions are relatively stable in the solution. These studies provide an ideal platform to perform further combined experimental and theoretical studies to understand the electrochemical reversibility and solubility of new quinone molecules as energy storage materials

A multivariate genetic analysis of anxiety sensitivity, environmental sensitivity and reported life events in adolescents

Background: Despite being considered a measure of environmental risk, reported life events are partly heritable. One mechanism that may contribute to this heritability is genetic influences on sensitivity, relating to how individuals process and interpret internal and external signals. The aim of this study was to explore the genetic and environmental overlap between self-reported life events and measures of sensitivity. Methods: At age 17, 2,939 individuals from the Twins Early Development Study (TEDS) completed measures of anxiety sensitivity (Children's Anxiety Sensitivity Index), environmental sensitivity (Highly Sensitive Child Scale) and reported their experience of 20 recent life events. Using multivariate Cholesky decomposition models, we investigated the shared genetic and environmental influences on the associations between these measures of sensitivity and the number of reported life events, as well as both negative and positive ratings of life events. Results: The majority of the associations between anxiety sensitivity, environmental sensitivity and reported life events were explained by shared genetic influences (60%-75%), with the remainder explained by non-shared environmental influences (25%-40%). Environmental sensitivity showed comparable genetic correlations with both negative and positive ratings of life events (rA=.21 and .15), anxiety sensitivity only showed a significant genetic correlation with negative ratings of life events (rA=.33). Approximately 10% of the genetic influences on reported life events were accounted for by influences shared with anxiety sensitivity and environmental sensitivity. Conclusion: Differences in how individuals process the contextual aspects of the environment or interpret their own physical and emotional response to environmental stimuli may be one mechanism through which genetic liability influences the subjective experience of life events

BF[subscript 3]-Promoted Electrochemical Properties of Quinoxaline in Propylene Carbonate

Electrochemical and density functional studies demonstrate that coordination of electrolyte constituents to quinoxalines modulates their electrochemical properties. Quinoxalines are shown to be electrochemically inactive in most electrolytes in propylene carbonate, yet the predicted reduction potential is shown to match computational estimates in acetonitrile. We find that in the presence of LiBF[subscript 4] and trace water, an adduct is formed between quinoxaline and the Lewis acid BF[subscript 3], which then displays electrochemical activity at 1–1.5 V higher than prior observations of quinoxaline electrochemistry in non-aqueous media. Direct synthesis and testing of a bis-BF[subscript 3] quinoxaline complex further validates the assignment of the electrochemically active species, presenting up to a ~26-fold improvement in charging capacity, demonstrating the advantages of this adduct over unmodified quinoxaline in LiBF[subscript 4]-based electrolyte. The use of Lewis acids to effectively “turn on” the electrochemical activity of organic molecules may lead to the development of new active material classes for energy storage applications

Metalloenzyme-like catalyzed isomerizations of sugars by Lewis acid zeolites

Isomerization of sugars is used in a variety of industrially relevant processes and in glycolysis. Here, we show that hydrophobic zeolite beta with framework tin or titanium Lewis acid centers isomerizes sugars, e.g., glucose, via reaction pathways that are analogous to those of metalloenzymes. Specifically, experimental and theoretical investigations reveal that glucose partitions into the zeolite in the pyranose form, ring opens to the acyclic form in the presence of the Lewis acid center, isomerizes into the acyclic form of fructose, and finally ring closes to yield the furanose product. The zeolite catalysts provide processing advantages over metalloenzymes such as an ability to work at higher temperatures and in acidic conditions that allow for the isomerization reaction to be coupled with other important conversions

Evolutionary Design of Low Molecular Weight Organic Anolyte Materials for Applications in Nonaqueous Redox Flow Batteries

The integration of renewable energy sources into the electric grid requires low-cost energy storage systems that mediate the variable and intermittent flux of energy associated with most renewables. Nonaqueous redox-flow batteries have emerged as a promising technology for grid-scale energy storage applications. Because the cost of the system scales with mass, the electroactive materials must have a low equivalent weight (ideally 150 g/(mol·<i>e</i>⁻) or less), and must function with low molecular weight supporting electrolytes such as LiBF₄. However, soluble anolyte materials that undergo reversible redox processes in the presence of Li-ion supports are rare. We report the evolutionary design of a series of pyridine-based anolyte materials that exhibit up to two reversible redox couples at low potentials in the presence of Li-ion supporting electrolytes. A combination of cyclic voltammetry of anolyte candidates and independent synthesis of their corresponding charged-states was performed to rapidly screen for the most promising candidates. Results of this workflow provided evidence for possible decomposition pathways of first-generation materials and guided synthetic modifications to improve the stability of anolyte materials under the targeted conditions. This iterative process led to the identification of a promising anolyte material, <i>N</i>-methyl 4-acetylpyridinium tetrafluoroborate. This compound is soluble in nonaqueous solvents, is prepared in a single synthetic step, has a low equivalent weight of 111 g/(mol·<i>e</i>⁻), and undergoes two reversible 1<i>e</i>^<i>–</i> reductions in the presence of LiBF₄ to form reduced products that are stable over days in solution