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

Abstract

According 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.