The goal of this thesis is to provide a comprehensive etiological model in terms of the putative genetic and environmental pathways which increase vulnerability to psychological distress as measured by the symptoms of depression, anxiety and somatic complaints. It is hoped that this knowledge will facilitate more precisely targeted public health interventions and prevention strategies. The diathesis-stress model which is introduced in Chapter 1, predicts that genetic precursors and stable characteristics of temperament will interact with environmental stressors to increase the probability of experiencing psychological distress. The diathesis in this thesis will be indexed by the personality dimension of Neuroticism because it encompasses stable psychological and behavioural characteristics and has a strong heritable component. Moreover, it represents one the most reliable vulnerability markers for major mood and anxiety disorders.
When data from twins are available it becomes possible to quantify the genetic and environmental relationship between a diathesis and the environment, as well as their relationship with dependent measures of psychological distress. The methodology underpinning the discipline of behaviour genetics is complex, and Chapter 2 begins with an introduction to the classical twin design which provides a robust means to explain natural variation in human behaviour in terms of genetic and environmental effects. In a series of studies, the models described in chapter 2 are used to explore the genetic etiology of personality, parenting and stressful life events, and how these interact with psychological distress. Data for these analyses are based on eight QIMR studies of three twin cohorts conducted between 1980 and 1999, which are described in Chapter 3.
Factor analyses in Chapter 4 examine whether symptoms of somatic distress fall within the taxonomy of neurotic
conditions as measured by symptoms of anxiety and depression. In Chapter 5, multivariate models are fitted to the same measures to examine whether they share common genetic influences or are partly distinct from one another. Existing personality measures already provide an accurate means for predicting individuals likely to be diagnosed with a mood or anxiety disorder. The extent to which Boyce and Parker's Interpersonal Sensitivity Measure (IPSM) provides a better means of identifying 'at risk' individuals is tested empirically in Chapter 6, by estimating the proportion of genetic and environmental variance in the IPSM which can be explained by the personality dimensions of Eysenck and Cloninger. While not entirely germane to the thesis. Chapter 7 applies the same multivariate methods to estimate the degree to which genetic and environmental variance in Cloninger's dimensions of character can be explained by the dimensions of temperament.
technique, using cross sectional data, is introduced in Chapter 8 to model a series of hypotheses regarding the direction of causation between latent constructs of parenting and psychological distress. In Chapter 9, simplex models are used to estimate the extent to which the genetic variation in anxiety and depression persists across the life span. In Chapter 10, the quantitative or qualitative changes over time in the magnitude of genetic and environmental effects in measures of adolescent Neuroticism will be examined.
The current thrust of behaviour and molecular genetics is the identification of predisposing genes for complex behaviours and quantitative trait loci (QTL) for phenotypes of biomedical interest. Given its significant genetic covariation with depression and anxiety, Neuroticism is an ideal phenotype for identifying QTLs underpinning anxiety and depression. Chapter 11 includes results from the first genome-wide linkage scan of Neuroticism in
adolescents. The identification and firm replication of genes predisposing to mood and anxiety disorders will represent a major breakthrough in psychiatric genetics.
Only a subset of environmental risk factors has consistently been shown to precede the onset of major mood and anxiety disorders. Among these, stressful life events increase the risk for depressive illnesses but their genetic and environmental etiologies remain largely unknown. Analyses in Chapter 12 will explore the genetic and environmental etiology of stressful life events and at the same time, explore whether there are any main effects of the serotonin transporter (5-HTTLPR) genotype on Neuroticism. The final analyses in this thesis explore whether variation in the 5- HTTLPR genotype can moderate the influence of stressful life events on major depression.