Fig. 1.

Hypothesised model of the complex relationship between biological variation and some major forms of psychopathology.

This is a simplified model of a highly complex set of relationships between genotype and clinical phenotype. Starting at the level of genetic variation (lowest tier in figure), we have represented DNA structural variation (in purple) as contributing particularly to neurodevelopmental disorders and associated particularly with enduring cognitive and functional impairment. Single gene variants, of which there are many, are shown as asterisks. In general, even single base-pair changes in a gene may influence multiple biological systems because genes typically have multiple functions and produce proteins that interact with multiple other proteins. For simplicity, we have shown only an example of a variant that influences three biological systems (blue asterisk and arrows) and another that influences only one system (black asterisk and arrow). Variation in the relevant biological systems is influenced by genotype at many genetic loci and by environmental exposures/experiences both historically during development and currently to influence the dynamic state of the systems. The relevant biological systems influence the neural modules that comprise the key relevant functional elements of the brain (shown as solid turquoise circles). Typically, multiple biological systems influence each neural module. The (abnormal) functioning of the neural modules together influences the domains of psychopathology experienced and ultimately the clinical syndromes. We have ordered some important clinical syndromes along a single major axis with a gradient of decreasing proportional neurodevelopmental contribution to causation and reciprocal increasing gradient of proportion of episodic affective disturbance (we use the term ‘mental retardation’ in the diagram because it is understood internationally, but recognise that the terms intellectual disability and learning disability are commonly used in the UK). The single axis is a simplifying device – there is substantial individual variation and it is recognised that, for example, it is not uncommon for individuals diagnosed with autism to experience substantial mood pathology. Key features of the model are described within the text.