Identifying the impact of mental disorder risk alleles on childhood neurodevelopment

Mental disorders are common; they account for the largest global burden of morbidity-more than any other disorder group. A serious challenge to progress in managing mental disorders is that for diagnosis, treatment and early intervention, we rely on late manifestations of disease and patient reports alone with no biological tests. For other complex medical disorders (e.g. coronary heart disease), the identification of early risk processes in the general population during childhood has been critical in terms of informing public health strategies to reduce risks of later disorder.

In this proposal our starting point is the progress that has been made in gene discoveries from large patient populations that provide independent biologically-based and clinically relevant illness "markers". We will take these discoveries into the general population and use them to define composite scores of "mental disorder risk allele profiles". We then identify the impact of these mental disorder genetic risk scores on key aspects of normal child development - "neurodevelopmental" domains (e.g. fear, concentration) to specifically find out which aspects of child development are affected by genetic risk. We will then examine whether gene scores contribute to how these normal childhood processes develop from a very young age to just before puberty (after which time many mental disorders start). We will also begin to examine how tractable the genetic risk score-identified childhood neurodevelopment measures are over time-via one example of an early environmental risk exposure-childhood bullying victimisation.

Many mental disorders such as schizophrenia are highly heritable. International studies have led to risk gene and risk gene profile discoveries. However we have yet to understand the processes by which gene variants in the general population become translated into psychiatric disorders. In this proposal, we begin to address this using two UK population cohorts. We focus on childhood as most mental disorders have their origins in childhood so risks begin to operate then. We begin with mental disorder risk allele scores found in large scale gene discovery patient studies and examine their impact in the general population. The hypothesis we will test is that mental disorder risk alleles when summed together as a risk score affect normative and dimensional childhood neurodevelopmental domains in the general population (e.g. mood regulation, attention), that differ from the defining features of illness (e.g. hallucinations) and that will cut across different disorders (as indicated by risk gene profiles). We will examine the impact of mental disorder risk allele scores on the longitudinal course of key neurodevelopmental domains and test, using one example, that they are shifted by exposure to early adversity.

1. One impact is to inform scientists as to which neurodevelopmental dimensions are important to assess more deeply in patient and longitudinal high-risk clinical and early intervention studies.

2. A second potential impact is to provide invaluable information on potential early intervention targets for early public health and indicated interventions/preventions-in schools, the community and mental health services.

3. Finally results will also contribute significantly to on-going ambitions of scientific and clinical communities, as exemplified by NIMH RDoc, to develop cross diagnostic nosology and identify trans-diagnostic dimensional processes relevant to mental disorder. The proposal will have a different impact to other types of research in that it focuses across different mental disorders rather than on one diagnosis.

The time line for these impacts would be 5 to 7 years.

4. The post doc will acquire strong analytic skills by working on two UK cohorts and across research areas-genetics, child psychiatry, adult psychiatry, social epidemiology and across psychiatric disorders. The person appointed will contribute to UK mental health research. We have an excellent track record in developing research capacity at post-doctoral levels and beyond. The timeline for this is 5 years.