Interaction between genetic risk and childhood adversity in the development of psychosis and depression.

Mental health problems such as depression and psychosis (e.g., schizophrenia) can be extremely disabling disorders and result in a massive cost for both the individual and NHS services. Greater understanding of what factors are involved in development and persistence of such disorders would assist attempts to prevent and treat them. One of the major factors thought to cause these disorders is an individual‘s genetic make-up but researchers have struggled to identify the exact genes involved in this process possibly because they have largely ignored the role of environmental factors. Therefore, I propose to investigate whether individuals who have a genetic risk (either positive family history or specific genetic variant) and have been exposed to potentially distressing experiences in childhood (severely beaten by or separated from their parents) are more likely to be diagnosed with depression and psychosis than individuals with only one or neither of these factors. To test this proposition I will analyse data from two different cross-sectional case-control studies: an ongoing study of psychosis patients and unaffected individuals from the same geographical area; and a completed study of depressed patients and general population controls that have provided information about their family and childhood history and given DNA samples.

Aims: The research component of this fellowship aims to replicate my PhD findings of a quantitative gene-environment interaction in psychosis and extend this work to depression using molecular genetic data.

Objectives:

1. Determine whether the association with psychotic disorder is replicated for (i) severe maternal physical abuse, and (ii) maternal separation for a year or more during childhood in a different sample to that of my PhD. Furthermore, to explore whether quantitative genetic risk (parental history of mental illness) is also found to moderate these associations.

2. To explore whether there is an interaction between childhood adversity and 5-HTTLPR and BDNF val66met genotypes in recurrent unipolar depression.

Design: Study 1 forms part of the Genes and Psychosis (GAP) cross-sectional case-control study in South London whilst Study 2 utilises data from the multi-centre UK-based DeCC case-control study and the European DeNT affected sibling pairs study.

Methodology: In Study 1 400 first-presentation psychosis patients aged 18-64 years recruited from inpatient wards and a convenience sample of 400 unaffected individuals completed the Family Interview for Genetic Studies (parental history of mental illness) and the Childhood Experiences of Care and Abuse Questionnaire (childhood adversity). Logistic regression analysis will be conducted to explore the prevalence of maternal physical abuse and maternal separation amongst the psychosis cases compared to controls and the potentially confounding and moderating effects of family history of mental illness on these associations will be tested using regression, likelihood-ratio tests and synergism equations.

In Study 2, 3596 patients with recurrent unipolar depression recruited through medical clinics and a convenience sample of 573 unaffected community individuals aged 18 or over completed the Childhood Trauma Questionnaire (childhood adversity), provided a detailed family psychiatric history and blood or cheek samples which were genotyped for 5-HTTLPR and BDNF val66met polymorphisms. Chi-square tests will be used to assess prevalence of 5-HTTLPR and BDNF val66met genotypes amongst abused and non-abused depressed patients. Adversity-genotype interactions will be investigated in terms of presence of recurrent unipolar depression, age of onset of disorder and depressive symptomatology using likelihood-ratio tests and synergism equations.

Scientific & Medical opportunities: This research should improve understanding of the role adverse childhood experiences and genetic risk play in the aetiology of psychosis and depression and how these factors combine to increase risk of these disorders. These findings therefore have massive implications for prevention and treatment of both depression and psychosis.