Common genetic variants in psychosis across the lifespan

: from the beginnings of psychosis to cognition in later age

Abstract

Theory and practice of psychiatric genetics transformed within a decade. Genetics has gone through a century of unsuccessfully trying to find individual specific genes, basic units of heritability, which would explain risk for complex disorders. For the past ten years, genetics has been exploring joint contributions of thousands of genes instead. Research on psychosis has been a strong focus throughout this shift. Psychosis is an umbrella term for multiple types of experience (hallucinations, voices or visions which are not there, delusions, fixed, false beliefs, changes in emotion and drive, and decline in memory and other cognitive skills). Psychosis is a spectrum: it is not distressing and negative to all who experience it and it does not always result in clinical intervention, but also, patients with psychosis live with substantial disability and have a shortened life expectancy, often due to disorders simultaneously present with psychosis (e.g., individuals with schizophrenia lose the equivalent of on average 73% of healthy life per year due to comorbid mental and substance use disorders). Thus, clinical interventions try to alleviate psychosis and improve patient outcomes. As psychosis has a genetic component (its heritability is 70% or more, depending on a psychotic disorder), the aim of psychiatric genetics is to develop measures which would incorporate genetic factors to help explain and predict psychotic symptoms to anticipate, improve, and time, optimal treatment.

As it is now understood that no single candidate gene explains risk for psychosis, a measure including information on multiple genetic variants has been developed. This measure, a polygenic score, is supposed to reflect individual genetic predisposition towards a trait. Polygenic scores sum up information on thousands of common genetic variants into a single score. Each genetic variant is weighted by its effect size from a genome-wide association study (GWAS). For associations with disorder, GWAS compares common genetic variants between participants with a disorder and controls to determine which variants are more statistically likely to be related to the disorder. Polygenic scores have been primarily used to differentiate cases with psychotic disorders from controls. However, psychosis is a complex and heterogenous disorder. It can have different trajectories (from single episodes and complete remission to multiple relapses throughout life), different combinations of symptoms, and symptoms which change over time. Thus, the aim of this thesis was to explore if polygenic scores for major psychiatric disorders predict specific psychosis manifestations which may impact psychosis trajectories over time: age of onset of psychosis (age of first symptom manifestations which eventually lead to psychiatric intervention; AOO); duration of untreated psychosis (from symptom onset to either hospitalisation or first antipsychotic treatment; DUP); and longitudinal cognitive decline of memory and executive function in later life (after the age of 50).

In Chapter 3, I show that polygenic scores for major psychiatric disorders (schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder, and attention deficit hyperactivity disorder) do not predict AOO in first episode psychosis patients from different European cities. In Chapter 4, I demonstrate that these polygenic scores do not predict DUP in first episode psychosis patients. However, in both studies, research sites, from which the data come, are significantly related to AOO and DUP. Finally, in Chapter 5, I show that the polygenic score for schizophrenia predicts baseline cognitive performance, but not decline of memory and executive function, over a decade-long follow-up.

These findings suggest a nuanced picture of common genetic variants in psychosis: they may be related to increased risk for specific psychosis symptoms (e.g., general cognitive deficit), but not all clinical features which are labelled as “psychosis”, such as early psychotic symptoms or cognitive decline over time. Alternatively, findings in this thesis may be a result of differences between research sites in how psychosis manifestations are measured, inaccurate patient recall of their medical history, bias in diagnosis, or suboptimal methods of generating polygenic scores (these issues, and suggestions for future research, are discussed in Chapter 6).

Date of Award	1 Jan 2022
Original language	English
Awarding Institution	King's College London
Supervisor	Robin Murray (Supervisor), James Maccabe (Supervisor) & Olesya Ajnakina (Supervisor)