Clinical and genotypic analysis in determining dystonia non-motor phenotypic heterogeneity: a UK Biobank study

The spectrum of non-motor symptoms in dystonia remains unclear. Using UK Biobank data, we analysed clinical phenotypic and genetic information in the largest dystonia cohort reported to date. Case–control comparison of dystonia and matched control cohort was undertaken to identify domains (psychiatric, pain, sleep and cognition) of increased symptom burden in dystonia. Whole exome data were used to determine the rate and likely pathogenicity of variants in Mendelian inherited dystonia causing genes and linked to clinical data. Within the dystonia cohort, phenotypic and genetic single-nucleotide polymorphism (SNP) data were combined in a mixed model analysis to derive genetically informed phenotypic axes. A total of 1572 individuals with dystonia were identified, including cervical dystonia (n = 775), blepharospasm (n = 131), tremor (n = 488) and dystonia, unspecified (n = 154) groups. Phenotypic patterns highlighted a predominance of psychiatric symptoms (anxiety and depression), excess pain and sleep disturbance. Cognitive impairment was limited to prospective memory and fluid intelligence. Whole exome sequencing identified 798 loss of function variants in dystonia-linked genes, 67 missense variants (MPC > 3) and 305 other forms of non-synonymous variants (including inframe deletion, inframe insertion, stop loss and start loss variants). A single loss of function variant (ANO3) was identified in the dystonia cohort. Combined SNP and clinical data identified multiple genetically informed phenotypic axes with predominance of psychiatric, pain and sleep non-motor domains. An excess of psychiatric, pain and sleep symptoms were evident across all forms of dystonia. Combination with genetic data highlights phenotypic subgroups consistent with the heterogeneity observed in clinical practice

Discovery and impact of schizophrenia rare genetic variation using next generation sequencing

Schizophrenia is a complex psychiatric disorder, a key feature of which is impaired cognitive function. Common alleles and copy number variants conferring risk for schizophrenia are associated with lower cognition in the general population, however current understanding of the impact of schizophrenia-associated rare coding variants on cognition in the general population is limited. This thesis explores the impact of damaging rare coding variants in genes with a known role in schizophrenia liability on generalised cognition in individuals without a psychiatric or developmental disorder. The UK Biobank, a large-scale biomedical database, was utilised for this investigation. Chapter 2 describes the processing and analysis of whole exome sequencing and phenotypic data from this cohort. These data were used to demonstrate an association of higher burden of damaging rare coding variants in schizophrenia-associated genes with lower cognition in a volunteer population-based cohort (Chapters 3 and 4). This thesis then examines a potential bias in those who undertook optional cognitive assessments in the UK Biobank, and demonstrates evidence that this bias may, in part, reflect genetic effects (Chapter 5). This research strengthens and extends evidence for overlapping genetic architecture between schizophrenia risk and lower cognition in individuals without a psychiatric disorder. It indicates the presence of shared underlying biology between schizophrenia risk and general cognition in the population, and improves current understanding of the pleiotropic nature of genes involved in cognition and schizophrenia. It also presents evidence for the presence of a participation bias in cognitive measures in the UK Biobank, and evaluates how this bias may impact rare coding variant findings in this thesis, and elsewhere. Furthermore, my analyses demonstrate the utility of large-scale datasets such as the UK Biobank to identify genes with pleiotropic effects, and have the potential to provide a well-powered route towards determining biological processes underlying cognitive impairment in schizophrenia