Browsing by Author "Dalvie, Shareefa"

Now showing 1 - 11 of 11
  • Thumbnail Image
    Item
    Open Access
    The BDNF p.Val66Met polymorphism, childhood trauma, and brain volumes in adolescents with alcohol abuse
    (BioMed Central, 2014-12-16) Dalvie, Shareefa; Stein, Dan J; Koenen, Karestan; Cardenas, Valerie; Cuzen, Natalie L; Ramesar, Raj; Fein, George; Brooks, Samantha J
    Background: Previous studies have indicated that early life adversity, genetic factors and alcohol dependence are associated with reduced brain volume in adolescents. However, data on the interactive effects of early life adversity, genetic factors (e.g. p.Met66 allele of BDNF), and alcohol dependence, on brain structure in adolescents is limited. We examined whether the BDNF p.Val66Met polymorphism interacts with childhood trauma to predict alterations in brain volume in adolescents with alcohol use disorders (AUDs). Methods: We examined 160 participants (80 adolescents with DSM-IV AUD and 80 age- and gender-matched controls) who were assessed for trauma using the Childhood Trauma Questionnaire (CTQ). Magnetic resonance images were acquired for a subset of the cohort (58 AUD and 58 controls) and volumes of global and regional structures were estimated using voxel-based morphometry (VBM). Samples were genotyped for the p.Val66Met polymorphism using the TaqMan® Assay. Analysis of covariance (ANCOVA) and post-hoc t-tests were conducted using SPM8 VBM. Results: No significant associations, corrected for multiple comparisons, were found between the BDNF p.Val66Met polymorphism, brain volumes and AUD in adolescents with childhood trauma. Conclusions: These preliminary findings suggest that the BDNF p.Met66 allele and childhood trauma may not be associated with reduced structural volumes in AUD. Other genetic contributors should be investigated in future studies.
  • Thumbnail Image
    Item
    Open Access
    Elucidating the genetic aetiology of Bipolar Disorder
    (2018) Engelbrecht, Hannah-Ruth; Ramesar, Rajkumar; Dalvie, Shareefa
    Introduction: Bipolar disorder (BD) is a debilitating mood disorder with substantial genetic contributions. However, while the existence of its heritability is well-established, the precise genetic components and mechanisms of BD remain unknown. This is a pilot study aimed at optimising the use of small-scale next generation sequencing (NGS) of family members affected with BD and extending the finding of variants to larger scale association studies, and an attempt at replicating associations from a large genome-wide association study. Methods and Materials: This thesis describes the pathway analysis of whole-genome sequencing (WGS) data from four Afrikaner individuals to identify candidate variants for genotyping in a Family-Based Association Test (FBAT) of 621 individuals of Caucasian and Mixed Ancestry families from South Africa. This was followed by whole-exome sequencing (WES) of eight members of an Afrikaner family to identify rare, coding variation. These two approaches were used to identify both common and rare variation which may be involved in BD. Results: FBAT indicated that variants in the genes ACTN2 (rs4659702) and ANK3 (rs10994318) are associated with BD in a combined group of both Mixed Ancestry and Caucasian individuals, p = 0.0339 and 0.0443, respectively. Furthermore, this study identified a variant in ACTN2 (rs11355106) which was associated with a broad psychiatric phenotype in Mixed Ancestry families (p = 0.0083). WES revealed 168 exomic variants that were shared by five affected members of the family, one of which was rs142375896, a rare and potentially damaging missense variant in SLC26A9. Conclusions: Pathway analysis of both WGS and WES data implicated that the burden of variation in affected individuals lies in regulatory networks, including the regulation of the actin cytoskeleton and circadian entrainment pathways. The association of ANK3 (rs10994318) with BD in a European ancestry cohort was replicated in a South African cohort comprising of Caucasian and Mixed Ancestry individuals, indicating that some risk variants for the disorder could be shared across populations. This thesis confirms the validity of relatively small-scale family-based studies for the study of complex disorders.
  • Thumbnail Image
    Item
    Open Access
    Elucidation of bipolar disorder : a convergent approach using genetics and imaging
    (2011) Dalvie, Shareefa; Ramesar, Rajkumar S
    The aims were to determine whether variants, within ten selected candidate genes, have an association with BPD and whether any relationship exists between these variants and brain imaging volumes in subjects with BPD. The objectives were to i) select a list of BPD candidate genes, ii) identify a cohort of individuals from the BPD registry, iii) genotype the candidate genes using a polymerase chain reaction (PCR) based technology, iv) analyse the genotyping data with the appropriate statistical methods, and v) obtain brain imaging data and perform the appropriate statistical analysis.
  • Thumbnail Image
    Item
    Open Access
    Genetic analysis of bipolar disorder and alcohol use disorder
    (2015) Dalvie, Shareefa; Ramesar, Rajkumar; Stein, Dan J
    Background: Mental health disorders represent a major public health problem in most countries around the world. In South Africa, the lifetime prevalence of psychiatric disorders is 30.3%, with substance-use disorders and mood disorders being the second and third most prevalent classes of lifetime disorders, respectively. Bipolar disorder (BD) has a lifetime prevalence of 1.4% and alcohol use disorder (AUD) a lifetime prevalence of 30.3%, and they are frequently comorbid. Both of these disorders have a relatively high heritability, yet the exact genetic basis of each remains unknown. Genetic variants within the hypothalamic-pituitary-adrenal (HPA)-axis and glutamatergic pathways have previously been implicated in both phenotypes. The aim of this project was to investigate the aetiology of BD and AUD, using high-throughput genomic technologies, bioinformatics, brain-imaging and environmental measures. An additional aim was to assess the genetic aetiology of BD-AUD comorbidity. Methods: For the genetic analysis underlying BD, a South African 'Afrikaner' family was investigated. Whole-genome sequencing (WGS) and whole-genome linkage analysis was performed for individuals with BD Type I (BDI) and unaffected family members using the Illumina HiSeq2000 and Affymetrix Axiom TM Genome-wide CEU 1 Array, respectively. For the AUD analysis, two groups were investigated; a South African adolescent group comprising 80 individuals with AUD and 80 controls, and a group of 8123 individuals from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. The South African group of adolescents were genotyped using the Illumina Infinium iSelect custom 6000 BeadChip, childhood trauma data was obtained and brain magnetic resonance images were collected for a subset of this group. Genotype data on HPA-axis genes were obtained from a previous study for the ALSPAC cohort. The fourth group of individuals investigated in this thesis comprised 233 individuals with BD-AUD comorbidity from the Systemic Treatment Enhancement Program for BD (STEP-BD). Genotype data for genes from the glutamatergic and HPA-axis pathways were obtained from a previous study conducted on these individuals. Results: The chromosomal regions 6p25, 10p14-10p15.1, 11q23-11q25, and 13q21-22 scored the highest LOD scores for BD and the most over-represented pathway in the affected family members was the T-cell receptor signalling pathway. In the South African adolescent group, circadian rhythm genes were associated with AUD and childhood trauma predicted alcohol use in adolescence. The gene-imaging analysis identified a SNP in the glutamate receptor, ionotropic, N-methyl D-aspartate 2B (GRIN2B) gene as being associated with brain volume in the left orbitofrontal cortex and posterior cingulate. HPA-axis genes did not show an association with AUD and no significant gene x environment interactions were detected for AUD in the ALSPAC cohort. Single variants in the glutamatergic genes and HPA-axis were not associated with BD-AUD comorbidity. However, from the gene-based analysis, the glutamatergic gene PRKCI was associated with BD-AUD comorbidity. Conclusions: It appears that disruption in immune-related genes may contribute to the development of BD in an Afrikaner family. No significant gene x environment interactions were detected for adolescent AUD. The circadian pathway and childhood trauma may play a role in the development of adolescent AUD. Differential brain volume and BD-AUD comorbidity may be characterised by variation in the glutamatergic pathway. These pathways and the interactions between them should be further investigated in BD and AUD.
  • No Thumbnail Available
    Item
    Open Access
    Genetic and epigenetic associations with child development and mental health in a South African birth cohort
    (2025) Moyakhe, Lihle; Koen, Nastassja; Stein, Dan; Dalvie, Shareefa
    Childhood developmental and mental disorders – including internalising and externalising symptoms – are prevalent in low- and middle-income countries (LMICs) such as South Africa. There is growing interest in the associations between polygenic risk scores (PRS), epigenetic age (EA) deviation, DNA methylation risk scores (MRS), and key neurodevelopmental disorders such as attention-deficit hyperactivity disorder (ADHD). However, most work has thus far been undertaken in high-income countries (HICs) with participants of European ancestry; and populations of African ancestry have been notably under-represented. The Drakenstein Child Health Study (DCHS), an ongoing South African birth cohort study, provides an opportunity to investigate the associations of PRS, EA deviation, and MRS, with childhood developmental and mental health outcomes, in an ancestrally diverse study population. This doctoral project aimed to investigate potential genetic and epigenetic associations with adverse developmental and mental outcomes in children. This aim was addressed via five objectives. First, a systematic review was undertaken to collate existing work (both in HICs and LMICs) on associations between PRS (the weighted sum of risk alleles) and developmental and mental health disorders in childhood and adolescence. A second systematic review focused on associations between EA deviation (relative to chronological age) and the outcomes of interest. Third, empirical analyses of DCHS data investigated the relationship between a PRS for ADHD, and child developmental outcomes, as well as internalising and externalising symptoms. Fourth, the relationship between gestational EA deviation at birth, and child developmental and mental health outcomes in the DCHS, was explored. Finally, the association between MRS (the weighted sum of methylation markers' beta values) at birth, and the outcomes of interest, was investigated. The systematic reviews adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, and standard methods were used to collate and analyse the data. In the DCHS, a PRS for ADHD was generated (target n=958) using summary statistics from the Early Genetics and Lifecourse Epidemiology (EAGLE) consortium (discovery n=17,666). Gestational EA deviation at birth and MRS were calculated using DCHS umbilical cord blood samples (n=275) and summary statistics from the Pregnancy and Childhood Epigenetics (PACE) consortium (n=2,477 for the MRS analyses). Child developmental outcomes (i.e. cognitive, language and motor development) were derived from the Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley-III), and child mental health outcomes (i.e. internalising and externalising symptoms) from the Child Behaviour Checklist (CBCL). Associations of interest were investigated using bivariate and multivariable linear and logistic regression models, controlling for relevant covariates (including sociodemographic characteristics, psychosocial risk factors, child anthropometric measures and genomic principal components). In the first systematic review (of 14 studies, with ~50,000 participants), significant associations between PRS for several mental health disorders and adverse developmental/mental health outcomes were found. For example, a high ADHD PRS was found to be associated with adverse outcomes in childhood and adolescence in 5 of the 14 included studies. Additionally, 4 studies described associations between PRS for bipolar disorder and impaired cognitive function, and poor executive functioning, in children and adolescents; and 2 studies highlighted associations between schizophrenia PRS and ADHD, as well as internalising and externalising symptoms in children. In the second systematic review (of 4 studies with N~700 participants), gestational EA acceleration was found to be significantly associated with internalising symptoms in children. The empirical analyses yielded no significant genetic or epigenetic associations with the developmental or mental health outcomes of interest in the DCHS children. However, trend-level associations were observed - in both the unadjusted and the adjusted models - between gestational EA deviation at birth and child externalising symptoms (at 42 months) in the DCHS (unadjusted β = −0.19, p = 0.072; adjusted β = -0.17, p= 0.10). While limited by sample size and lack of ancestry-matched summary statistics, this work nonetheless represents a novel exploration of the potential genetic and epigenetic underpinnings of developmental and mental disorders in South African children. In future, further studies – ideally with larger sample sizes, ancestry-matched summary statistics and longitudinal developmental phenotype data – would be warranted to expand on this preliminary work. Ultimately, such research may provide insight into the genetic and epigenetic risk factors of developmental and mental health outcomes in children; and may inform targeted early interventions for at-risk children – particularly in resource-limited settings such as South Africa.
  • Thumbnail Image
    Item
    Open Access
    Investigation of the Shared Genetic Influences on Bipolar Disorder, Borderline Personality Disorder and Regional Brain Structures
    (2021) Campbell, Megan; Dalvie, Shareefa; Stein, Dan; Ramesar, Raj; Rockiki, Jaroslav
    Background: The heritabilities of bipolar disorder (BD) and borderline personality disorder (BPD) are 80% and 65%, respectively, indicating substantial genetic contributions to both disorders. BD and BPD are often comorbid, and both disorders have a polygenic architecture. These variants are thought to subtly affect multiple pathways, associated with structural brain abnormalities commonly observed in patients with BD and BPD. Brain regions have been shown to be highly heritable and under distinct genetic influences. However, the overlap in genetic risk between BD and BPD and altered brain regions, respectively, has not yet been determined. Aims and Objectives: The aim of this project was to determine whether genetic risk for BD and BPD overlaps with genetic risk for altered brain regions. Methods: Genome-wide association study (GWAS) summary statistics for BD (Ncases=20,352; Ncontrols= 31,358), BPD (Ncase=998; Ncontrol=1,545), eight subcortical brain volumes (nucleus accumbens, amygdala, caudate nucleus, hippocampus, pallidum, putamen and thalamus) and intracranial volume (ICV) (N=27,087), and cortical surface area and thickness (N=37,479) were obtained. Pleiotropy and concordance were assessed using SNP-Effect Concordance Analysis. Conditional false discovery rate (cFDR) was used to condition BD and BPD GWAS results on genetic variants that influence brain regions. Linkage Disequilibrium Score Regression was used to examine genome-wide correlations between BD, BPD and brain regions. Mendelian randomization was used to test for causal associations between BD, BPD and each brain region, respectively. Results: There was evidence of significant pleiotropy and positive concordance between BD and BPD (ppleiotropy=5x10-4; pconcordance=1x10-6, OR=1.29). Significant pleiotropy was observed between BD and the thickness of several cortical regions and two gyri, namely the lateral occipital (p=2.25x10-5), pars triangularis (p=1.1x10-4), rostral anterior cingulate regions (p=2.18x10-4) and post central (p=7.9x10-6) and supramarginal gyri (p=1.45x10-7). Significant positive concordance was noted between BPD and thickness of the lateral occipital region (p=3x10-4; OR=1.02). After conditioning BD onto BPD and each regional brain GWAS, 171 additional variants were significantly associated with BD (FDR<0.05). Three additional SNPs were significantly associated with BPD when conditioned on thickness of the lateral orbitofrontal, lingual, precentral and supramarginal regions. Discussion: The findings here of genetic overlap between BD, BPD and altered brain structure, while novel, are consistent with previous work. The cFDR analyses, highlight synapse and neurotransmitter regulation as a key underlying mechanism between BD and altered brain regions. Further fine-grained delineation of the role of the environment in these relationships and the inclusion of non-European populations are critical next steps, as they may provide insight into risk factors, new areas of treatment and aid in early detection of at risk individuals.
  • Thumbnail Image
    Item
    Open Access
    Novel CYP2E1 haplotype identified in a South African cohort
    (2014) Heathfield, Laura J; Dalvie, Shareefa; Kalideen, Kusha; Dandara, Collet
    Alcohol abuse accounts for approximately 2.5 million deaths annually and is the third highest risk factor for disease and disability. Alcohol is metabolised by polymorphic enzymes and the status of an individual with respect to alcohol metabolising enzymes may have forensic relevance in post-mortems. Baseline frequencies of gene variants involved in alcohol metabolism need to be established to aid the identification of suitable population-specific polymorphisms to genotype during molecular autopsies. The principal alcohol metabolising enzymes include alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH) and cytochrome P450 2E1 (CYP2E1). Six single nucleotide polymorphisms (SNPs) – rs1229984G>A and rs2066702C>T in ADH1B, rs671G>A in ALDH2, and rs3813867G>C, rs2031920C>T and rs6413432T>A in CYP2E1 – were genotyped in 150 individuals from four South African populations: Xhosa, Zulu, South African white and South African coloured. Allele frequencies for each SNP in the four population groups were 0–10% for rs1229984A, 2–12% for rs2066702T, 0–2% for rs671A, 1–4% for rs3813867C, 0–1% for rs2031920T and 3–15% for rs6413432A. Haplotype analysis revealed a novel combination of three SNPs in CYP2E1 whose effects on alcohol metabolism need further investigation. Establishment of baseline frequencies adds to our knowledge of genetic variation in alcohol metabolising enzymes and additional research is required to determine the functional significance of this novel CYP2E1 haplotype.
  • No Thumbnail Available
    Item
    Open Access
    Psychiatric genetic counselling: current landscape and opinions of psychiatric healthcare professionals in public hospitals in Cape Town, South Africa
    (2025) Ellis, Lize; Laing, Nakita; Dalvie, Shareefa; Stein, Dan
    Psychiatric genetic counselling: Current landscape and opinions of psychiatric healthcare professionals in public hospitals in Cape Town, South Africa Psychiatric conditions are common, and psychiatric genetic counselling (PGC) aims to help people understand their, or a family member's, mental illness better, as well as help them understand the factors that can contribute to the development of a mental illness. However, PGC services are not implemented routinely despite reported patient benefits of increased patient empowerment and self-efficacy. This study serves as a pilot project to investigate current practices of mental illness counselling services, focusing on aetiology, provided by psychiatric healthcare professionals at a single unit in the public health sector in Cape Town, South Africa. A pragmatic qualitative research approach, using semi-structured interviews, was used to explore the questions patients ask in terms of recurrence and causes of their mental illness, as well as healthcare provider's (HCPs) opinions on offering a PGC service. Ten interviews were thematically analysed. Results showed that PGC is not being routinely implemented in psychiatric consultations, patients and families have limited genetic knowledge, and family members frequently ask about the mental health condition and its causes. Psychiatric HCPs seemed to believe PGC is likely to be beneficial to the patient, their families and mental health services, and would use such a service if available to them. However, there were several perceived barriers to establishing a PGC service, such as limited resources and available time, which makes a PGC service unfeasible at this point. These results will contribute to the body of knowledge on PGC (such as potential applications, benefits and obstacles, and acceptability of PGC) and may serve as a starting point to considering the implementation of a PGC service in Cape Town, South Africa.
  • No Thumbnail Available
    Item
    Open Access
    Psychiatric genetic counselling: current landscape and opinions of psychiatric healthcare professionals in public hospitals in Cape Town, South Africa
    (2025) Ellis, Lize; Laing, Nakita; Dalvie, Shareefa; Stein, Dan
    Psychiatric genetic counselling: Current landscape and opinions of psychiatric healthcare professionals in public hospitals in Cape Town, South Africa Psychiatric conditions are common, and psychiatric genetic counselling (PGC) aims to help people understand their, or a family member's, mental illness better, as well as help them understand the factors that can contribute to the development of a mental illness. However, PGC services are not implemented routinely despite reported patient benefits of increased patient empowerment and self-efficacy. This study serves as a pilot project to investigate current practices of mental illness counselling services, focusing on aetiology, provided by psychiatric healthcare professionals at a single unit in the public health sector in Cape Town, South Africa. A pragmatic qualitative research approach, using semi-structured interviews, was used to explore the questions patients ask in terms of recurrence and causes of their mental illness, as well as healthcare provider's (HCPs) opinions on offering a PGC service. Ten interviews were thematically analysed. Results showed that PGC is not being routinely implemented in psychiatric consultations, patients and families have limited genetic knowledge, and family members frequently ask about the mental health condition and its causes. Psychiatric HCPs seemed to believe PGC is likely to be beneficial to the patient, their families and mental health services, and would use such a service if available to them. However, there were several perceived barriers to establishing a PGC service, such as limited resources and available time, which makes a PGC service unfeasible at this point. These results will contribute to the body of knowledge on PGC (such as potential applications, benefits and obstacles, and acceptability of PGC) and may serve as a starting point to considering the implementation of a PGC service in Cape Town, South Africa.
  • No Thumbnail Available
    Item
    Open Access
    The genetic relationship between the corpus callosum, bipolar disorder and alcohol use
    (2025) Campbell, Megan Loraine; Stein, Dan; Rokicki, Jaroslav; Dalvie, Shareefa
    Background: The corpus callosum (CC) is a brain structure responsible for the integration of information across the two cerebral hemispheres to facilitate language, affective- and sensorimotor function. Morphological alterations in sub-regions of this structure have been observed in various psychiatric disorders, particularly bipolar disorder and alcohol consumption. Although the CC has a high heritability (0.67 for total CC; family study) the genetic architecture of the entire structure, its subregions, and any genetic links with psychiatric disorders remain largely unclear. Therefore, the aim of this study was to investigate the genetic architecture of the CC, and this was accomplished by the following objectives: elucidating the single nucleotide polymorphism (SNP)- based heritability and polygenic architecture of the CC and its subregions, and by investigating the genetic overlap between the CC and its subregions with psychiatric disorders, including bipolar disorder and alcohol consumption. Methods: Multivariate and univariate genome-wide association studies (GWAS) were conducted utilizing genetic and T1-weighted magnetic resonance imaging (MRI) data of 40,894 individuals from the UK Biobank. The volume of the five subregions of the CC (posterior, mid-posterior, central, mid-anterior and anterior) were extracted using FreeSurfer v7.1. Multivariate GWAS was run combining volumes of all CC subregions. Multivariate GWAS was conducted to boost genetic discovery and to assess the pleiotropic effects across volumes of the five subregions of the CC. Univariate GWAS was conducted across CC subregion volumes and the 28 diffusion weighted imaging modalities. All analyses were co varied for age, age squared, sex, scanning site, Euler score (a proxy of image quality), total intracranial volume and the first 20 genetic principal components. Annotations of GWAS summary statistics were conducted using OpenTargets and gene-set enrichment analyses were performed using hypergeometric tests. Linkage disequilibrium score regression (LDSC) was 5 used to determine SNP-based heritability of the CC and subregions (for both volume and diffusion weighted modalities), as well as to assess genetic correlations between these subregions and relevant psychiatric and substance use phenotypes. A causal mixture model framework was employed to determine the polygenicity of each subregion and related psychiatric traits and, leveraging pleiotropy using the conjunctional false discovery rate (cFDR) framework, shared loci between the CC and psychiatric phenotypes were identified. Results: This study identified seventy independent loci with distributed effects across volumes of the CC subregions, with additional loci showing subregion-specific associations. Univariate GWAS analysis of diffusion metrics revealed a total of 1,520 significant genetic loci associated with diffusion metrics in the subregions of the CC. The polygenicity varied across diffusion modalities and subregions, ranging from 268 to 7,069 trait-influencing variants. The mean number of trait-influencing variants ranged from 1,560 to 2,865 across different diffusion metric groups and 2,385 to 3,108 across subregions. It was found that CC subregion volumes are influenced by approximately 1,400 to 1,800 genetic variants, with approximately 1,800 variants influencing total CC volume. The SNP-based heritability estimates varied, with CC volume showing a relatively high heritability (h2 snp=0.38, SE=0.03) and subregion volumes ranging from 0.22 (SE=0.02; mid-posterior) to 0.37 (SE=0.03; posterior). Significant genetic correlations were observed between CC volume and bipolar disorder, major depressive disorder, drinks per week, cannabis use. The diffusion metrics also showed subregion-specific correlations with CC volume, bipolar disorder and alcohol consumption. The genetic overlap between the CC and psychiatric phenotypes differed across subregions, with anterior regions showing almost complete overlap with bipolar disorder and schizophrenia, while the central region exhibited substantial overlap with drinks per week. In conjunctional analysis, I identified 138 significant independent variants between CC subregions and psychiatric 6 phenotypes, and gene-set enrichment analysis implicated antigen processing, regulation of the extracellular matrix, and hyaluronan metabolism as significant pathways. Conclusion: These results demonstrate that the CC possesses a polygenic architecture and has a substantial SNP-based heritability across its subregions. Distinct genetic loci were implicated in the CC's anterior and posterior subregions, which is in line with their different functional specializations. There was evidence of significant genetic correlation of the CC with BD, MDD, as well as between the CC and substance use phenotypes (drinks per week and cannabis consumption). Moreover, substantial genetic overlap was observed between the CC with SCZ and BD, and alcohol consumption. These findings of overlapping genetic architectures of the CC and these psychiatric phenotypes suggest the existence of shared biological pathways that may have value in the development of targeted treatment strategies
  • No Thumbnail Available
    Item
    Open Access
    The genetics of cognition in Schizophrenia
    (2024) Wootton, Olivia; Dalvie, Shareefa; Shadrin , Alexey; Stein , Dan
    Background: Cognitive impairment is a well-documented feature of schizophrenia and a major determinant of functional outcomes. Cognitive function may be assessed by measuring mean performance measures on cognitive tasks or by measuring variability in performance across tasks or trials of a task that make up a cognitive test battery. Previous research has demonstrated that both cognitive ability and schizophrenia are highly heritable, and that there is a genetic contribution to cognitive impairment in schizophrenia. However, insights into the genetic determinants of cognitive function in schizophrenia remain limited. The overarching aim of the study is to extend current understanding of cognitive impairment in schizophrenia by using previously under-researched or novel metrics of cognitive performance. First, the significance of the phenotype, within-individual variability (WIV) in cognitive performance, was examined in a South African study of people living with schizophrenia. Second, data from the UK Biobank was used to investigate the common genetic determinants of WIV. Third, genetically informed factors corresponding to broad cognitive abilities were used to explore the overlap between the latent cognitive factors, schizophrenia, and schizophrenia symptom dimensions. Methods: A narrative review of the key literature on the clinical, neural, and genetic correlates of WIV was conducted. Multivariable linear regression analyses were then used to assess the relationship between WIV in cognitive performance and selected demographic and clinical variables in 544 people with schizophrenia and 861 matched controls from a South African case-control study. To explore the common genetic basis of WIV, a genome-wide association study (GWAS) of reaction time variability, a measurement of across-task WIV, was conducted in 404,302 individuals from the UK Biobank, a large population-based cohort. Linkage disequilibrium score regression was used to assess the genetic correlations between reaction time variability and selected neuropsychiatric traits, including schizophrenia. Lastly, Genomic Structural Equation Modelling was applied to cognitive data from the UK Biobank to derive latent factors corresponding to broad dimensions of cognitive function. The overlap between the latent cognitive factors, schizophrenia, and schizophrenia symptom dimensions was explored using a variety of statistical approaches, including bivariate MiXeR, the conjunctional false discovery rate method, and polygenic risk score analysis. Results: On a phenotypic level, increased WIV in performance speed across cognitive tests was significantly associated with a diagnosis of schizophrenia, older age, a lower level of education, and a lower score on the global assessment of functioning scale. The GWAS of reaction time variability yielded 161 genome-wide significant single nucleotide polymorphisms distributed across 7 loci, implicating genes involved in synaptic function and neural development. Reaction time variability showed a significant genetic correlation with several traits, including a positive correlation with schizophrenia. Lastly, three latent factors (visuo-spatial, verbal analytic and decision/reaction time) underlying the genetic correlations between the UK Biobank cognitive tests were identified. There was evidence of substantial polygenic overlap between each cognitive factor and schizophrenia but despite the extensive overlap, most significant loci shared between each latent cognitive factor and schizophrenia showed unique patterns of association with the respective factor. Biological annotation of the shared loci implicated gene-sets related to neurodevelopment and neuronal function. Conclusions: The significant relationship between measurements of WIV in performance speed and schizophrenia as well as global functioning in the disorder supports the use of WIV as a measure of cognitive dysfunction in schizophrenia. This thesis demonstrates that reaction time variability is heritable, has a positive genetic correlation with schizophrenia, and that genes associated with reaction time variability have similar biological functions to those affected in schizophrenia. Lastly, substantial overlap in the common genetic influences of latent cognitive factors and schizophrenia was demonstrated. This research suggests that genes related to neurodevelopment and neuronal function underpin cognitive deficits in schizophrenia.