Laboratory manager: Lundi Korkie, MSc Postdoctoral Researchers: Kevin O’Connell, PhD
Our group focuses predominantly on neuropsychiatric genetics and pharmacogenomics. Specific focus is placed on (i) characterising the variation present in pharmacogenes, (ii) schizophrenia / antipsychotic pharmacogenetics / anxiety disorders, (iii) HIV/antiretroviral pharmacogenetics, (iv) elucidating the molecular aetiology of neuropsychiatric disorders (by considering gene-gene, gene-environment and gene-gene-environment correlations and interactions, and (v) metabolic syndrome and comorbid psychiatric disorders (MRC SHARED ROOTS Flagship Project).
Characterising the variation present in pharmacogenes
Both environmental and genetic factors can influence an individual's response to medication. Much of the variation in drug response between individuals can, however, be ascribed to genetic variation present in genes encoding drug receptors, drug metabolising enzymes and drug transporters. Pharmacogenetics, the study of variability in drug response due to heritability, can revolutionise drug therapy by facilitating both the choice and dosage of the drugs utilised. Genetic variation and functional defects in relevant genes can, however, differ considerably between different population groups. It is thus imperative that this genetic variation is examined in different population groups. Currently very little information is available for populations from Africa. Therefore, our group is involved in performing population based studies to determine the prevalence and frequency of genetic variants in important pharmacogenes in the unique South African populations. This should aid in facilitating the application of pharmacogenetics in health care in the South African context.
Both schizophrenia, a prevalent psychiatric disorder, and antipsychotic treatment response (with antipsychotics being the most effective treatment for psychosis) are heritable. As the genetic variants contributing to antipsychotic treatment response outcomes and schizophrenia aetiology are interlinked, our group focuses on genetic variants contributing to (i) antipsychotic treatment response outcomes (including adverse drug reactions, or ADRs), (ii) schizophrenia susceptibility and (iii) symptom severity. Our group focuses specifically on two South African populations: the Xhosa and the Cape Mixed Ancestry (Coloured) populations and we have performed both candidate gene and exome sequencing studies in these populations. In addition to these analyses we have begun to use various bioinformatic pipelines to investigate the functional relevance of significant associations that have been reported by past antipsychotic and schizophrenia GWAS. We have also, in conjunction with our international collaborators, performed our own GWAS on a previously drug naïve, clinically well-defined first episode schizophrenia cohort. Furthermore, neuroimaging and cognition data exists for these individuals. Through the different strategies implemented in our laboratory, we have replicated previous associations observed in other population groups and identified novel findings that appear to be of specific relevance to South African populations. We will also take research one step further, by evaluating treatment response, susceptibility and symptom severity using clinical and genetic correlates across multiple levels.
The prevalence of HIV/AIDs in South Africa is of serious concern and in order to combat this disease, effective treatment is required. For this reason the field of antiretroviral pharmacogenetics is of paramount importance, particularly in the context of South Africa. Our group therefore focuses on characterising the variation present in important antiretroviral pharmacogenes in two South African populations: the Cape Mixed Ancestry (Coloured) and Xhosa populations. In addition to this we have genotyped the most important pharmacogenetic variants in several candidate genes to determine if any of these variants are associated with altered antiretroviral treatment response outcomes and antiretroviral hair levels. Through these studies we have reported novel variants and haplotype structures. In addition, we have identified robust associations with variants in antiretroviral pharmacogenes that are likely to be important for future applications of antiretroviral pharmacogenetics in the clinic.
Elucidating the molecular aetiology of neuropsychiatric disorders
Anxiety disorders are recognised as of the world's most disabling conditions associated with substantial morbidity and poor quality of life. Twenty years ago, an estimated 3% of the world's population was affected by one or more anxiety disorders, while today these statistics are estimated to be higher. Global statistics for the prevalence of anxiety disorders are staggering, with South Africa and the United States having the highest global life-time prevalence rates for any anxiety disorders in the world (South Africa at 30.1% and USA at 36.0%). The aetiology of anxiety disorders remains incompletely understood, but it is generally accepted that gene-environment (GxE) interactions may underpin the pathogenesis of these disorders. Our research focuses on (i) genetic variables which may be involved in susceptibility to anxiety disorder(s) (ii) environmental factors (such as childhood adversity) which may contribute and / or interact with genetic variables resulting in the complexity of anxiety disorder(s) phenotypes observed and (iii) the unique genetic make-up of South African populations which may often deviate from the significant global findings reported.
Investigating the SHARED ROOTS of Metabolic syndrome and comorbid psychiatric disorders
The SHARED ROOTS project was established following the award, to Prof Soraya Seedat (Chair of the Department of Psychiatry, Stellenbosch University), of a competitive, prestigious Flagship Project Grant from the SA Medical Research Council (MRC) at the end of 2013. The broad goal of the shared roots study is to interrogate genomic, neural, cellular and environmental signatures that are common to neuropsychiatric disorders (NPDs) and cardiovascular disease (CVD) risk and that contribute to co-morbidity, symptom severity, and treatment outcomes. This is being done using an innovative, multi-omics, systems-biology approach that combines genomic, transcriptomic, epigenetics and complementary phenotypic and multimodal neuroimaging data, to disentangle mechanistic pathways that lead to the development of comorbidity of these disorders. Recruitment is on-going for the targeted 600 patients with NPDs, half of whom will meet criteria for metabolic syndrome (MetS).
NPDs, such as posttraumatic stress disorder (PTSD), schizophrenia and Parkinson's disease (PD), are underpinned by complex and dynamic gene-environment interactions that intervene across the lifespan. Clinical diagnosis on the basis of current clinical criteria remains largely unsatisfactory as these NPDs are complicated by marked phenotypic heterogeneity and the concurrence of other medical conditions, such as cardiovascular disease (CVD) and metabolic syndrome (MetS). MetS, an important predictor of cardiovascular events, is highly comorbid in patients with NPDs yet the molecular pathophysiology linking these conditions is poorly understood. A better understanding of 'nature' and 'nurture' factors influencing the convergence of NPD and MetS is needed to design targeted interventions aimed at reducing cardiovascular and cardiometabolic morbidity and mortality.
Our group forms part of the schizophrenia core subdivision of the aforementioned SHARED ROOTS project where we focus on genetic, environmental, imaging (structural and functional), gastrointestinal (microbiome) and functional contributions to comorbid metabolic syndrome, cardiovascular disease and neuropsychiatric disorders. More information about the SHARED ROOTS project can be found here.