198 research outputs found
Functional analysis of A 5' untranslated variant in rhodopsin : implications for the retinitis pigmentosa phenotype
No full textRetinitis Pigmentosa (RP) is a group of heterogeneous retinal degenerative diseases that predominantly affect rod photoreceptor cells. Symptoms include night blindness and gradual peripheral vision loss, which progresses to a complete loss of vision. Clinical, phenotypic and genetic heterogeneity are frequently observed in RP. Mutations in Rhodopsin (RHO) have been identified as a major cause of RP. A sequence variant identified in the 5' untranslated region of RHO, g.269A>G, also known as c.-26A>G, was proposed to increase the risk of developing RP. In this study, the functional effect of this variant, individually and in cis with known pathogenic variants, was investigated using mammalian cell lines in order to determine whether the variant is a modifier of disease phenotype
Glutamatergic and HPA-axis pathway genes in bipolar disorder comorbid with alcohol- and substance use disorders
No full textGlutamatergic neurotransmission has been shown to be dysregulated in bipolar disorder (BD), alcohol use disorder (AUD) and substance use disorder (SUD). Similarly, disruption in the hypothalamic-pituitary-adrenal (HPA)-axis has also been observed in these conditions. BD is often comorbid with AUD and SUD. The effects of the glutamatergic and HPA systems have not been extensively examined in individuals with BD-AUD and BD-SUD comorbidity. The aim of this investigation was to determine whether variants in the glutamatergic pathway and HPA-axis are associated with BD-AUD and BD-SUD comorbidity. The research cohort consisted of 498 individuals with BD type I from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). A subset of the cohort had comorbid current AUD and current SUD. A total of 1935 SNPs from both the glutamatergic and HPA pathways were selected from the STEP-BD genome-wide dataset. To identify population stratification, IBS clustering was performed using the program Plink 1.07. Single SNP association and gene-based association testing were conducted using logistic regression. A pathway analysis of glutamatergic and HPA genes was performed, after imputation using IMPUTE2. No single SNP was associated with BD-AUD or BD-SUD comorbidity after correction for multiple testing. However, from the gene-based analysis, the gene PRKCI was significantly associated with BD-AUD. The pathway analysis provided overall negative findings, although several genes including GRIN2B showed high percentage of associated SNPs for BD-AUD. Even though the glutamatergic and HPA pathways may not be involved in BD-AUD and BD-SUD comorbidity, PRKCI deserves further investigation in BD-AUD
The molecular genetics of bipolar affective disorder : South African populations, endophenotypes, and environmental influence
No full textIncludes bibliographical references.The identification of the genetic variants underpinning bipolar disorder (BPD) has been impeded by a complex pattern of inheritance that may include by genetic heterogeneity, genetic epistasis, gene-environment interactions, incomplete penetrance and variable expressivity. In this thesis three strategies were employed to ameliorate these confounding factors. The first strategy was to focus on a theoretically genetically-homogeneous population with BPD. A unique South African sample including 190 individuals of the relativity reproductively-isolated Afrikaner population yielded promising evidence of linkage to chromosome 1 q31-32 and weaker peaks at lOq23 and 13q32, regions previously implicated in the disorder. A family-based analysis suggested that the 3' variable number tandem repeat (VNTR) variant of the dopamine transporter gene (DAT) is associated with bipolar-spectrum illness in the 132-strong sample of British ancestry. The second strategy was to carry out genetic linkage and association analyses using quantitative traits (elldophenotypes) that were closely associated with BPD. As part of this process a variety of personality traits were evaluated in the cohort, and anxiety related, novelty-seeking, hyperthymic, and cyclothymic personality traits were found to aggregate in participants with BPD and to a lesser extent repeated unipolar illness (MDE-R). These traits were therefore used as quantitative markers or endophenotypes of BPD. The quantitative linkage analysis indicated that a variant in the region of 13q32 may influence the development of novelty-seeking-related traits in the largest Afrikaner pedigree, while the personality trait, ""Stability"", was weakly linked to 4p16 in the total sample. The catechol-o-methytransferase (COM1) Va1l58Mct and the Brain Derived Neurotrophic Factor (BDNF) Va1l66Met polymorphisms were associated with mood-labile-cyclothymic and hyperthymic·-novelty-seeking traits, respectively. the DA T VNTR and the Notch4 exonic repeat variants were associated with a broad range of ""pathological"" personality traits in the sa11lples of British and Afrikaner origin, respectively. The sample was also evaluated with a battery of neuropsychological tasks and the BPD 1 and MDE-R groups displayed both verbal and visual memory recall deficits while the BPD 1 sample also suffered from recognition memory deficits. The neurocognitive trait, ""Memory"" was therefore used as a second endophenotype generating potential linkage signals on IOq23 and 22q 11. The exonic 48bp VNTR polymorphism in the dopamine 4 receptor (DRD4) gene was associated with '""Memory"" performance. As a third strategy, a potentially important aetiological factor, childhood trauma, was measured, and used to test for gene-environment interactions between the various candidate genes and bipolar-illness or BPD-related endophenotypes in the cohort. BPD and M DE-R individuals displayed significantly higher levels of emotional and physical abuse, and the former variable was also associated with the development of anxiety-related and unstable personality traits. A functional variant of the COM1 gene was found to interact with abuse to predispose to anxiety-related, unstable cyclothymic and novelty-seeking related personality traits. The combination of childhood abuse and possession of low-activity MAO-A gene variants was also associated the development of more anxious and unstable personality traits. All interaction between sexual abuse and the B])NF gene modulated performance on verbal and visual memory tasks. A similar interaction between the ApoE gene and sexual abuse was observed. Although a number of theoretical obstacles remain to be resolved, the analyses of isolated populations coupled with the use of endophenotypes and the testing or gene environment interactions, holds out great promise for the eventual elucidation of the genetic basis of hi polar affective disorder
Single nucleotide polymorphism array analysis in copy number variant detection: assessment of its feasibility in the diagnostic setting
No full textIntellectual disability/developmental delay (ID/DD) is a significant problem in child health affecting 2 to 3% of the population worldwide. While the underlying aetiology of ID/DD in a large proportion (about 50%) of these patients is unknown, 15 to 20% of the internationally reported cases detected using microarray technologies are due to copy number variants (CNVs), whereas only 3 to 5% of ID/DD can be identified with conventional cytogenetics. The Affymetrix® Cytoscan™ High Density (HD) Array (Affymetrix, Santa Clara, CA) containing over 2.4 million markers for copy number (CN) was used to detect genome-wide high resolution CN and single nucleotide polymorphisms (SNPs) in a cohort of 27 carefully selected patient samples. The patient selection was done based on relevant phenotypes, which included dysmorphism, ID/DD, suspected syndromes, and family history. Data analysis was performed using the Affymetrix Chromosome Analysis Suite (ChAS) (Affymetrix, Santa Clara, CA, USA software). Seven of the patients demonstrated pathogenic CNVs. Diagnoses included Kleefstra syndrome, Mowat-Wilson syndrome, Wolf-Hirschhorn syndrome, tetrasomy 9p, and a susceptibility locus for neurodevelopmental disorders due to a deletion of chromosome 1q21.1. This indicated a 26% detection rate in this cohort. In addition, three variants of unknown significance (VOUS) were detected. The aim of this study was to determine the potential relevance and applicability of microarray technologies for the detection of CNVs in the Western Cape ID/DD population of South Africa (SA) and in so doing, to introduce and develop molecular cytogenetics skills in the routine diagnostic cytogenetic environment. The results obtained in this study confirmed the significant improvement in the detection rate of CNVs in patients with ID/DD and thus the diagnostic utility of this technology for the detection of CNVs in ID/DD patients was confirmed
Pharmacogenetics of African populations : variation in major drug metabolising enzyme genes and potential impact on personalised medicine.
No full textIncludes bibliographical references (leaves 167-200
Pharmacogenomic profiling and clarification of the role of the mismatch repair genes in response to the chemotherapeutic agent 5-Fluorouracil in a South African colorectal cancer cohort
No full textIncludes abstract.Includes bibliographical references (leaves 106-120).To date, surgery is the mainstay treatment for HNPCC. Adjuvant chemotherapy and radiotherapy are often used to reduce systemic and locoregional recurrence, respectively, after curative surgical resection. The main chemotherapeutic agent is 5-Fluoroucacil (5-FU). Studies have attempted to elucidate whether the MMR status of a colorectal cancer (CRC) cohort will define a response to 5-FU therapy. However, no difference in long term response or survival after 5-FU treatment between patients with MMR-proficient and MMR-deficient tomours were detected
The genetics of lithium-induced adverse drug reactions in bipolar disorder patients : a pilot study
No full textIncludes abstract.Includes bibliographical references.Name of degree provided by the Faculty of Health Sciences.Lithium is regarded as the first-line pharmacotherapy for the treatment of acute mood episodes, suicide prevention and prophylactic treatment in patients with bipolar disorder (BPD). Response to lithium has a strong genetic component and lithium-responders have an increased frequency of BPD among their family members. Lithium has a narrow therapeutic index and 75-90% of patients on long-term lithium treatment experience one or more side effects, such as weight gain, cognitive decline and skin problems, amongst at least 20 side effects. The research project is immersed in a larger project on the genetics of bipolar disorder, in which a large number of individuals in families have been investigated over several years. The present pilot study explored whether single nucleotide polymorphisms (SNPs) within GSK3B, AKT1, ARRB2, GRIA2 and PPPARGC1A could be associated with the incidence and severity of lithium-induced side effects
Reconstructing ancient Southern African mitochondrial genomes at Faraoskop
No full textTwelve human skeletons, approximately 2000 years old, were recovered from the Faraoskop archaeological site in the Western Cape Province, South Africa (Manhire 1993). Several of the skeletons were well enough preserved to determine the osteological profiles (sex, age and stature etc.). Additionally, paleopathological and traumatic changes were observed on some of these skeletal remains. Given suggested context that these human remains were drawn from a single mortuary event, this paper investigates the possibility of familial relationships between the individuals by establishing maternal profiles from mitochondrial DNA. The mitochondrial DNA analysis resulted in the identification of four full genomes from the Faraoskop (FK) individuals and the two Khoesan pastoralist individuals chosen as reference samples for the analysis. Three other FK individuals provided partial genomes which could be assigned to incomplete haplotypes. Five individuals could not be sequenced due to poor DNA preservation. Molecular sex could be confirmed for five FK and two reference individuals, adding to the sex assessment from osteological data. All but one of the mitochondrial haplotypes were L0d1 or L0d2 which is consistent with mtDNA from living Khoesan populations in southern Africa. One individual (FK1) was L0f1, a haplotype which is not present southern African Khoesan, but is currently centred in Uganda and Tanzania. It is occasionally found amongst southern African Bantu speakers which suggests that the presence of L0f1 is a remnant of an earlier distribution which is now lost. The three L0 mitochondrial haplotypes from the six Faraoskop individuals (L0d1, L0d2, and L0f) suggest a diversity of maternal lineages compatible with the diversity of Khoesan groups but given the simultaneity of the burial, it is tempting to suggest that those with similar maternal haplotypes were closely related
A Genome-wide Association Study of Schizophrenia in the South African Xhosa and Generalizability of Polygenic Risk Score across African populations
No full textAfrican populations are vastly underrepresented in genetic studies despite having the most genetic variation globally and facing wide-ranging environmental exposures. Most of these studies have been conducted in populations of European (EUR) ancestry using GWAS arrays that represent the genetic variation in these populations. Thus, the prediction accuracy of polygenic risk scores (PRS) derived from EUR ancestry populations is less accurate in populations of non-European ancestry, and least accurate in African (AFR) ancestry populations. The extent to which PRS prediction accuracy varies within AFR ancestry populations has not, however, been previously investigated. This study had two aims: the first was to investigate the contribution of common variants to the risk of schizophrenia in the South African Xhosa (SAX) population through genome-wide association study (GWAS) analysis, and to determine if PRS derived from EUR and East Asian (EAS) ancestry populations from the Psychiatric Genomics Consortium (PGC) Schizophrenia Working Group were generalizable to SAX. The second aim was to assess the generalizability of PRS for non-psychiatric phenotypes that were derived from EUR ancestry individuals from the UK Biobank (UKB, n = ~350,000) in the Uganda General Population Cohort (GPC, n = 4,778) and the South African Drakenstein Child Health Study (DHCS, n = 638). To address the first aim, a GWAS was conducted in 2,086 Xhosa individuals from South Africa with and without schizophrenia (ncases = 1,038; ncontrols = 1,048) using a custom-designed Affymetrix GWAS array designed to capture variation in the Xhosa population. The schizophrenia GWAS in SAX yielded one SNP (rs35172303 ; P = 4.74e-08, OR = 0.6004, 95%CI:[0.499,0.721]) in ZFP3 that met genome-wide significance. The association of variants in ZFP3 from the schizophrenia GWAS is consistent with those from an earlier exomesequence study in SAX undertaken by colleagues, but this gene has not previously been associated with schizophrenia in large-scale schizophrenia GWAS of predominantly EUR ancestry. After characterizing the genetic architecture of schizophrenia in SAX, it was found that the heritability was enriched across functional categories involved in the regulation of gene expression. Then, the accuracy of PRS derived from PGC Schizophrenia Working Group from both EUR and EAS ancestries in predicting schizophrenia in SAX was quantified. There was low PRS prediction accuracy using PGC-derived summary statistics in SAX (PGC-EUR: max R2 = 0.0057, P = 0.008; PGC-EAS: max R2 = 0.0059, P = 0.007). These findings are consistent with previous findings that showed that PRS predication accuracy is low when discovery and target cohorts come from different ancestral backgrounds. For the second aim, PRS prediction accuracy was quantified in simulations using data from the African Genome Variation project (AGVP) to represent continental AFR diversity. Samples were categorised by geographical region into West, East and South Africa cohorts. Each cohort was divided into a discovery and target datasets. The West and East African discovery data was used to predict the simulated phenotype in the three target cohorts. Using UKB EUR ancestry individuals, PRS prediction accuracy was assessed for 34 anthropometric and blood panel traits in the Uganda GPC, and then meta-analysed UKB with PAGE (Population Architecture using Genomics and Epidemiology, comprising about 50,000 Latino/Hispanic and African-American individuals) and BBJ (Biobank Japan, n = ~162,000) to assess how the inclusion of diverse sample impacts PRS prediction accuracy. Simulations were limited by sample size but showed that PRS prediction accuracy was highest when the discovery and target cohorts were matched by African region, and for phenotypes with the sparsest genetic architecture. Using empirical data from UKB and the Uganda GPC, a low prediction accuracy was observed across all 34 quantitative traits in GPC when using GWAS data from UKB. There was differential prediction accuracy across AFR ancestry groups within UKB, i.e. the prediction accuracy was highest for the Ethiopian and admixed populations, and lowest for southern African populations. When comparing PRS prediction accuracy of East African individuals from the UKB to that of individuals from GPC, the prediction accuracy was lowest in the Ugandan GPC population, indicating that the difference in environments between the two groups may be contributing to the difference in PRS accuracy. Moreover, the cross-ancestry meta-analyses showed that the inclusion of diverse samples in large scale studies improves PRS prediction accuracy, most especially for phenotypes with population-enriched variants. It was demonstrated for the first time in this thesis that EUR ancestry-derived PRS prediction accuracy varied within continental AFR ancestry groups, and tracks with population history and the evolution of humans. The higher prediction accuracy observed in Ethiopians can be explained by their genetic proximity to Europeans as a result of the back to Africa migration, whereas the southern African populations (including SAX) are more proximal to the ancestral populations that never left the continent. It is therefore imperative to not only include more African samples in future large-scale studies, but to have samples that adequately represent the genetic and environmental diversity on the African continent
Massively parallel sequencing in sudden unexpected death in infants: A case report in South Africa
No full textSudden unexpected death in infants (SUDI) is a devastating event for a family, and unfortunately occurs relatively frequently in South Africa. These cases are referred for a forensic post-mortem investigation to establish the cause of death; however, despite thorough analyses, some cases remain undetermined. Internationally, a molecular autopsy has assisted in resolving these types of cases by revealing genetic variants which contributed to the demise. Motivated by lack of local research in this field, a study was launched at the University of Cape Town (South Africa) in 2015 to explore the use of molecular autopsies in the medico-legal investigation of local SUDI cases. An ethical framework was established and used to prospectively recruit SUDI cases from one of the busiest forensic facilities: Salt River Mortuary. A next generation sequencing approach was used to assess 43 genes previously associated with cardiac arrhythmias. In a particular infant, a putative pathogenic variant was identified (rs750771811 T/T) in the SCN10A gene. The variant is rare, but was homozygous in this infant, and appears to be the first time it has been observed in a SUDI victim. Previous functional studies on the amino-acid residue suggested that this variant may reduce SCN5A activity, which has been linked to Brugada syndrome. A genetic counselling session was arranged with the parents; a full family history was obtained, which revealed that the parents had a previous miscarriage and had recently had a second SUDI. The parents have subsequently been enrolled in the study for genetic screening and have been referred for electrocardiogram assessments. The findings highlight a new possible candidate variant to assess in SUDI cases, and also demonstrate the value of molecular autopsies to families
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