Genetic mapping of retinitis pigmentosa implications for South African patients

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Epigenetics – an introductory overview

Epigenetics or imprinting refers to the process of ‘chemically’ marking the central A, C, G, T double-stranded DNA code. In the past several decades a deeper understanding has been gained of a wide range of mechanisms that have been invoked in biology for the purpose of regulating gene expression and dosage of protein products that are effectively translated and functional in the cells. We mostly carry two copies of a gene (one per non-sex chromosome inherited from each of our parents) in each of our somatic cells; however, some genes are required to have two functional copies in each cell, while others require no less than one copy, but are tolerant of more than one copy. There are very specific genes, often dealing with growth and development, which are, however, only ever needed in a single copy; any more or any less is problematic and even lethal. Epigenetics is the process of reversibly ‘marking’ genes, either driven by endogenous processes or through exposure to environmental factors, such that they may be effectively silenced. Human development requires an orderly and systematic means of switching on and off of genes; understandably, if there is a mutation affecting this process, it leads to disease, while exposure to chemicals or other experiential stimuli may have a similar effect. This review provides a broad outline of epigenetics and genetic imprinting on human and mammalian development and disease

The burden of sickle cell disease in Cape Town

Background. South Africa has a low incidence of sickle cell disease (SCD). However, its demographics are changing because of immigration from sub-Saharan African countries where SCD is prevalent.Objectives. We aimed to determine the frequency of SCD presenting to the Haematology/Oncology Service at Red Cross War Memorial Children’s Hospital in Cape Town and to measure the associated disease burden.Methods. This was a retrospective cross-sectional study of patients first attending the Haematology Service between January 2001 and June 2010.Results. A total of 58 SCD patients were indentified, with an annual frequency that increased over the study period by 300 -400%. Up to 93.1% (n=54) were originally from other African countries, mainly the Democratic Republic of Congo (62.1%, n=36). One patient had sickle D-Punjab genotype, and all the other patients had the homozygous sickle cell anaemia genotype (Hb SS). Their haematological parameters  demonstrated a normocytic anaemia with high white cell counts. The mean number of clinic visits per patient per year was 22.2 (range 0 - 64), and the mean number of hospital admissions per patient per year was 1.2 (range 0 - 5). All the patients were on antibiotic prophylaxis. The majorityhad at least one blood transfusion (65.5%, n=38), and a significantproportion required intravenous analgesia on admission (29.3%, n=17) and hydroxyurea treatment (36.2%, n=21).Conclusions. Over the past 10 years the frequency of SCD has increased considerably, imposing a significant burden and new challenges to the health services in Cape Town

Genetic variation within GRIN2B in adolescents with alcohol use disorder may be associated with larger left posterior cingulate cortex volume.

OBJECTIVE: Brain structure differences and adolescent alcohol dependence both show substantial heritability. However, exactly which genes are responsible for brain volume variation in adolescents with substance abuse disorders are currently unknown. The aim of this investigation was to determine whether genetic variants previously implicated in psychiatric disorders are associated with variation in brain volume in adolescents with alcohol use disorder (AUD). METHODS: The cohort consisted of 58 adolescents with DSM-IV AUD and 58 age and gender-matched controls of mixed ancestry ethnicity. An Illumina Infinium iSelect custom 6000 bead chip was used to genotype 5348 single nucleotide polymorphisms (SNPs) in 378 candidate genes. Magnetic resonance images were acquired and volumes of global and regional structures were estimated using voxel-based morphometry. To determine whether any of the genetic variants were associated with brain volume, association analysis was conducted using linear regression in Plink. RESULTS: From the exploratory analysis, the GRIN2B SNP rs219927 was associated with brain volume in the left posterior cingulate cortex (p<0.05), whereby having a G-allele was associated with a bigger volume. CONCLUSION: The GRIN2B gene is involved in glutamatergic signalling and may be associated with developmental differences in AUD in brain regions such as the posterior cingulate cortex. Such differences may play a role in risk for AUD, and deserve more detailed investigation

Psychosis and relapse in bipolar disorder are related to GRM3, DAOA, and GRIN2B genotype

Objective:  Key Words: Manic-Depressive Psychosis; Glutamate; GRIN2B receptor; mGluR3; G72 protein; HumanDysfunction in glutamate signalling is thought to play a role in the pathophysiology of bipolar disorder (BD). There is evidence of associations between single nucleotide polymorphisms (SNPs) in GRM3, GRIN2B, and DAOA genes and the diagnosis of BD. In this pilot study, we investigated the frequency of SNP variants in these 3 genes within South African population groups, and assessed interactions between genes and phenotypes of BD disease severity. Method: Multiplex SNaPshotTM PCR was used to genotype 191 case and 188 control samples. Cases comprised of 191 individuals in a South African cohort of mixed ancestry and Caucasians, with BD Type 1. Phenotypes of BD disease severity were: age of onset, number of illness episodes, number of hospitalisations for depression or mania and history of psychotic symptoms. Results: There were no significant difference in SNP allele frequencies between cases and controls. In the case-only analysis, the GRM3 rs6465084 heterozygote was associated with a 4-fold increased risk of lifetime history of psychotic symptoms, and the specific variants within the gene pair, DAOA and GRIN2B, had a significant interaction with the number of hospitalisations for mania, with lowest admission rates associated with both pairs of ancestral alleles. Conclusion: In BD, variations in glutamatergic genes may influence phenotypes related to the severity of illness. Speculatively, newly derived genes associated with various evolutionary advantages, may also increase the risk for more severe BD. These preliminary findings deserve validation in a larger cohort

A Genomic Portrait of Haplotype Diversity and Signatures of Selection in Indigenous Southern African Populations

We report a study of genome-wide, dense SNP (∼900K) and copy number polymorphism data of indigenous southern Africans. We demonstrate the genetic contribution to southern and eastern African populations, which involved admixture between indigenous San, Niger-Congo-speaking and populations of Eurasian ancestry. This finding illustrates the need to account for stratification in genome-wide association studies, and that admixture mapping would likely be a successful approach in these populations. We developed a strategy to detect the signature of selection prior to and following putative admixture events. Several genomic regions show an unusual excess of Niger-Kordofanian, and unusual deficiency of both San and Eurasian ancestry, which were considered the footprints of selection after population admixture. Several SNPs with strong allele frequency differences were observed predominantly between the admixed indigenous southern African populations, and their ancestral Eurasian populations. Interestingly, many candidate genes, which were identified within the genomic regions showing signals for selection, were associated with southern African-specific high-risk, mostly communicable diseases, such as malaria, influenza, tuberculosis, and human immunodeficiency virus/AIDs. This observation suggests a potentially important role that these genes might have played in adapting to the environment. Additionally, our analyses of haplotype structure, linkage disequilibrium, recombination, copy number variation and genome-wide admixture highlight, and support the unique position of San relative to both African and non-African populations. This study contributes to a better understanding of population ancestry and selection in south-eastern African populations; and the data and results obtained will support research into the genetic contributions to infectious as well as non-communicable diseases in the region