Browsing by Author "Ramesar, Raj"

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    ASSAf consensus study on the ethical, legal and social implications of genetics and genomics in South Africa
    (Academy of Science of South Africa, 2018) Pepper, Michael S.; Dandara, Collet; De Vries, Jantina; Dhai, Amaboo; Labuschaigne, Melodie; Mnyongani, Freddy; Moodley, Keymanthri; Olckers, Antonel; Pope, Anne; Ramesar, Raj; Ramsay, Michele; Soodyall, Himla; Towers, Wayne
    No abstract available.
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    Concordance of genetic variation that increases risk for Tourette Syndrome and that influences its underlying neurocircuitry
    (Springer Nature, 2019) Mufford, Mary; Cheung, Josh; Jahanshad, Neda; Van Der Merwe, Celia; Ding, Linda; Groenewold, Nynke; Koen, Nastassja; Chimusa, Emile R.; Dalvie, Shareefa; Ramesar, Raj; Knowles, James A.; Lochner, Christine; Hibar, Derrek P.; Paschou, Peristera; Van Den Heuvel, Odile A.; Medland, Sarah E.; Scharf, Jeremiah M.; Mathews, Carol A.; Thompson, Paul M.; Stein, Dan J.; Psychiatric Genomics Consortium - Tourette Syndrome working group
    ENGLISH ABSTRACT: There have been considerable recent advances in understanding the genetic architecture of Tourette Syndrome (TS) as well as its underlying neurocircuitry. However, the mechanisms by which genetic variation that increases risk for TS—and its main symptom dimensions—influence relevant brain regions are poorly understood. Here we undertook a genome-wide investigation of the overlap between TS genetic risk and genetic influences on the volume of specific subcortical brain structures that have been implicated in TS. We obtained summary statistics for the most recent TS genome-wide association study (GWAS) from the TS Psychiatric Genomics Consortium Working Group (4644 cases and 8695 controls) and GWAS of subcortical volumes from the ENIGMA consortium (30,717 individuals). We also undertook analyses using GWAS summary statistics of key symptom factors in TS, namely social disinhibition and symmetry behaviour. SNP effect concordance analysis (SECA) was used to examine genetic pleiotropy—the same SNP affecting two traits—and concordance—the agreement in single nucelotide polymorphism (SNP) effect directions across these two traits. In addition, a conditional false discovery rate (FDR) analysis was performed, conditioning the TS risk variants on each of the seven subcortical and the intracranial brain volume GWAS. Linkage disequilibrium score regression (LDSR) was used as validation of the SECA method. SECA revealed significant pleiotropy between TS and putamen (p = 2 × 10−4) and caudate (p = 4 × 10−4) volumes, independent of direction of effect, and significant concordance between TS and lower thalamic volume (p = 1 × 10−3). LDSR lent additional support for the association between TS and thalamus volume (p = 5.85 × 10−2). Furthermore, SECA revealed significant evidence of concordance between the social disinhibition symptom dimension and lower thalamus volume (p = 1 × 10−3), as well as concordance between symmetry behaviour and greater putamen volume (p = 7 × 10−4). Conditional FDR analysis further revealed novel variants significantly associated with TS (p < 8 × 10−7) when conditioning on intracranial (rs2708146, q = 0.046; and rs72853320, q = 0.035) and hippocampal (rs1922786, q = 0.001) volumes, respectively. These data indicate concordance for genetic variation involved in disorder risk and subcortical brain volumes in TS. Further work with larger samples is needed to fully delineate the genetic architecture of these disorders and their underlying neurocircuitry.
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    Determining ancestry proportions in complex admixture scenarios in South Africa using a novel proxy ancestry selection method
    (PLoS, 2013-09) Chimusa, Emile R.; Daya, Michelle; Möller, Marlo; Ramesar, Raj; Henn, Brenna M.; Van Helden, Paul D.; Mulder, Nicola J.; Hoal, Eileen G.
    Admixed populations can make an important contribution to the discovery of disease susceptibility genes if the parental populations exhibit substantial variation in susceptibility. Admixture mapping has been used successfully, but is not designed to cope with populations that have more than two or three ancestral populations. The inference of admixture proportions and local ancestry and the imputation of missing genotypes in admixed populations are crucial in both understanding variation in disease and identifying novel disease loci. These inferences make use of reference populations, and accuracy depends on the choice of ancestral populations. Using an insufficient or inaccurate ancestral panel can result in erroneously inferred ancestry and affect the detection power of GWAS and meta-analysis when using imputation. Current algorithms are inadequate for multi-way admixed populations. To address these challenges we developed PROXYANC, an approach to select the best proxy ancestral populations. From the simulation of a multi-way admixed population we demonstrate the capability and accuracy of PROXYANC and illustrate the importance of the choice of ancestry in both estimating admixture proportions and imputing missing genotypes. We applied this approach to a complex, uniquely admixed South African population. Using genome-wide SNP data from over 764 individuals, we accurately estimate the genetic contributions from the best ancestral populations: isiXhosa (33%±0:226), {Khomani SAN (31%±0:195), European (16%±0:118), Indian (13%±0:094), and Chinese (7%±0:0488). We also demonstrate that the ancestral allele frequency differences correlate with increased linkage disequilibrium in the South African population, which originates from admixture events rather than population bottlenecks.
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    Investigation on the hereditary basis of colorectal cancers in an African population with frequent early onset cases
    (Public Library of Science, 2019-10-24) Katsidzira, Leolin; Vorster, Anna; Gangaidzo, Innocent T.; Makunike-Mutasa, Rudo; Govender, Dhiren; Rusakaniko, Simbarashe; Thomson, Sandie; Matenga, Jonathan A.; Ramesar, Raj
    Background: Approximately 25% of colorectal cancer patients in sub-Saharan Africa are younger than 40 years, and hereditary factors may contribute. We investigated the frequency and patterns of inherited colorectal cancer among black Zimbabweans. Methods: A population-based cross-sectional study of ninety individuals with a new diagnosis of colorectal cancer was carried out in Harare, Zimbabwe between November 2012 and December 2015. Phenotypic data was obtained using interviewer administered questionnaires, and reviewing clinical and pathology data. Cases were screened for mismatch repair deficiency by immunohistochemistry and/or microsatellite instability testing, and for MLH1, MSH2 and EPCAM deletions using multiplex ligation-dependent probe amplification. Next generation sequencing using a 16-gene panel was performed for cases with phenotypic features consistent with familial colorectal cancer. Variants were assessed for pathogenicity using the mean allele frequency, phenotypic features and searching online databases. Results: Three Lynch syndrome cases were identified: MSH2 c.2634G>A pathogenic mutation, c.(1896+1_1897–1)_(*193_?)del , and one fulfilling the Amsterdam criteria, with MLH1 and PMS2 deficiency, but no identifiable pathogenic mutation. Two other cases had a strong family history of cancers, but the exact syndrome was not identified. The prevalence of Lynch syndrome was 3·3% (95% CI 0·7–9·4), and that of familial colorectal cancer was 5·6% (95% CI, 1·8–12·5). Conclusions: Identifying cases of inherited colorectal cancer in sub-Saharan Africa is feasible, and our findings can inform screening guidelines appropriate to this setting.
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    PROTEA, a Southern African multicenter congenital heart disease registry and biorepository: rationale, design, and initial results
    (Frontiers Media S.A., 2021-10) Aldersley, Thomas; Lawrenson, John; Human, Paul; Shaboodien, Gasnat; Cupido, Blanche; Comitis, George; De Decker, Rik; Fourie, Barend; Swanson, Lenise; Joachim, Alexia; Magadla, Phaphama; Ngoepe, Malebogo; Swanson, Liam; Revell, Alistair; Ramesar, Raj; Brooks, Andre; Saacks, Nicole; De Koning, Bianca; Sliwa, Karen; Anthony, John; Osman, Ayesha; Keavney, Bernard; Zühlke, Liesl
    Objectives: The PartneRships in cOngeniTal hEart disease (PROTEA) project aims to establish a densely phenotyped and genotyped Congenital Heart Disease (CHD) cohort for southern Africa. This will facilitate research into the epidemiology and genetic determinants of CHD in the region. This paper introduces the PROTEA project, characterizes its initial cohort, from the Western Cape Province of South Africa, and compares the proportion or “cohort-prevalences” of CHD-subtypes with international findings. Methods: PROTEA is a prospective multicenter CHD registry and biorepository. The initial cohort was recruited from seven hospitals in the Western Cape Province of South Africa from 1 April 2017 to 31 March 2019. All patients with structural CHD were eligible for inclusion. Descriptive data for the preliminary cohort are presented. In addition, cohort-prevalences (i.e., the proportion of patients within the cohort with a specific CHD-subtype) of 26 CHD-subtypes in PROTEA's pediatric cohort were compared with the cohort-prevalences of CHD-subtypes in two global birth-prevalence studies. Results: The study enrolled 1,473 participants over 2 years, median age was 1.9 (IQR 0.4–7.1) years. Predominant subtypes included ventricular septal defect (VSD) (339, 20%), atrial septal defect (ASD) (174, 11%), patent ductus arteriosus (185, 11%), atrioventricular septal defect (AVSD) (124, 7%), and tetralogy of Fallot (121, 7%). VSDs were 1.8 (95% CI, 1.6–2.0) times and ASDs 1.4 (95% CI, 1.2–1.6) times more common in global prevalence estimates than in PROTEA's pediatric cohort. AVSDs were 2.1 (95% CI, 1.7–2.5) times more common in PROTEA and pulmonary stenosis and double outlet right ventricle were also significantly more common compared to global estimates. Median maternal age at delivery was 28 (IQR 23–34) years. Eighty-two percent (347/425) of mothers used no pre-conception supplementation and 42% (105/250) used no first trimester supplements. Conclusions: The cohort-prevalence of certain mild CHD subtypes is lower than for international estimates and the cohort-prevalence of certain severe subtypes is higher. PROTEA is not a prevalence study, and these inconsistencies are unlikely the result of true differences in prevalence. However, these findings may indicate under-diagnosis of mild to moderate CHD and differences in CHD management and outcomes. This reemphasizes the need for robust CHD epidemiological research in the region.
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    Whole-genome sequencing for an enhanced understanding of genetic variation among South Africans
    (Nature Research (part of Springer Nature), 2017) Choudhury, Ananyo; Ramsay, Michele; Hazelhurst, Scott; Aron, Shaun; Bardien, Soraya; Botha, Gerrit; Chimusa, Emile R.; Christoffels, Alan; Gamieldien, Junaid; Sefid-Dashti, Mahjoubeh J.; Joubert, Fourie; Meintjes, Ayton; Mulder, Nicola; Ramesar, Raj; Rees, Jasper; Scholtz, Kathrine; Sengupta, Dhriti; Soodyall, Himla; Venter, Philip; Warnich, Louise; Pepper, Michael S.
    ENGLISH ABSTRACT: The Southern African Human Genome Programme is a national initiative that aspires to unlock the unique genetic character of southern African populations for a better understanding of human genetic diversity. In this pilot study the Southern African Human Genome Programme characterizes the genomes of 24 individuals (8 Coloured and 16 black southeastern Bantu-speakers) using deep whole-genome sequencing. A total of ~16 million unique variants are identified. Despite the shallow time depth since divergence between the two main southeastern Bantu-speaking groups (Nguni and Sotho-Tswana), principal component analysis and structure analysis reveal significant (p < 10−6) differentiation, and FST analysis identifies regions with high divergence. The Coloured individuals show evidence of varying proportions of admixture with Khoesan, Bantu-speakers, Europeans, and populations from the Indian sub-continent. Whole-genome sequencing data reveal extensive genomic diversity, increasing our understanding of the complex and region-specific history of African populations and highlighting its potential impact on biomedical research and genetic susceptibility to disease.