Browsing by Author "Ramsay, Michèle"

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Apolipoprotein L1 High-Risk Genotypes and Albuminuria in Sub-Saharan African Populations
(2022-06) Jean-Tristan Brandenburg; Melanie A. Govender; Winkler, Cheryl A.; Boua, Palwende Romuald; Agongo, Godfred; Fabian, June; Ramsay, Michèle
Background and objectives: Recessive inheritance of African-specific APOL1 kidney risk variants is associated with higher risk of nondiabetic kidney disease, progression to kidney failure, and early-onset albuminuria that precedes eGFR decline. The effect of APOL1 risk variants on kidney disease in continental Africans is understudied. Objectives of this study were to determine APOL1 risk allele prevalence and associations between APOL1 genotypes and kidney disease in West, East, and South Africa. Design, setting, participants, & measurements: This cross-sectional population-based study in four African countries included 10,769 participants largely aged 40-60 years with sociodemographic and health information, anthropometry data, and blood and urine tests for biomarkers of kidney disease. APOL1 risk alleles were imputed from the H3Africa genotyping array, APOL1 risk allele and genotype frequencies were determined, and genetic associations were assessed for kidney disease. Kidney disease was defined as the presence of eGFR <60 ml/min per 1.73 m2, albuminuria, or a composite end point including eGFR <60 ml/min per 1.73 m2 and/or albuminuria. Results: High G1 allele frequencies occurred in South and West Africa (approximately 7%-13%). G2 allele frequencies were highest in South Africa (15%-24%), followed by West Africa (9%-12%). Associations between APOL1 risk variants and albuminuria were significant for recessive (odds ratio, 1.63; 95% confidence interval, 1.25 to 2.12) and additive (odds ratio, 1.39; 95% confidence interval, 1.09 to 1.76) models. Associations were stronger for APOL1 G1/G1 genotypes versus G0/G0 (odds ratio, 3.87; 95% confidence interval, 2.16 to 6.93) compared with either G2/G2 (odds ratio, 1.65; 95% confidence interval, 1.09 to 2.51) or G1/G2 (odds ratio, 1.24; 95% confidence interval, 0.83 to 1.87). No association between APOL1 risk variants and eGFR <60 ml/min per 1.73 m2 was observed. Conclusions: APOL1 G1 and G2 alleles and high-risk genotype frequencies differed between and within West and South Africa and were almost absent from East Africa. APOL1 risk variants were associated with albuminuria but not eGFR <60 ml/min per 1.73 m2. There may be differential effects of homozygous G1 and G2 genotypes on albuminuria that require further investigation.
Assessing runs of Homozygosity: a comparison of SNP Array and whole genome sequence low coverage data
(BMC, 2018) Ceballos, Francisco C.; Hazelhurst, Scott; Ramsay, Michèle
Background: Runs of Homozygosity (ROH) are genomic regions where identical haplotypes are inherited from each parent. Since their first detection due to technological advances in the late 1990s, ROHs have been shedding light on human population history and deciphering the genetic basis of monogenic and complex traits and diseases. ROH studies have predominantly exploited SNP array data, but are gradually moving to whole genome sequence (WGS) data as it becomes available. WGS data, covering more genetic variability, can add value to ROH studies, but require additional considerations during analysis. Results: Using SNP array and low coverage WGS data from 1885 individuals from 20 world populations, our aims were to compare ROH from the two datasets and to establish software conditions to get comparable results, thus providing guidelines for combining disparate datasets in joint ROH analyses. By allowing heterozygous SNPs per window, using the PLINK homozygosity function and non-parametric analysis, we were able to obtain non-significant differences in number ROH, mean ROH size and total sum of ROH between data sets using the different technologies for almost all populations. Conclusions: By allowing 3 heterozygous SNPs per ROH when dealing with WGS low coverage data, it is possible to establish meaningful comparisons between data using SNP array and WGS low coverage technologies.
Assessing runs of Homozygosity: a comparison of SNP Array and whole genome sequence low coverage data
(BMC, 2018-01) Ceballos, Francisco C.; Hazelhurst, Scott; Ramsay, Michèle
Background: Runs of Homozygosity (ROH) are genomic regions where identical haplotypes are inherited from each parent. Since their first detection due to technological advances in the late 1990s, ROHs have been shedding light on human population history and deciphering the genetic basis of monogenic and complex traits and diseases. ROH studies have predominantly exploited SNP array data, but are gradually moving to whole genome sequence (WGS) data as it becomes available. WGS data, covering more genetic variability, can add value to ROH studies, but require additional considerations during analysis. Results: Using SNP array and low coverage WGS data from 1885 individuals from 20 world populations, our aims were to compare ROH from the two datasets and to establish software conditions to get comparable results, thus providing guidelines for combining disparate datasets in joint ROH analyses. By allowing heterozygous SNPs per window, using the PLINK homozygosity function and non-parametric analysis, we were able to obtain non-significant differences in number ROH, mean ROH size and total sum of ROH between data sets using the different technologies for almost all populations. Conclusions: By allowing 3 heterozygous SNPs per ROH when dealing with WGS low coverage data, it is possible to establish meaningful comparisons between data using SNP array and WGS low coverage technologies
Insights into the genetics of blood pressure in black South African individuals: the Birth to Twenty cohort
(BMC, 2018) Hendry, Liesl M.; Sahibdeen, Venesa; Choudhury, Ananyo; Norris, Shane A.; Ramsay, Michèle; Lombard, Zané
Background: Cardiovascular diseases (CVDs) are the leading cause of non-communicable disease deaths globally, with hypertension being a major risk factor contributing to CVDs. Blood pressure is a heritable trait, with relatively few genetic studies having been performed in Africans. This study aimed to identify genetic variants associated with variance in systolic (SBP) and diastolic (DBP) blood pressure in black South Africans. Methods: Genotyping was performed using the Metabochip in a subset of participants (mixed sex; median age 17.9) and their adult female caregivers (median age 41.0) from the Birth to Twenty cohort (n = 1947). Data were analysed as a merged dataset (all participants and caregivers together) in GEMMA (v0.94.1) using univariate linear mixed models, incorporating a centered relatedness matrix to account for the relatedness between individuals and with adjustments for age, sex, BMI and principal components of the genotype information. Results: Association analysis identified regions of interest in the NOS1AP (DBP: rs112468105 - p = 7.18 × 10−5 and SBP: rs4657181 - p = 4.04 × 10−5), MYRF (SBP: rs11230796 - p = 2.16 × 10−7, rs400075 - p = 2.88 × 10−7) and POC1B (SBP: rs770373 - p = 7.05 × 10−5, rs770374 - p = 9.05 × 10−5) genes and some intergenic regions (DACH1|LOC440145 (DBP: rs17240498 - p = 4.91 × 10−6 and SBP: rs17240498 - p = 2.10 × 10−5) and INTS10|LPL (SBP: rs55830938 - p = 1.30 × 10−5, rs73599609 - p = 5.78 × 10−5, rs73667448 - p = 6.86×10−5)). Conclusions: The study provided further insight into the contribution of genetic variants to blood pressure in black South Africans. Future functional and replication studies in larger samples are required to confirm the role of the identified loci in blood pressure regulation and whether or not these variants are African-specific.
The contribution of common genetic variants to breast cancer risk in South African black populations
(University of the Witwatersrand, Johannesburg, 2023-08) Hayat, Mahtaab; Brandenburg, Jean-Tristan; Ramsay, Michèle; Mathew, Christopher
Breast cancer is the second most common cancer in South African black women. The contribution of common genetic variants to breast cancer risk is well studied in non-African populations, but little is known about their role in resident African populations, and there are no published genome-wide association studies (GWAS) on breast cancer in Africa. This PhD thesis aimed to determine the contribution of common genetic variants to breast cancer in a South African black population. A GWAS was carried out in 2,573 black female breast cancer patients from the Johannesburg Cancer Study and 744 population-matched, female controls from the AWI-Gen study. All participants were from Soweto, Johannesburg, South Africa. Samples were genotyped on the H3Africa SNP array. Replication testing was done of existing loci from European and African American (AA) populations in the resident African data, and loci from the resident African data in European and AA populations. A meta-analysis was carried out with an AA population. Finally, existing polygenic risk scores (PRSs) were tested in the resident African dataset. Three variants at two loci were strongly associated with breast cancer in this study. Two variants (rs77422433, p-value=2.89x10-08, odds ratio (OR):0.46, 95% confidence interval (95%CI): 0.40-0.52 and rs112410019, p-value=3.01x10-08, OR: 0.47, 95%CI: 0.41-0.53) were located within the DNA repair gene XRCC5. These variants were not previously associated with breast cancer, suggesting that it may be an African specific risk locus. The second locus is on chromosome 16 in CES5A (rs3859109, p-value=4.54x10-08, OR=0.70, 95%CI: 0.68-0.73), and had not previously been associated with breast cancer. None of these SNPs were replicated in European and AA populations. The meta-analysis with AA data revealed strong association of an intergenic SNP with breast cancer (rs139299680, pmeta=7.25x10-08) on chromosome 3. A polygenic risk score (PRS) developed in European populations demonstrated poor transferability to this African dataset. This GWAS is the first to be conducted in a resident black African population. This study suggests that there may be African-specific genetic risk factors for African breast cancer, and that large genome-wide studies in African populations are essential to develop a comprehensive understanding of the genetics of breast cancer in Africa.