Application of Genomic Medicine in Africa: 14th Conference of the African Society of Human Genetics and the 2nd International Congress of the Moroccan Society of Genomics and Human Genetics, Rabat, Morocco 2022.

The 14th African Society of Human Genetics (AfSHG) Morocco Meeting and 2nd International Congress of the Moroccan Society of Genomics and Human Genetics (SM2GH), held in Rabat, Morocco, from December 12 through 17, 2022, brought together 298 attendees from 23 countries, organized by the AfSHG in collaboration with the SM2GH. The conference's overarching theme was "Applications of Genomics Medicine in Africa," covering a wide range of topics, including population genetics, genetics of infectious diseases, hereditary disorders, cancer genetics, and translational genetics. The conference aimed to address the lag in the field of genetics in Africa and highlight the potential for genetic research and personalized medicine on the continent. The goal was to improve the health of African populations and global communities while nurturing the careers of young African scientists in the field. Distinguished scientists from around the world shared their recent findings in genetics, immunogenetics, genomics, genome editing, immunotherapy, and ethics genomics. Precongress activities included a 2-day bioinformatics workshop, "NGS Analysis for Monogenic Disease in African Populations," and a Young Investigators Forum, providing opportunities for young African researchers to showcase their work. The vast genetic diversity of the African continent poses a significant challenge in investigating and characterizing public health issues at the genetic and functional levels. Training, research, and the development of expertise in genetics, immunology, genomics, and bioinformatics are vital for addressing these challenges and advancing genetics in Africa. The AfSHG is committed to leading efforts to enhance genetic research, coordinate training, and foster research collaborations on the continent.

Expanding the human gut microbiome atlas of Africa.

Population studies are crucial in understanding the complex interplay between the gut microbiome and geographical, lifestyle, genetic, and environmental factors. However, populations from low- and middle-income countries, which represent ~84% of the world population, have been excluded from large-scale gut microbiome research. Here, we present the AWI-Gen 2 Microbiome Project, a cross-sectional gut microbiome study sampling 1,803 women from Burkina Faso, Ghana, Kenya, and South Africa. By intensively engaging with communities that range from rural and horticultural to urban informal settlements and post-industrial, we capture population diversity that represents a far greater breadth of the world's population. Using shotgun metagenomic sequencing, we find that study site explains substantially more microbial variation than disease status. We identify taxa with strong geographic and lifestyle associations, including loss of Treponema and Cryptobacteroides species and gain of Bifidobacterium species in urban populations. We uncover a wealth of prokaryotic and viral novelty, including 1,005 new bacterial metagenome-assembled genomes, and identify phylogeography signatures in Treponema succinifaciens. Finally, we find a microbiome signature of HIV infection that is defined by several taxa not previously associated with HIV, including Dysosmobacter welbionis and Enterocloster sp. This study represents the largest population-representative survey of gut metagenomes of African individuals to date, and paired with extensive clinical biomarkers, demographic data, and lifestyle information, provides extensive opportunity for microbiome-related discovery and research.

Postprandial glucose variability and clusters of sex hormones, liver enzymes, and cardiometabolic factors in a South African cohort of African ancestry.

INTRODUCTION: This study aimed to, first, determine the clusters of sex hormones, liver enzymes, and cardiometabolic factors associated with postprandial glucose (PPG) and, second to evaluate the variation these clusters account for jointly and independently with polygenic risk scores (PRSs) in South Africans of African ancestry men and women. RESEARCH DESIGN AND METHODS: PPG was calculated as the integrated area under the curve for glucose during the oral glucose tolerance test (OGTT) using the trapezoidal rule in 794 participants from the Middle-aged Soweto Cohort. Principal component analysis was used to cluster sex hormones, liver enzymes, and cardiometabolic factors, stratified by sex. Multivariable linear regression was used to assess the proportion of variance in PPG accounted for by principal components (PCs) and type 2 diabetes (T2D) PRS while adjusting for selected covariates in men and women. RESULTS: The T2D PRS did not contribute to the PPG variability in both men and women. In men, the PCs' cluster of sex hormones, liver enzymes, and cardiometabolic explained 10.6% of the variance in PPG, with PC1 (peripheral fat), PC2 (liver enzymes and steroid hormones), and PC3 (lipids and peripheral fat) contributing significantly to PPG. In women, PC factors of sex hormones, cardiometabolic factors, and liver enzymes explained a similar amount of the variance in PPG (10.8%), with PC1 (central fat) and PC2 (lipids and liver enzymes) contributing significantly to PPG. CONCLUSIONS: We demonstrated that inter-individual differences in PPG responses to an OGTT may be differentially explained by body fat distribution, serum lipids, liver enzymes, and steroid hormones in men and women.

Proteomic insights into the pathophysiology of hypertension-associated albuminuria: Pilot study in a South African cohort.

BACKGROUND: Hypertension is an important public health priority with a high prevalence in Africa. It is also an independent risk factor for kidney outcomes. We aimed to identify potential proteins and pathways involved in hypertension-associated albuminuria by assessing urinary proteomic profiles in black South African participants with combined hypertension and albuminuria compared to those who have neither condition. METHODS: The study included 24 South African cases with both hypertension and albuminuria and 49 control participants who had neither condition. Protein was extracted from urine samples and analysed using ultra-high-performance liquid chromatography coupled with mass spectrometry. Data were generated using data-independent acquisition (DIA) and processed using Spectronaut™ 15. Statistical and functional data annotation were performed on Perseus and Cytoscape to identify and annotate differentially abundant proteins. Machine learning was applied to the dataset using the OmicLearn platform. RESULTS: Overall, a mean of 1,225 and 915 proteins were quantified in the control and case groups, respectively. Three hundred and thirty-two differentially abundant proteins were constructed into a network. Pathways associated with these differentially abundant proteins included the immune system (q-value [false discovery rate] = 1.4 × 10- 45), innate immune system (q = 1.1 × 10- 32), extracellular matrix (ECM) organisation (q = 0.03) and activation of matrix metalloproteinases (q = 0.04). Proteins with high disease scores (76-100% confidence) for both hypertension and chronic kidney disease included angiotensinogen (AGT), albumin (ALB), apolipoprotein L1 (APOL1), and uromodulin (UMOD). A machine learning approach was able to identify a set of 20 proteins, differentiating between cases and controls. CONCLUSIONS: The urinary proteomic data combined with the machine learning approach was able to classify disease status and identify proteins and pathways associated with hypertension-associated albuminuria.

Genetic Association and Transferability for Urinary Albumin-Creatinine Ratio as a Marker of Kidney Disease in four Sub-Saharan African Populations and non-continental Individuals of African Ancestry.

BACKGROUND: Genome-wide association studies (GWAS) have predominantly focused on populations of European and Asian ancestry, limiting our understanding of genetic factors influencing kidney disease in Sub-Saharan African (SSA) populations. This study presents the largest GWAS for urinary albumin-to-creatinine ratio (UACR) in SSA individuals, including 8,970 participants living in different African regions and an additional 9,705 non-resident individuals of African ancestry from the UK Biobank and African American cohorts. METHODS: Urine biomarkers and genotype data were obtained from two SSA cohorts (AWI-Gen and ARK), and two non-resident African-ancestry studies (UK Biobank and CKD-Gen Consortium). Association testing and meta-analyses were conducted, with subsequent fine-mapping, conditional analyses, and replication studies. Polygenic scores (PGS) were assessed for transferability across populations. RESULTS: Two genome-wide significant (P<5x10-8) UACR-associated loci were identified, one in the BMP6 region on chromosome 6, in the meta-analysis of resident African individuals, and another in the HBB region on chromosome 11 in the meta-analysis of non-resident SSA individuals, as well as the combined meta-analysis of all studies. Replication of previous significant results confirmed associations in known UACR-associated regions, including THB53, GATM, and ARL15. PGS estimated using previous studies from European ancestry, African ancestry, and multi-ancestry cohorts exhibited limited transferability of PGS across populations, with less than 1% of observed variance explained. CONCLUSION: This study contributes novel insights into the genetic architecture of kidney disease in SSA populations, emphasizing the need for conducting genetic research in diverse cohorts. The identified loci provide a foundation for future investigations into the genetic susceptibility to chronic kidney disease in underrepresented African populations Additionally, there is a need to develop integrated scores using multi-omics data and risk factors specific to the African context to improve the accuracy of predicting disease outcomes. METHODS: Urine biomarkers and genotype data were obtained from two SSA cohorts (AWI-Gen and ARK), and two non-resident African-ancestry studies (UK Biobank and CKD-Gen Consortium). Association testing and meta-analyses were conducted, with subsequent fine-mapping, conditional analyses, and replication studies. Polygenic scores (PGS) were assessed for transferability across populations. RESULTS: Two genome-wide significant (P<5x10-8) UACR-associated loci were identified, one in the BMP6 region on chromosome 6, in the meta-analysis of resident African individuals, and another in the HBB region on chromosome 11 in the meta-analysis of non-resident SSA individuals, as well as the combined meta-analysis of all studies. Replication of previous significant results confirmed associations in known UACR-associated regions, including THB53, GATM, and ARL15. PGS estimated using previous studies from European ancestry, African ancestry, and multi-ancestry cohorts exhibited limited transferability of PGS across populations, with less than 1% of observed variance explained. CONCLUSION: This study contributes novel insights into the genetic architecture of kidney function in SSA populations, emphasizing the need for conducting genetic research in diverse cohorts. The identified loci provide a foundation for future investigations into the genetic susceptibility to chronic kidney disease in underrepresented African populations.

Factors associated with frequency of fruit and vegetable consumption among selected sub-Saharan African populations: evidence from the Cardiovascular H3Africa Innovation Resource Project.

BACKGROUND: Frequent fruit and vegetable consumption is considered a promising dietary behaviour that protects health. However, most existing studies about the factors associated with this phenomenon among Africans are based on single-country reports, apart from one meta-regression combining smaller studies. This study harmonized large datasets and assessed factors associated with the frequency of fruit and vegetable consumption in this population. METHODS: Individual-level data on sociodemographics, lifestyle and diet from 20 443 participants across five African countries (Burkina Faso, Ghana, Kenya, South Africa and Nigeria), from the Stroke Investigative Research and Educational Network (SIREN) and Africa Wits-INDEPTH partnership for Genomic Research (AWI-Gen) studies, were harmonized. Total frequency of fruit and vegetable consumption (in portions/week) was classified as 'low' (≤6), 'moderate' (7-14) and 'high' (≥15). Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) of factors associated with the total frequency of fruit and vegetable consumption (using 'low' consumption as the reference) were estimated using multinomial regression models. RESULTS: Mean age of participants was 54.3 ± 11.8 years, 10 641 (52.1%) were female, and the median (interquartile range) frequency of total fruit and vegetable consumption was 10.0 (4.0, 21.0) portions/week. Participants with a family history of cardiovascular disease [moderate (aOR, 0.92; 95% CI, 0.85, 1.00) and high (aOR, 0.85; 95% CI, 0.78, 0.92)], current smokers [moderate (aOR, 0.83; 95% CI, 0.74, 0.94) and high (aOR, 0.78; 95% CI, 0.69, 0.88)], current alcohol users [moderate (aOR, 0.92; 95% CI, 0.85, 1.00) and high (aOR, 0.82; 95% CI, 0.76, 0.89)] and physically inactive participants [moderate (aOR, 0.85; 95% CI, 0.75, 0.96) and high (aOR, 0.80; 95% CI, 0.70, 0.90)] were less likely to consume fruits and vegetables frequently. CONCLUSION: Africans with lifestyle risk factors for cardiovascular disease were less likely to consume fruit and vegetables frequently.

A multi-cohort genome-wide association study in African ancestry individuals reveals risk loci for primary open-angle glaucoma.

Primary open-angle glaucoma (POAG), the leading cause of irreversible blindness worldwide, disproportionately affects individuals of African ancestry. We conducted a genome-wide association study (GWAS) for POAG in 11,275 individuals of African ancestry (6,003 cases; 5,272 controls). We detected 46 risk loci associated with POAG at genome-wide significance. Replication and post-GWAS analyses, including functionally informed fine-mapping, multiple trait co-localization, and in silico validation, implicated two previously undescribed variants (rs1666698 mapping to DBF4P2; rs34957764 mapping to ROCK1P1) and one previously associated variant (rs11824032 mapping to ARHGEF12) as likely causal. For individuals of African ancestry, a polygenic risk score (PRS) for POAG from our mega-analysis (African ancestry individuals) outperformed a PRS from summary statistics of a much larger GWAS derived from European ancestry individuals. This study quantifies the genetic architecture similarities and differences between African and non-African ancestry populations for this blinding disease.

Characterization of CYP2B6 and CYP2A6 Pharmacogenetic Variation in Sub-Saharan African Populations.

Genetic variation in CYP2B6 and CYP2A6 is known to impact interindividual response to antiretrovirals, nicotine, and bupropion, among other drugs. However, the full catalogue of clinically relevant pharmacogenetic variants in these genes is yet to be established, especially across African populations. This study therefore aimed to characterize the star allele (haplotype) distribution in CYP2B6 and CYP2A6 across diverse and understudied sub-Saharan African (SSA) populations. We called star alleles from 961 high-depth full genomes using StellarPGx, Aldy, and PyPGx. In addition, we performed CYP2B6 and CYP2A6 star allele frequency comparisons between SSA and other global biogeographical groups represented in the new 1000 Genomes Project high-coverage dataset (n = 2,000). This study presents frequency information for star alleles in CYP2B6 (e.g., *6 and *18; frequency of 21-47% and 2-19%, respectively) and CYP2A6 (e.g., *4, *9, and *17; frequency of 0-6%, 3-10%, and 6-20%, respectively), and predicted phenotypes (for CYP2B6), across various African populations. In addition, 50 potentially novel African-ancestry star alleles were computationally predicted by StellarPGx in CYP2B6 and CYP2A6 combined. For each of these genes, over 4% of the study participants had predicted novel star alleles. Three novel star alleles in CYP2A6 (*54, *55, and *56) and CYP2B6 apiece, and several suballeles were further validated via targeted Single-Molecule Real-Time resequencing. Our findings are important for informing the design of comprehensive pharmacogenetic testing platforms, and are highly relevant for personalized medicine strategies, especially relating to antiretroviral medication and smoking cessation treatment in Africa and the African diaspora. More broadly, this study highlights the importance of sampling diverse African ethnolinguistic groups for accurate characterization of the pharmacogene variation landscape across the continent.

Multimorbidity in African ancestry populations: a scoping review.

OBJECTIVES: Multimorbidity (MM) is a growing concern linked to poor outcomes and higher healthcare costs. While most MM research targets European ancestry populations, the prevalence and patterns in African ancestry groups remain underexplored. This study aimed to identify and summarise the available literature on MM in populations with African ancestry, on the continent, and in the diaspora. DESIGN: A scoping review was conducted in five databases (PubMed, Web of Science, Scopus, Science Direct and JSTOR) in July 2022. Studies were selected based on predefined criteria, with data extraction focusing on methodology and findings. Descriptive statistics summarised the data, and a narrative synthesis highlighted key themes. RESULTS: Of the 232 publications on MM in African-ancestry groups from 2010 to June 2022-113 examined continental African populations, 100 the diaspora and 19 both. Findings revealed diverse MM patterns within and beyond continental Africa. Cardiovascular and metabolic diseases are predominant in both groups (80% continental and 70% diaspora). Infectious diseases featured more in continental studies (58% continental and 16% diaspora). Although many papers did not specifically address these features, as in previous studies, older age, being women and having a lower socioeconomic status were associated with a higher prevalence of MM, with important exceptions. Research gaps identified included limited data on African-ancestry individuals, inadequate representation, under-represented disease groups, non-standardised methodologies, the need for innovative data strategies, and insufficient translational research. CONCLUSION: The growing global MM prevalence is mirrored in African-ancestry populations. Recognising the unique contexts of African-ancestry populations is essential when addressing the burden of MM. This review emphasises the need for additional research to guide and enhance healthcare approaches for African-ancestry populations, regardless of their geographic location.

Genome-wide association study meta-analysis of blood pressure traits and hypertension in sub-Saharan African populations: an AWI-Gen study.

Most hypertension-related genome-wide association studies (GWASs) focus on non-African populations, despite hypertension (a major risk factor for cardiovascular disease) being highly prevalent in Africa. The AWI-Gen study GWAS meta-analysis for blood pressure (BP)-related traits (systolic and diastolic BP, pulse pressure, mean-arterial pressure and hypertension) from three sub-Saharan African geographic regions (N = 10,775), identifies two novel genome-wide significant signals (p < 5E-08): systolic BP near P2RY1 (rs77846204; intergenic variant, p = 4.95E-08) and pulse pressure near LINC01256 (rs80141533; intergenic variant, p = 1.76E-08). No genome-wide signals are detected for the AWI-Gen GWAS meta-analysis with previous African-ancestry GWASs (UK Biobank (African), Uganda Genome Resource). Suggestive signals (p < 5E-06) are observed for all traits, with 29 SNPs associating with more than one trait and several replicating known associations. Polygenic risk scores (PRSs) developed from studies on different ancestries have limited transferability, with multi-ancestry PRS providing better prediction. This study provides insights into the genetics of BP variation in African populations.

The African Liver Tissue Biorepository Consortium: Capacitating Population-Appropriate Drug Metabolism, Pharmacokinetics, and Pharmacogenetics Research in Drug Discovery and Development.

Pharmaceutical companies subject all new molecular entities to a series of in vitro metabolic characterizations that guide the selection and/or design of compounds predicted to have favorable pharmacokinetic properties in humans. Current drug metabolism research is based on liver tissue predominantly obtained from people of European origin, with limited access to tissue from people of African origin. Given the interindividual and interpopulation genomic variability in genes encoding drug-metabolizing enzymes, efficacy and safety of some drugs are poorly predicted for African populations. To address this gap, we have established the first comprehensive liver tissue biorepository inclusive of people of African origin. The African Liver Tissue Biorepository Consortium currently includes three institutions in South Africa and one in Zimbabwe, with plans to expand to other African countries. The program has collected 67 liver samples as of July 2023. DNA from the donors was genotyped for 120 variants in 46 pharmacogenes and revealed variants that are uniquely found in African populations, including the low-activity, African-specific CYP2C9*5 and *8 variants relevant to the metabolism of diclofenac. Larger liver tissue samples were used to isolate primary human hepatocytes. Viability of the hepatocytes and microsomal fractions was demonstrated by the activity of selected cytochrome P450s. This resource will be used to ensure the safety and efficacy of existing and new drugs in African populations. This will be done by characterizing compounds for properties such as drug clearance, metabolite and enzyme identification, and drug-drug and drug-gene interactions. SIGNIFICANCE STATEMENT: Standard optimization of the drug metabolism of new molecular entities in the pharmaceutical industry uses subcellular fractions such as microsomes and isolated primary hepatocytes, being done mainly with tissue from donors of European origin. Pharmacogenetics research has shown that variants in genes coding for drug-metabolizing enzymes have interindividual and interpopulation differences. We established an African liver tissue biorepository that will be useful in ensuring drug discovery and development research takes into account drug responses in people of African origin.

Genome-wide association study of esophageal squamous cell cancer identifies shared and distinct risk variants in African and Chinese populations.

Esophageal squamous cell carcinoma (ESCC) has a high disease burden in sub-Saharan Africa and has a very poor prognosis. Genome-wide association studies (GWASs) of ESCC in predominantly East Asian populations indicate a substantial genetic contribution to its etiology, but no genome-wide studies have been done in populations of African ancestry. Here, we report a GWAS in 1,686 African individuals with ESCC and 3,217 population-matched control individuals to investigate its genetic etiology. We identified a genome-wide-significant risk locus on chromosome 9 upstream of FAM120A (rs12379660, p = 4.58 × 10-8, odds ratio = 1.28, 95% confidence interval = 1.22-1.34), as well as a potential African-specific risk locus on chromosome 2 (rs142741123, p = 5.49 × 10-8) within MYO1B. FAM120A is a component of oxidative stress-induced survival signals, and the associated variants at the FAM120A locus co-localized with highly significant cis-eQTLs in FAM120AOS in both esophageal mucosa and esophageal muscularis tissue. A trans-ethnic meta-analysis was then performed with the African ESCC study and a Chinese ESCC study in a combined total of 3,699 ESCC-affected individuals and 5,918 control individuals, which identified three genome-wide-significant loci on chromosome 9 at FAM120A (rs12379660, pmeta = 9.36 × 10-10), chromosome 10 at PLCE1 (rs7099485, pmeta = 1.48 × 10-8), and chromosome 22 at CHEK2 (rs1033667, pmeta = 1.47 × 10-9). This indicates the existence of both shared and distinct genetic risk loci for ESCC in African and Asian populations. Our GWAS of ESCC conducted in a population of African ancestry indicates a substantial genetic contribution to ESCC risk in Africa.

Non-invasive harvesting of conjunctival cells for whole transcriptome sequencing.

The purpose of this study was to determine the feasibility of using a non-invasive technique, the EYEPRIM™ conjunctival cell impression device, to harvest sufficient RNA from conjunctival cells for the whole-transcriptome sequencing. Conjunctival cells from 40 participants were collected using an EYEPRIM™ conjunctival cell impression device. RNA was extracted from the samples, followed by library construction and transcriptome sequencing. Quality checks were performed for each technical step of the experiment, and the feasibility of this procedure was examined. RNA of sufficient yield and quality was successfully extracted following additional disruption and homogenization of the conjunctival cells and collection of two impression samples per eye. Successful library preparation and RNA sequencing were performed, with all 40 samples passing the various quality checks used for each step. In conclusion, harvesting cells from the ocular surface using an impression cytology device yields good quality and sufficient mRNA for whole transcriptome sequencing to study diseases of the eye. This technique provides a convenient alternative to using post-mortem tissues or surgical excisions.

Trans-ethnic genomic informed risk assessment for Alzheimer's disease: An International Hundred K+ Cohorts Consortium study.

BACKGROUND: As a collaboration model between the International HundredK+ Cohorts Consortium (IHCC) and the Davos Alzheimer's Collaborative (DAC), our aim was to develop a trans-ethnic genomic informed risk assessment (GIRA) algorithm for Alzheimer's disease (AD). METHODS: The GIRA model was created to include polygenic risk score calculated from the AD genome-wide association study loci, the apolipoprotein E haplotypes, and non-genetic covariates including age, sex, and the first three principal components of population substructure. RESULTS: We validated the performance of the GIRA model in different populations. The proteomic study in the participant sites identified proteins related to female infertility and autoimmune thyroiditis and associated with the risk scores of AD. CONCLUSIONS: As the initial effort by the IHCC to leverage existing large-scale datasets in a collaborative setting with DAC, we developed a trans-ethnic GIRA for AD with the potential of identifying individuals at high risk of developing AD for future clinical applications.

Clinical characteristics and one-year all-cause mortality outcomes in Africans with dilated cardiomyopathy.

AIMS: Dilated cardiomyopathy (DCM) is a common cause of heart failure in sub-Saharan Africa (SSA). The affected individuals present with new-onset heart failure with reduced ejection fraction and no identifiable primary or secondary aetiology. We aim to describe the clinical characteristics of participants with heart failure of unknown origin. METHODS: We screened 161 participants with heart failure of unknown origin and prospectively excluded primary and secondary causes of DCM. All study participants were subjected to laboratory biochemical testing, echocardiography, cardiovascular magnetic resonance (CMR) imaging and invasive coronary angiography. RESULTS: The study comprised 93 participants with a mean age of 47.5 SD 13.1 years. Forty-six (56.1%) participants had evidence of late gadolinium enhancement (LGE) on imaging, and LGE was visualised in the mid wall in 28 (61.0%) of these participants. After a median duration of 13.4 months [interquartile range (IQR): 8.8-28.9 months], 18 (19%) participants died. Non-survivors had a higher median left atrial volume index (44.9 mL/m2 (IQR: 34.4-58.7) compared to survivors [32.9 mL/m2 (IQR: 24.5-47.0), p = 0.017)]. The rate of all-cause rehospitalisation was 29.3%, of which 17 of the 22 re-hospitalisations were heart failure related. CONCLUSION: Dilated cardiomyopathy in Africans primarily affects young males. In our cohort, this disease was associated with an all-cause mortality of 19% in one year. In SSA, large multicenter studies are required to investigate this disease's pathogenesis and outcomes.

Performance and accuracy evaluation of reference panels for genotype imputation in sub-Saharan African populations.

Based on evaluations of imputation performed on a genotype dataset consisting of about 11,000 sub-Saharan African (SSA) participants, we show Trans-Omics for Precision Medicine (TOPMed) and the African Genome Resource (AGR) to be currently the best panels for imputing SSA datasets. We report notable differences in the number of single-nucleotide polymorphisms (SNPs) that are imputed by different panels in datasets from East, West, and South Africa. Comparisons with a subset of 95 SSA high-coverage whole-genome sequences (WGSs) show that despite being about 20-fold smaller, the AGR imputed dataset has higher concordance with the WGSs. Moreover, the level of concordance between imputed and WGS datasets was strongly influenced by the extent of Khoe-San ancestry in a genome, highlighting the need for integration of not only geographically but also ancestrally diverse WGS data in reference panels for further improvement in imputation of SSA datasets. Approaches that integrate imputed data from different panels could also lead to better imputation.

Telomere Length, Health, and Mortality in a Cohort of Older Black South African Adults.

Telomere length (TL) may be a biomarker of aging processes as well as age-related diseases. However, most studies of TL and aging are conducted in high-income countries. Less is known in low- and middle-income countries (LMICs) such as South Africa, where life expectancy remains lower despite population aging. We conducted a descriptive analysis of TL in a cohort of older adults in rural South Africa. TL was assayed from venous blood draws using quantitative polymerase chain reaction (T/S ratio). We examined the correlation between TL and biomarkers, demographic characteristics, mental/cognitive health measures, and physical performance measures in a subsample of the Wave 1 2014-2015 "Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa" (HAALSI) cohort (n = 510). We used logistic regression to measure the association between TL and mortality through Wave 3 (2021-2022). In bivariate analyses, TL was significantly correlated with age (r = -0.29, p < .0001), self-reported female sex (r = 0.13, p = .002), mortality (r = -0.1297, p = .003), diastolic blood pressure (r = 0.09, p = .037), pulse pressure (r = -0.09, p = .045), and being a grandparent (r = -0.17, p = .0001). TL was significantly associated with age (ß = -0.003; 95% confidence interval [CI] = -0.005, -0.003). TL was significantly associated in unadjusted multivariate analyses with mortality, but the relationship between TL and mortality was attenuated after adjusting for age (odds ratio [OR] = 0.19; 95% CI = 0.03, 1.27) and other covariates (OR = 0.17; 95% CI = 0.02, 1.19). Our study is the first analysis of TL in an older adult South African population. Our results corroborate existing relationships between TL and age, sex, cardiometabolic disease, and mortality found in higher-income countries.

Diabetes care cascade and associated factors in 10 700 middle-aged adults in four sub-Saharan African countries: a cross-sectional study.

OBJECTIVES: We investigated progression through the care cascade and associated factors for people with diabetes in sub-Saharan Africa to identify attrition stages that may be most appropriate for targeted intervention. DESIGN: Cross-sectional study. SETTING: Community-based study in four sub-Saharan African countries. PARTICIPANTS: 10 700 individuals, aged 40-60 years. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measure was the diabetes cascade of care defined as the age-adjusted diabetes prevalence (self-report of diabetes, fasting plasma glucose (FPG) ≥7 mmol/L or random plasma glucose ≥11.1 mmol/L) and proportions of those who reported awareness of having diabetes, ever having received treatment for diabetes and those who achieved glycaemic control (FPG <7.2 mmol/L). Secondary outcome measures were factors associated with having diabetes and being aware of the diagnosis. RESULTS: Diabetes prevalence was 5.5% (95% CI 4.4% to 6.5%). Approximately half of those with diabetes were aware (54%; 95% CI 50% to 58%); 73% (95% CI 67% to 79%) of aware individuals reported ever having received treatment. However, only 38% (95% CI 30% to 46%) of those ever having received treatment were adequately controlled. Increasing age (OR 1.1; 95% CI 1.0 to 1.1), urban residence (OR 2.3; 95% CI 1.6 to 3.5), hypertension (OR 1.9; 95% CI 1.5 to 2.4), family history of diabetes (OR 3.9; 95% CI 3.0 to 5.1) and measures of central adiposity were associated with higher odds of having diabetes. Increasing age (OR 1.1; 95% CI 1.0 to 1.1), semi-rural residence (OR 2.5; 95% CI 1.1 to 5.7), secondary education (OR 2.4; 95% CI 1.2 to 4.9), hypertension (OR 1.6; 95% CI 1.0 to 2.4) and known HIV positivity (OR 2.3; 95% CI 1.2 to 4.4) were associated with greater likelihood of awareness of having diabetes. CONCLUSIONS: There is attrition at each stage of the diabetes care cascade in sub-Saharan Africa. Public health strategies should target improving diagnosis in high-risk individuals and intensifying therapy in individuals treated for diabetes.

Cardiometabolic disease risk factors in pre- and postmenopausal women from four sub-Saharan African countries: A cross-sectional study.

OBJECTIVE: To compare the risk factors for cardiometabolic disease between pre- and postmenopausal women from four sub-Saharan African countries. STUDY DESIGN: This cross-sectional study included 3609 women (1740 premenopausal and 1869 postmenopausal) from sites in Ghana (Navrongo), Burkina Faso (Nanoro), Kenya (Nairobi), and South Africa (Soweto and Dikgale). Demographic, anthropometric and cardiometabolic variables were compared between pre- and postmenopausal women, within and across sites using multivariable regression analyses. The sites represent populations at different stages of the health transition, with those in Ghana and Burkina Faso being rural, whilst those in Kenya and South Africa are more urbanised. MAIN OUTCOME MEASURES: Anthropometric and cardiometabolic variables. RESULTS: The prevalence rates of risk factors for cardiometabolic disease were higher in South (Soweto and Dikgale) and East (Nairobi) Africa than in West Africa (Nanoro and Navrongo), irrespective of menopausal status. Regression models in combined West African populations demonstrated that postmenopausal women had a larger waist circumference (ß = 1.28 (95 % CI: 0.58; 1.98) cm), log subcutaneous fat (ß =0.15 (0.10; 0.19)), diastolic (ß = 3.04 (1.47; 4.62) mm Hg) and log systolic (ß = 0.04 (0.02; 0.06)) blood pressure, log carotid intima media thickness (ß = 0.03 (0.01; 0.06)), low-density lipoprotein cholesterol (ß = 0.14 (0.04; 0.23) mmol/L) and log triglyceride (ß= 0.10 (0.04; 0.16)) levels than premenopausal women. No such differences were observed in the South and East African women. CONCLUSIONS: Menopause-related differences in risk factors for cardiometabolic disease were prominent in West but not East or South African study sites. These novel findings should inform cardiometabolic disease prevention strategies in midlife women specific to rural and urban and peri-urban locations in sub-Saharan Africa.

Genome-wide association study of population-standardised cognitive performance phenotypes in a rural South African community.

Cognitive function is an indicator for global physical and mental health, and cognitive impairment has been associated with poorer life outcomes and earlier mortality. A standard cognition test, adapted to a rural-dwelling African community, and the Oxford Cognition Screen-Plus were used to capture cognitive performance as five continuous traits (total cognition score, verbal episodic memory, executive function, language, and visuospatial ability) for 2,246 adults in this population of South Africans. A novel common variant, rs73485231, reached genome-wide significance for association with episodic memory using data for ~14 million markers imputed from the H3Africa genotyping array data. Window-based replication of previously implicated variants and regions of interest support the discovery of African-specific associated variants despite the small population size and low allele frequency. This African genome-wide association study identifies suggestive associations with general cognition and domain-specific cognitive pathways and lays the groundwork for further genomic studies on cognition in Africa.