Populations Of African Ancestry Research Articles

Multi-omics in nasal epithelium reveals three axes of dysregulation for asthma risk in the African Diaspora populations

Asthma has striking disparities across ancestral groups, but the molecular underpinning of these differences is poorly understood and minimally studied. A goal of the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) is to understand multi-omic signatures of asthma focusing on populations of African ancestry. RNASeq and DNA methylation data are generated from nasal epithelium including cases (current asthma, N = 253) and controls (never-asthma, N = 283) from 7 different geographic sites to identify differentially expressed genes (DEGs) and gene networks. We identify 389 DEGs; the top DEG, FN1, was downregulated in cases (q = 3.26 × 10−9) and encodes fibronectin which plays a role in wound healing. The top three gene expression modules implicate networks related to immune response (CEACAM5; p = 9.62 × 10−16 and CPA3; p = 2.39 × 10−14) and wound healing (FN1; p = 7.63 × 10−9). Multi-omic analysis identifies FKBP5, a co-chaperone of glucocorticoid receptor signaling known to be involved in drug response in asthma, where the association between nasal epithelium gene expression is likely regulated by methylation and is associated with increased use of inhaled corticosteroids. This work reveals molecular dysregulation on three axes – increased Th2 inflammation, decreased capacity for wound healing, and impaired drug response – that may play a critical role in asthma within the African Diaspora.

High-resolution African HLA resource uncovers HLA-DRB1 expression effects underlying vaccine response.

How human genetic variation contributes to vaccine effectiveness in infants is unclear, and data are limited on these relationships in populations with African ancestries. We undertook genetic analyses of vaccine antibody responses in infants from Uganda (n = 1391), Burkina Faso (n = 353) and South Africa (n = 755), identifying associations between human leukocyte antigen (HLA) and antibody response for five of eight tested antigens spanning pertussis, diphtheria and hepatitis B vaccines. In addition, through HLA typing 1,702 individuals from 11 populations of African ancestry derived predominantly from the 1000 Genomes Project, we constructed an imputation resource, fine-mapping class II HLA-DR and DQ associations explaining up to 10% of antibody response variance in our infant cohorts. We observed differences in the genetic architecture of pertussis antibody response between the cohorts with African ancestries and an independent cohort with European ancestry, but found no in silico evidence of differences in HLA peptide binding affinity or breadth. Using immune cell expression quantitative trait loci datasets derived from African-ancestry samples from the 1000 Genomes Project, we found evidence of differential HLA-DRB1 expression correlating with inferred protection from pertussis following vaccination. This work suggests that HLA-DRB1 expression may play a role in vaccine response and should be considered alongside peptide selection to improve vaccine design.

Using genome and transcriptome data from African-ancestry female participants to identify putative breast cancer susceptibility genes

African-ancestry (AA) participants are underrepresented in genetics research. Here, we conducted a transcriptome-wide association study (TWAS) in AA female participants to identify putative breast cancer susceptibility genes. We built genetic models to predict levels of gene expression, exon junction, and 3′ UTR alternative polyadenylation using genomic and transcriptomic data generated in normal breast tissues from 150 AA participants and then used these models to perform association analyses using genomic data from 18,034 cases and 22,104 controls. At Bonferroni-corrected P < 0.05, we identified six genes associated with breast cancer risk, including four genes not previously reported (CTD-3080P12.3, EN1, LINC01956 and NUP210L). Most of these genes showed a stronger association with risk of estrogen-receptor (ER) negative or triple-negative than ER-positive breast cancer. We also replicated the associations with 29 genes reported in previous TWAS at P < 0.05 (one-sided), providing further support for an association of these genes with breast cancer risk. Our study sheds new light on the genetic basis of breast cancer and highlights the value of conducting research in AA populations.

Characterizing genetic profiles for high triglyceride levels in U.S. patients of African ancestry

Hypertriglyceridemia (HTG) is a common cardiovascular risk factor characterized by elevated circulating triglyceride (TG) levels. Researchers have assessed the genetic factors that influence HTG in studies focused predominantly on individuals of European ancestry (EA). However, relatively little is known about the contribution of genetic variation to HTG in people of AA, potentially constraining research and treatment opportunities; the lipid profile for African ancestry (AA) populations differs from that of EA populations-which may be partially attributable to genetics. Our objective was to characterize genetic profiles among individuals of AA with mild-to-moderate HTG and severe HTG versus those with normal TGs by leveraging whole genome sequencing (WGS) data and longitudinal electronic health records (EHRs) available in the All of Us (AoU) program. We compared the enrichment of functional variants within five canonical TG metabolism genes, an AA-specific polygenic risk score for TGs, and frequencies of 145 known potentially causal TG variants between patients with HTG and normal TG among a cohort of AA patients (N=15,373). Those with mild-to-moderate HTG (N=342) and severe HTG (N≤20) were more likely to carry APOA5 p.S19W (OR=1.94, 95% CI [1.48-2.54], p=1.63×10-6 and OR=3.65, 95% CI [1.22-10.93], p=0.02, respectively) than those with normal TG. They were also more likely to have an elevated (top 10%) PRS, elevated carriage of potentially causal variant alleles, and carry any genetic risk factor. Alternative definitions of HTG yielded comparable results. In conclusion, individuals of AA with HTG were enriched for genetic risk factors compared to individuals with normal TGs.

An ensemble penalized regression method for multi-ancestry polygenic risk prediction

Great efforts are being made to develop advanced polygenic risk scores (PRS) to improve the prediction of complex traits and diseases. However, most existing PRS are primarily trained on European ancestry populations, limiting their transferability to non-European populations. In this article, we propose a novel method for generating multi-ancestry Polygenic Risk scOres based on enSemble of PEnalized Regression models (PROSPER). PROSPER integrates genome-wide association studies (GWAS) summary statistics from diverse populations to develop ancestry-specific PRS with improved predictive power for minority populations. The method uses a combination of L1\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${{{{{{\\mathscr{L}}}}}}}_{1}$$\\end{document} (lasso) and L2\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${{{{{{\\mathscr{L}}}}}}}_{2}$$\\end{document} (ridge) penalty functions, a parsimonious specification of the penalty parameters across populations, and an ensemble step to combine PRS generated across different penalty parameters. We evaluate the performance of PROSPER and other existing methods on large-scale simulated and real datasets, including those from 23andMe Inc., the Global Lipids Genetics Consortium, and All of Us. Results show that PROSPER can substantially improve multi-ancestry polygenic prediction compared to alternative methods across a wide variety of genetic architectures. In real data analyses, for example, PROSPER increased out-of-sample prediction R2 for continuous traits by an average of 70% compared to a state-of-the-art Bayesian method (PRS-CSx) in the African ancestry population. Further, PROSPER is computationally highly scalable for the analysis of large SNP contents and many diverse populations.

MUSSEL: Enhanced Bayesian polygenic risk prediction leveraging information across multiple ancestry groups

Polygenic risk scores (PRSs) are now showing promising predictive performance on a wide variety of complex traits and diseases, but there exists a substantial performance gap across populations. We propose MUSSEL, a method for ancestry-specific polygenic prediction that borrows information in summary statistics from genome-wide association studies (GWASs) across multiple ancestry groups via Bayesian hierarchical modeling and ensemble learning. In our simulation studies and data analyses across four distinct studies, totaling 5.7 million participants with a substantial ancestral diversity, MUSSEL shows promising performance compared to alternatives. For example, MUSSEL has an average gain in prediction R2 across 11 continuous traits of 40.2% and 49.3% compared to PRS-CSx and CT-SLEB, respectively, in the African ancestry population. The best-performing method, however, varies by GWAS sample size, target ancestry, trait architecture, and linkage disequilibrium reference samples; thus, ultimately a combination of methods may be needed to generate the most robust PRSs across diverse populations.

Sex differences in Alzheimer's disease blood biomarkers in a Caribbean population of African ancestry: The Tobago Health Study.

Alzheimer's disease (AD) is increasing in the Caribbean, especially for persons of African ancestry (PAA) and women. However, studies have mostly utilized surveys without AD biomarkers. In the Tobago Health Study (n = 309; 109 women, mean age 70.3±6.6), we assessed sex differences and risk factors for serum levels of phosphorylated tau-181 (p-tau181), amyloid-beta (Aβ)42/40 ratio, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Blood samples were from 2010 to 2013 for men and from 2019 to 2023 for women. Women were more obese, hypertensive, and sedentary but reported less smoking and alcohol use than men (age-adjusted p<0.04). Compared to men, women had worse levels of AD biomarkers, with higher p-tau181 and lower Aβ42/40, independent of covariates (p<0.001). In sex-stratified analyses, higher p-tau181 was associated with older age in women and with hypertension in men. GFAP and NfL did not differ by sex. Women had worse AD biomarkers than men, unexplained by age, cardiometabolic diseases, or lifestyle. Studying risk factors for AD in PAA is warranted, especially for women earlier in life.

Abstract P147: Alcohol Consumption and Its Relation to Ectopic Adiposity in African Caribbean Men

Introduction: Alcohol intake and ectopic fat are associated with cardiometabolic diseases. While previous studies primarily focused on visceral and/or liver fat, few studies to date have investigated the associations of alcohol intake with skeletal muscle fat infiltration, a fat depot which might contribute to the increased risk of diabetes and hypertension in African ancestry populations. Methods: Alcohol intake (drinks/day) was assessed using a 146-item semi-quantitative food frequency questionnaire in the Tobago Health Study (N=800). Ectopic fat was measured in the abdomen and thigh in a subset of this cohort (N=706, mean age=63.94 (8.66) years, mean BMI=27.72 (4.65) kg/m 2 ) using computed tomography. Men were divided into current drinkers/not current drinkers, and the current drinkers were further subdivided into types of alcohol consumed (wine, beer/stout, or liquor). Results: A majority of men (56.1%) were not current drinkers. Of drinking men, 76.1% were light drinkers (&lt;1 drink/day), 17.4% were moderate drinkers (1-3 drinks/day), and 6.5% were heavy drinkers (&gt;3 drinks/day). Men who did not drink were slightly older (65.1 vs 62.5, p&lt;0.001), with less visceral adiposity (91.4 vs. 101.9 cm 3 , p=0.002) and less psoas muscle fat (0.59 vs 0.64 cm 3 , p=0.017) than men who drank, independent of age. In fully adjusted models, drinking liquor was positively associated with BMI, waist circumference, visceral and subcutaneous adiposity, while drinking beer was positively associated with thigh muscle fat (Table). Conclusion: Alcohol intake was associated with greater ectopic fat accumulation in all studied compartments, except in the liver, in this cohort of African Caribbean men, who mostly had low alcohol consumption. We also report a novel finding that observed relationships differ by type of alcohol. † Adjusted for total energy intake, age, walking (hours/week), TV watching (≥14 hours/week), current smoking, diabetes, hypertension, and statin use status. * Additional adjustment for BMIHU = Houndsfield Units

Abstract P491: Functional Annotations for Improvements in Height and Blood Pressure Polygenic Risk Scores

Background: Genome-wide association studies (GWAS) have advanced our understanding of the polygenic basis of common, complex disorders. However, translating GWAS findings into clinical applications remains challenging. Polygenic risk scores (PRS) hold promise for clinical use with recent methodologies enhancing predictive accuracy. This study compared two PRS (LDpred-funct which incorporates functional annotations into the score and a traditional linear scoring system) for traits with varying heritability in European- (EA) and African-ancestry (AA) populations, addressing a need to evaluate novel approaches across diverse conditions and populations. Hypothesis: This study hypothesized that integrating functional annotations into PRS derivation will enhance performance compared to assessing the genetic load for a trait. The addition will provide improvement for (1) traits with high (height) compared to moderate (systolic blood pressure, SBP) heritability and (2) individuals with EA relative to AA. Methods: This study used multi-ancestry summary statistics representing data from 4,080,687 individuals for height (GIANT consortium) and 436,099 individuals for SBP adjusted for antihypertensive medication use (UK Biobank). Two PRS for these traits were constructed using LDpred-funct: PRS funct which incorporates the functional annotation and PRS raw which is a simple linear scoring system. Optimization was performed in 8,916 AA and 1,716 EA participants from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. PRS predictive performance was evaluated by calculating the proportion of trait variance explained by the PRS (R 2 ) after accounting for age, sex, and genetic ancestry. Results: For height, the PRS funct outperformed PRS raw among both race groups, with a greater improvement among EA (PRS funct R 2 =0.110 versus PRS raw R 2 =0.060, 5% difference) compared to AA (PRS funct R 2 =0.042 versus PRS raw R 2 =0.034, 0.8% difference). Similar findings were observed for medication-adjusted SBP, where PRS funct had better predictive performance than PRS raw , and with greater improvement observed in the EA (PRS funct R 2 =0.042 versus PRS raw R 2 =0.027, 1.5% difference) compared to AA participants (PRS funct R 2 =0.014 versus PRS raw R 2 =0.010, 0.4% difference). Conclusions: Incorporating functional priors into the PRS enhanced the predictive accuracy for both traits. A greater improvement was observed for the higher heritability (height) versus the moderate heritability (SBP) trait, as well as within individuals of EA compared to AA. These findings are currently undergoing validation, using data from the Electronic Medical Records and Genomics (eMERGE) Network, highlighting the potential of incorporating functional annotations into PRS development for broader clinical applications.

Abstract P535: Correlates of Cardiac Structure and Function in African-Ancestry Adults in the Caribbean: The Tobago Heart Study

Introduction: The population of Tobago is a unique African-ancestry population with a high prevalence of chronic disease, including hypertension and obesity. These conditions are associated with abnormalities in cardiac structure and function that confer an increased risk of heart failure. However, the distribution and correlates of these abnormalities have not been described in Tobagonian women, or any Afro-Caribbean population. Hypothesis: Abnormalities in cardiac structure and function will correlate with BMI and blood pressure. Methods: Participants from the Tobago Women’s Study aged 45+ were recruited for the Tobago Heart Study without regard to health status. Participants underwent transthoracic echocardiography, a health history, clinical examination, and blood draw. Hypertension was defined by blood pressure measures or prescription of relevant medication. The eventual recruitment goal is 900 men and women; the current analysis is a preliminary assessment of 376 women with data currently available. Statistical analyses included descriptive statistics and Spearman correlations. Results: The mean age of the study sample was 60.8 years (range 46-79). The prevalence of hypertension and obesity were 76.2% and 60.1%, respectively. Abnormalities in cardiac structure were detected in 77.5% of participants (of these, 87.9% concentric remodeling, 9.4% concentric hypertrophy, 2.7% eccentric hypertrophy). Diastolic dysfunction was present in 13.6% of participants (of these, 83.7% grade I, 14.3% grade II, and 2.0% grade III dysfunction); cardiomyopathy was found in 1.9%. Results of Spearman correlations are shown in Table 1. Conclusion: In a population of Tobagonian women, a low prevalence of diastolic dysfunction was observed despite highly prevalent abnormal left ventricle geometry. Blood pressure and BMI are important correlates of cardiac structure and function in this understudied population. In future analyses these results will be updated with greater sample size and compared to findings in men.

A genome-wide association study of neutrophil count in individuals associated to an African continental ancestry group facilitates studies of malaria pathogenesis

Background'Benign ethnic neutropenia' (BEN) is a heritable condition characterized by lower neutrophil counts, predominantly observed in individuals of African ancestry, and the genetic basis of BEN remains a subject of extensive research. In this study, we aimed to dissect the genetic architecture underlying neutrophil count variation through a linear-mixed model genome-wide association study (GWAS) in a population of African ancestry (N = 5976). Malaria caused by P. falciparum imposes a tremendous public health burden on people living in sub-Saharan Africa. Individuals living in malaria endemic regions often have a reduced circulating neutrophil count due to BEN, raising the possibility that reduced neutrophil counts modulate severity of malaria in susceptible populations. As a follow-up, we tested this hypothesis by conducting a Mendelian randomization (MR) analysis of neutrophil counts on severe malaria (MalariaGEN, N = 17,056).ResultsWe carried out a GWAS of neutrophil count in individuals associated to an African continental ancestry group within UK Biobank, identifying 73 loci (r2 = 0.1) and 10 index SNPs (GCTA-COJO loci) associated with neutrophil count, including previously unknown rare loci regulating neutrophil count in a non-European population. BOLT-LMM was reliable when conducted in a non-European population, and additional covariates added to the model did not largely alter the results of the top loci or index SNPs. The two-sample bi-directional MR analysis between neutrophil count and severe malaria showed the greatest evidence for an effect between neutrophil count and severe anaemia, although the confidence intervals crossed the null.ConclusionOur GWAS of neutrophil count revealed unique loci present in individuals of African ancestry. We note that a small sample-size reduced our power to identify variants with low allele frequencies and/or low effect sizes in our GWAS. Our work highlights the need for conducting large-scale biobank studies in Africa and for further exploring the link between neutrophils and severe malaria.

Untargeted metabolomic profiling reveals molecular signatures associated with type 2 diabetes in Nigerians

BackgroundType 2 diabetes (T2D) has reached epidemic proportions globally, including in Africa. However, molecular studies to understand the pathophysiology of T2D remain scarce outside Europe and North America. The aims of this study are to use an untargeted metabolomics approach to identify: (a) metabolites that are differentially expressed between individuals with and without T2D and (b) a metabolic signature associated with T2D in a population of Sub-Saharan Africa (SSA).MethodsA total of 580 adult Nigerians from the Africa America Diabetes Mellitus (AADM) study were studied. The discovery study included 310 individuals (210 without T2D, 100 with T2D). Metabolites in plasma were assessed by reverse phase, ultra-performance liquid chromatography and mass spectrometry (RP)/UPLC-MS/MS methods on the Metabolon Platform. Welch’s two-sample t-test was used to identify differentially expressed metabolites (DEMs), followed by the construction of a biomarker panel using a random forest (RF) algorithm. The biomarker panel was evaluated in a replication sample of 270 individuals (110 without T2D and 160 with T2D) from the same study.ResultsUntargeted metabolomic analyses revealed 280 DEMs between individuals with and without T2D. The DEMs predominantly belonged to the lipid (51%, 142/280), amino acid (21%, 59/280), xenobiotics (13%, 35/280), carbohydrate (4%, 10/280) and nucleotide (4%, 10/280) super pathways. At the sub-pathway level, glycolysis, free fatty acid, bile metabolism, and branched chain amino acid catabolism were altered in T2D individuals. A 10-metabolite biomarker panel including glucose, gluconate, mannose, mannonate, 1,5-anhydroglucitol, fructose, fructosyl-lysine, 1-carboxylethylleucine, metformin, and methyl-glucopyranoside predicted T2D with an area under the curve (AUC) of 0.924 (95% CI: 0.845–0.966) and a predicted accuracy of 89.3%. The panel was validated with a similar AUC (0.935, 95% CI 0.906–0.958) in the replication cohort. The 10 metabolites in the biomarker panel correlated significantly with several T2D-related glycemic indices, including Hba1C, insulin resistance (HOMA-IR), and diabetes duration.ConclusionsWe demonstrate that metabolomic dysregulation associated with T2D in Nigerians affects multiple processes, including glycolysis, free fatty acid and bile metabolism, and branched chain amino acid catabolism. Our study replicated previous findings in other populations and identified a metabolic signature that could be used as a biomarker panel of T2D risk and glycemic control thus enhancing our knowledge of molecular pathophysiologic changes in T2D. The metabolomics dataset generated in this study represents an invaluable addition to publicly available multi-omics data on understudied African ancestry populations.

Epigenetic modifications in solid tumor metastasis in people of African ancestry.

This review focuses on the critical role of epigenetic modifications in solid tumor metastasis, particularly in people of African ancestry. Epigenetic alterations, such as DNA methylation, histone modifications, alterations in non-coding RNAs, and mRNA methylation, significantly influence gene expression, contributing to cancer development and progression. Despite the primary focus on populations of European, American, and Asian descent in most cancer research, this work emphasizes the importance of studying the unique genetic and epigenetic landscapes of African populations for a more inclusive approach in understanding and treating cancer. Insights from this review have the potential to pave the way for the development of effective, tailored treatments, and provide a richer resource for understanding cancer progression and metastasis. Specific focus was placed on the role of DNA methylation, histone modifications, non-coding RNAs, and mRNA methylation in solid tumor metastasis, including how these modifications contribute to the regulation of tumor suppressor genes and oncogenes, influence cellular pathways and signaling, and interact with the immune system. Moreover, this review elaborates on the development of epigenetic-targeted therapeutic strategies and the current advances in this field, highlighting the promising applications of these therapies in improving outcomes for African ancestry populations disproportionately affected by certain types of cancer. Nevertheless, this work acknowledges the challenges that lie ahead, particularly the under-representation of African populations in cancer genomic and epigenomic studies and the technical complications associated with detecting subtle epigenetic modifications. Emphasis is placed on the necessity for more inclusive research practices, the development of more robust and sensitive methods for detecting and interpreting epigenetic changes, and the understanding of the interplay between genetic and epigenetic variations. The review concludes with an optimistic outlook on the future of epigenetic research in People of African ancestry, urging the concerted efforts of researchers, clinicians, funding agencies, and policymakers to extend the benefits of this research to all populations.

Phenotypes, endotypes and genotypes of atopic dermatitis and allergy in populations of African ancestry on the continent and diaspora.

Atopic dermatitis is a complex inflammatory condition characterized by synergist interactions between epidermal and immune related genotypes, skin barrier defects and immune dysregulation as well as microbial dysbiosis. Ethnicity-specific variations in clinical presentation, immune endotypes and genetic susceptibility have been described in diverse populations. We summarize available data with specific consideration of AD in populations of African ancestry. Some highlights include the observation of AD lesions on extensor surfaces, lichen planus-like AD, prurigo type AD and follicular AD in African populations. In addition, a consistent absence of dominant filaggrin gene defects has been reported. The detection of normal filaggrin protein content in AD skin implicates the contribution of alternative mechanisms in the pathogenesis of AD in African patients. Markedly high IgE has been described in paediatric and adult African AD. While Th2, Th22 and Th17 activation in African AD skin shares the same direction as with other populations, it has been noted that the magnitude of activation is dissimilar. Reduced Th17 cytokines have been observed in the circulation of moderate to severe paediatric AD.

ECCO Global Grant Genetic risk factors for IBD in its emergent phase in sub-Saharan Africa

Abstract Background and Aims Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is an idiopathic, chronic, and frequently disabling inflammatory disorder of the intestines characterized by a dysregulated mucosal immune response. The pathophysiology of the disease remains incompletely understood. Genetic factors affecting disease are under investigation, however, genetic studies in non-European populations are scarce and it is an urgent scientific, social, and ethical requirement that research in under-studied populations is prioritized. The objective of this study is to understand the genetics of IBD in sub-Saharan African ancestry populations and to identify genetic factors that affect pathogenesis of IBD in this region. Methodology A case-control study will be conducted from January 2024 to December 2025. Consecutive eligible subjects with IBD and controls will be invited to take part in the study. Data will be collected through chart review, structured interviews, and collection of saliva samples for genotyping using the H3Africa chip in the first instance. Genome-wide imputation and replication analysis will be done. Single-marker association analyses will be performed using the Cochran Armitage trend and logistic regression test after correction for population structure. We will look at known European ancestry and African American (AA) IBD-associated variants as well as variants that are unique to our populations (we will be able to look at local admixture in the AA population to see if these variants are replicated). Anticipated Impact This study will contribute significantly to knowledge of genetic risk factors for IBD in sub-Saharan Africa. It may also help to identify potential complications of treatments such as thiopurines which have been commonly used in European populations but where experience of use in sub-Saharan Africa is lacking.

Multimorbidity in African ancestry populations: a scoping review

ObjectivesMultimorbidity (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...

Abstract C002: Integrating multiomics data to identify African ancestry-informative markers acting as eQTLs in breast cancer

Abstract Ancestry-informative markers (AIMs) are SNPs that are found at relatively higher frequencies in a specific population and can be used to estimate genetic ancestry. Genetic ancestry is becoming more commonly used in biomedical research investigating the genetic basis of diseases. For many cancers, the literature suggests that African ancestry is associated with poor response to treatment, poorer prognosis, and poorer survival. More specifically, African American women with breast cancer are more likely to have more aggressive subtypes of the disease and diagnosed with a later stage of the disease at an earlier age compared to their European American counterparts. Some of this disparity remains after accounting for socioeconomic factors, suggesting a genetic basis for the health disparities observed in many cancers. To evaluate the genetic basis of cancer health disparities in populations of African ancestry, we identified a set of 46,787 African ancestry informative markers (AIMs) using 1000 Genomes Project data from African and European populations. These AIMs were functionally annotated and investigated for potential associations with cancer in the literature, using tools such as VEP, SIFT, and Polyphen. Using multiomics data (RNAseq, genotype, methylation, copy number variation) from The Cancer Genome Atlas and an integrative eQTL modeling approach, we are investigating which of these AIMs act as expression quantitative trait loci in breast cancer. Of the 47K SNPs identified, 0.6% percent was found to be in the coding regions of the genome and AIMS located on chromosomes 8, 10, 11, 15, 18, and 19 were found to be associated with different cancers in the literature including breast and colorectal cancers. Approximately 5K of the AIMs were found in the TCGA breast cancer data and preliminary results identified cis-eqtls in 4 different genes including SERINC2 and ZSCAN23, and trans-eqtls in about 8 genes including CLCN3 and DEDD. These eQTL AIMs are being evaluated for potential association with ancestry-specific differential survival and response to treatment in breast cancer. Citation Format: Samantha Boudeau. Integrating multiomics data to identify African ancestry-informative markers acting as eQTLs in breast cancer [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C002.

Validation of prevalent diabetes risk scores based on non-invasively measured predictors in Ghanaian migrant and non-migrant populations – The RODAM study

BackgroundNon-invasive diabetes risk models are a cost-effective tool in large-scale population screening to identify those who need confirmation tests, especially in resource-limited settings. AimsThis study aimed to evaluate the ability of six non-invasive risk models (Cambridge, FINDRISC, Kuwaiti, Omani, Rotterdam, and SUNSET model) to identify screen-detected diabetes (defined by HbA1c) among Ghanaian migrants and non-migrants. Study designA multicentered cross-sectional study. MethodsThis analysis included 4843 Ghanaian migrants and non-migrants from the Research on Obesity and Diabetes among African Migrants (RODAM) Study. Model performance was assessed using the area under the receiver operating characteristic curves (AUC), Hosmer-Lemeshow statistics, and calibration plots. ResultsAll six models had acceptable discrimination (0.70 ≤ AUC <0.80) for screen-detected diabetes in the overall/combined population. Model performance did not significantly differ except for the Cambridge model, which outperformed Rotterdam and Omani models. Calibration was poor, with a consistent trend toward risk overestimation for screen-detected diabetes, but this was substantially attenuated by recalibration through adjustment of the original model intercept. ConclusionThough acceptable discrimination was observed, the original models were poorly calibrated among populations of African ancestry. Recalibration of these models among populations of African ancestry is needed before use.

Worldwide Incidence of Ocular Melanoma and Correlation With Pigmentation-Related Risk Factors.

The worldwide incidence of ocular melanoma (OM), uveal melanoma (UM), and conjunctival melanoma has last been reported on 15years ago. Recently, light iris color and four specific single-nucleotide-polymorphisms (SNPs) have been identified as a UM-risk factor. Furthermore, six iris color predicting SNPs have been discovered (IrisPlex). Interestingly, two of these (rs129138329 and rs12203592) are also UM-risk factors. We collected worldwide incidence data of OM and investigated its correlations with iris color, IrisPlex SNPs, and UM-risk SNPs. Cases of OM, as defined by the International Classification of Diseases Oncology C69 (eye), 8720/3 to 8790/3 (malignant melanoma), and 8000 to 8005 (malignant neoplasm), between 1988 and 2012, were extracted from the Cancer Incidence in Five Continents. Incidence rates were age-standardized and their trends were analyzed with joinpoint regression and age period cohort modeling. Frequencies for each country of iris color, IrisPlex SNPs, and UM-risk SNPs were collected from the literature. Incidence rates were generally ≥8.0 cases per million person-years in Northern Europe, Western Europe, and Oceania; 2.0 to 7.9 in North America, Eastern Europe, and Southern Europe; and <2.0 in South America, Asia, and Africa. OM incidence correlated with latitude (r = 0.77, P ≤ 0.001) and is expressed as a north-to-south decreasing gradient in Europe. SNP rs12913832 correlated with OM incidence (r = 0.83, P ≤ 0.001), blue iris color (r = 0.56, P ≤ 0.05), green iris color (r = 0.51, P ≤ 0.05), and brown iris color (r = -0.64, P ≤ 0.01). Trends were stable for most countries (28/35). OM incidence is highest in populations of European ancestry and lowest in populations of Asian and African ancestry. Overall, trends are stable, and the spatial correlation among OM incidence, iris color, and rs12913832 may support the role of pigmentation-related risk factors in OM development.

Paving the way while playing catch up: mitochondrial genetics in African ancestry primary open-angle glaucoma

Glaucoma, the leading cause of irreversible blindness worldwide, disproportionately affects individuals of African descent. Specifically, previous research has indicated that primary open-angle glaucoma (POAG), the most common form of disease, is more prevalent, severe, early-onset, and rapidly-progressive in populations of African ancestry. Recent studies have identified genetic variations that may contribute to the greater burden of disease in this population. In particular, mitochondrial genetics has emerged as a profoundly influential factor in multiple neurodegenerative diseases, including POAG. Several hypotheses explaining the underlying mechanisms of mitochondrial genetic contribution to disease progression have been proposed, including nuclear-mitochondrial gene mismatch. Exploring the fundamentals of mitochondrial genetics and disease pathways within the understudied African ancestry population can lead to groundbreaking advancements in the research and clinical understanding of POAG. This article discusses the currently known involvements of mitochondrial genetic factors in POAG, recent directions of study, and potential future prospects in mitochondrial genetic studies in individuals of African descent.