African Ancestral Populations Research Articles

The genomic footprint of social stratification in admixing American populations.

Cultural and socioeconomic differences stratify human societies and shape their genetic structure beyond the sole effect of geography. Despite mating being limited by sociocultural stratification, most demographic models in population genetics often assume random mating. Taking advantage of the correlation between sociocultural stratification and the proportion of genetic ancestry in admixed populations, we sought to infer the former process in the Americas. To this aim, we define a mating model where the individual proportions of the genome inherited from Native American, European, and sub-Saharan African ancestral populations constrain the mating probabilities through ancestry-related assortative mating and sex bias parameters. We simulate a wide range of admixture scenarios under this model. Then, we train a deep neural network and retrieve good performance in predicting mating parameters from genomic data. Our results show how population stratification, shaped by socially constructed racial and gender hierarchies, has constrained the admixture processes in the Americas since the European colonization and the subsequent Atlantic slave trade.

Population-Specific Distribution of TPMT Deficiency Variants and Ancestry Proportions in Ecuadorian Ethnic Groups: Towards Personalized Medicine.

Thiopurine S-methyltransferase (TPMT) is an enzyme that metabolizes purine analogs, agents used in the treatment of acute lymphoblastic leukemia. Improper drug metabolism leads to toxicity in chemotherapy patients and reduces treatment effectiveness. TPMT variants associated with reduced enzymatic activity vary across populations. Therefore, studying these variants in heterogeneous populations, such as Ecuadorians, can help identify molecular causes of deficiency for this enzyme. We sequenced the entire TPMT coding region in 550 Ecuadorian individuals from Afro-Ecuadorian, Indigenous, Mestizo, and Montubio ethnicities. Moreover, we conducted an ancestry analysis using 46 informative ancestry markers. We identified 8 single nucleotide variants in the coding region of TPMT. The most prevalent alleles were TPMT*3A, TPMT*3B, and TPMT*3C, with frequencies of 0.055, 0.012, and 0.015, respectively. Additionally, we found rare alleles TPMT*4 and TPMT*8 with frequencies of 0.005 and 0.003. Correlating the ancestry proportions with TPMT-deficient genotypes, we observed that the Native American ancestry proportion influenced the distribution of the TPMT*1/TPMT*3A genotype (OR = 5.977, p = 0.002), while the contribution of African ancestral populations was associated with the TPMT*1/TPMT*3C genotype (OR = 9.769, p = 0.003). The rates of TPMT-deficient genotypes observed in Mestizo (f = 0.121) and Indigenous (f = 0.273) groups provide evidence for the influence of Native American ancestry and the prevalence of the TPMT*3A allele. In contrast, although Afro-Ecuadorian groups demonstrate similar deficiency rates (f = 0.160), the genetic factors involved are associated with contributions from African ancestral populations, specifically the prevalent TPMT*3C allele. The distribution of TPMT-deficient variants offers valuable insights into the populations under study, underscoring the necessity for genetic screening strategies to prevent thiopurine toxicity events among Latin American minority groups.

Genetic and environmental variation impact transferability of polygenic risk scores

Even when polygenic risk scores (PRSs) are trained in African ancestral populations, Kamiza and colleagues showed that genetic and environmental variation within sub-Saharan African populations impacts prediction performance, highlighting the challenges of clinical implementation of PRSs for risk assessment.

ApoL1 Overexpression Drives Variant-Independent Cytotoxicity.

Coding variants in the APOL1 gene are associated with kidney diseases in African ancestral populations; yet, the underlying biologic mechanisms remain uncertain. Variant-dependent autophagic and cytotoxic cell death have been proposed as pathogenic pathways mediating kidney injury. To examine this possibility, we conditionally expressed APOL1-G0 (reference), -G1, and -G2 (variants) using a tetracycline-regulated system in HEK293 cells. Autophagy was monitored biochemically and cell death was measured using multiple assays. We measured intracellular Na+ and K+ content with atomic absorption spectroscopy and APOL1-dependent currents with whole-cell patch clamping. Neither reference nor variant APOL1s induced autophagy. At high expression levels, APOL1-G0, -G1, and -G2 inserted into the plasma membrane and formed pH-sensitive cation channels, causing collapse of cellular Na+ and K+ gradients, phosphorylation of p38 mitogen-activated protein kinase, and cell death, without variant-dependent differences. APOL1-G0 and -G2 exhibited similar channel properties in whole-cell patch clamp experiments. At low expression levels, neither reference nor variant APOL1s localized on the plasma membrane, Na+ and K+ gradients were maintained, and cells remained viable. Our results indicate that APOL1-mediated pore formation is critical for the trypanolytic activity of APOL1 and drives APOL1-mediated cytotoxicity in overexpression systems. The absence of cytotoxicity at physiologic expression levels suggests variant-dependent intracellular K+ loss and cytotoxicity does not drive kidney disease progression.

Abstract P4-14-11: National trend in African American women breast cancer research productivity from 1992-2012

Abstract INTRODUCTION: Despite extensive progress in breast cancer prevention, diagnosis and treatment over the past 20 years, African American women suffer disproportionate breast cancer morbidity and mortality. In 1998, breast cancer deaths among African American women were 28% higher than in white women and the five-year survival rate for African American women was 71% compared with 86% for white women. The purpose of this bibliometric study is to assess our national research efforts to combat this racial disparity by analyzing breast cancer research productivity in the United States focusing on African American women from 1992 to 2012. METHODS: This retrospective bibliometric analysis of public data was exempt from Institutional Review Board approval. Articles with "Breast Neoplasm" as a major medical subject heading (MeSH) term published between 1992 and 2012 were identified in the National Library of Medicine MEDLINE database. In addition, articles with "African Continental Ancestry Group" which included African American as a major MeSH term were identified. Country of origin, methodology, journal name, first author specialty and funding sources were recorded. Growth in number of publications was analyzed using linear and nonlinear regression statistical analysis. RESULTS: A total of 113,721 journal articles were identified with "Breast Neoplasm" as a major MeSH term worldwide, of which 34,155 (30.0%) were published from the United States. Among United States publications, 668 (2.0%) were specific to African ancestral populations. From 1992 to 2012, both African ancestral and non-African ancestral specific articles displayed linear growth patterns (p < 0.0001). National Institute of Health (NIH) funded studies displayed an exponential growth pattern (p < 0.0001) for African ancestral specific articles and displayed a linear growth pattern (p < 0.0001) for non-African ancestral articles. The largest specialty contributor of African ancestral specific articles was Epidemiology and Public Health (33.2%), followed by Medicine (internal medicine, family medicine, obstetrics & gynecology, nursing) (24.7%), Basic Sciences (17.4%), Surgery (15%), Medical and Radiation Oncology (4.7%), Pathology (2.9%) and Radiology (2.1%). African ancestral specific articles were most frequently published in Cancer (10.8%). CONCLUSION: Among breast cancer publications from the United States, only 2% of the articles were specific to African ancestral population, which is concerning given recent data indicating the persistent ethnic disparity in survival. However, the trend in research productivity in this population is encouraging, largely due to the exponential growth of NIH-funded studies specific for African American women in the past 20 years. NIH-funded research accounts for 52% of all published African American specific breast cancer studies as compared to 40.5% of studies that are non-specific to this population. Ultimately, improvements in breast cancer incidence, mortality, and survival rates in African American women will undoubtedly result from quality research and should continue to be a priority in our nation’s breast cancer research agenda. Citation Format: Ralph T Wynn, Daniel S Chow, Victoria L Mango, Lauren C Friedlander, Richard Ha. National trend in African American women breast cancer research productivity from 1992-2012 [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-14-11.

Admixture mapping identifies a quantitative trait locus associated with FEV1/FVC in the COPDGene Study.

African Americans are admixed with genetic contributions from European and African ancestral populations. Admixture mapping leverages this information to map genes influencing differential disease risk across populations. We performed admixture and association mapping in 3,300 African American current or former smokers from the COPDGene Study. We analyzed estimated local ancestry and SNP genotype information to identify regions associated with FEV1 /FVC, the ratio of forced expiratory volume in one second to forced vital capacity, measured by spirometry performed after bronchodilator administration. Global African ancestry inversely associated with FEV1 /FVC (P = 0.035). Genome-wide admixture analysis, controlling for age, gender, body mass index, current smoking status, pack-years smoked, and four principal components summarizing the genetic background of African Americans in the COPDGene Study, identified a region on chromosome 12q14.1 associated with FEV1 /FVC (P = 2.1 × 10(-6) ) when regressed on local ancestry. Allelic association in this region of chromosome 12 identified an intronic variant in FAM19A2 (rs348644) as associated with FEV1 /FVC (P = 1.76 × 10(-6) ). By combining admixture and association mapping, a marker on chromosome 12q14.1 was identified as being associated with reduced FEV1 /FVC ratio among African Americans in the COPDGene Study.

The Admixture Structure and Genetic Variation of the Archipelago of Cape Verde and Its Implications for Admixture Mapping Studies

Recently admixed populations offer unique opportunities for studying human history and for elucidating the genetic basis of complex traits that differ in prevalence between human populations. Historical records, classical protein markers, and preliminary genetic data indicate that the Cape Verde islands in West Africa are highly admixed and primarily descended from European males and African females. However, little is known about the variation in admixture levels, admixture dynamics and genetic diversity across the islands, or about the potential of Cape Verde for admixture mapping studies. We have performed a detailed analysis of phenotypic and genetic variation in Cape Verde based on objective skin color measurements, socio-economic status (SES) evaluations and data for 50 autosomal, 34 X-chromosome, and 21 non-recombinant Y-chromosome (NRY) markers in 845 individuals from six islands of the archipelago. We find extensive genetic admixture between European and African ancestral populations (mean West African ancestry = 0.57, sd = 0.08), with individual African ancestry proportions varying considerably among the islands. African ancestry proportions calculated with X and Y-chromosome markers confirm that the pattern of admixture has been sex-biased. The high-resolution NRY-STRs reveal additional patterns of variation among the islands that are most consistent with differentiation after admixture. The differences in the autosomal admixture proportions are clearly evident in the skin color distribution across the islands (Pearson r = 0.54, P-value<2e–16). Despite this strong correlation, there are significant interactions between SES and skin color that are independent of the relationship between skin color and genetic ancestry. The observed distributions of admixture, genetic variation and skin color and the relationship of skin color with SES relate to historical and social events taking place during the settlement history of Cape Verde, and have implications for the design of association studies using this population.

Genome-wide Association and Population Genetic Analysis of C-Reactive Protein in African American and Hispanic American Women

C-reactive protein (CRP) is a systemic inflammation marker that predicts future cardiovascular risk. CRP levels are higher in African Americans and Hispanic Americans than in European Americans, but the genetic determinants of CRP in these admixed United States minority populations are largely unknown. We performed genome-wide association studies (GWASs) of 8,280 African American (AA) and 3,548 Hispanic American (HA) postmenopausal women from the Women's Health Initiative SNP Health Association Resource. We discovered and validated a CRP-associated variant of triggering receptors expressed by myeloid cells 2 (TREM2) in chromosomal region 6p21 (p = 10(-10)). The TREM2 variant associated with higher CRP is common in Africa but rare in other ancestral populations. In AA women, the CRP region in 1q23 contained a strong admixture association signal (p = 10(-17)), which appears to be related to several independent CRP-associated alleles; the strongest of these is present only in African ancestral populations and is associated with higher CRP. Of the other genomic loci previously associated with CRP through GWASs of European populations, most loci (LEPR, IL1RN, IL6R, GCKR, NLRP3, HNF1A, HNF4A, and APOC1) showed consistent patterns of association with CRP in AA and HA women. In summary, wehave identified a common TREM2 variant associated with CRP in United States minority populations. The genetic architecture underlying the CRP phenotype in AA women is complex and involves genetic variants shared across populations, as well as variants specific topopulations of African descent.

Risk of NOD2 in African-American subjects with Crohnʼs disease is exclusively contributed by Caucasian admixture

Crohn's disease (CD) is a highly heritable disorder. Candidate gene studies and GWAS have been highly successful at identifying many susceptibility loci in CD. Among them, the highest risk is attributed by NOD2, confirmed by over 100 studies; nearly all studies were done on population with European ancestry. It is not known whether NOD2 contributes to the risk of CD among African Americans (AA) who are admixed individuals in whom each chromosome is a mosaic of blocks of DNA from West African (80%) and European (20%) ancestral populations. We genotyped 3 well known disease causing SNPs (R702W, G908R and 1007fs) within the NOD2 gene in 210 CD cases and 101 controls. All the cases and controls were self-identified AAs. In addition, we also have genotyped 40 controls that are non-admixted individuals from West Africa. Two additional SNPs, R790Q only found in African ancestral populations and JW1 which is typically found in Jewish were also genotyped. Genotyping by the Taqman method was performed and association analysis was done to determine the association with CD in AA. We used existing data from Caucasians for comparison. No association was found when genotypic and allelic frequencies of the risk alleles were compared for SNPs R702W and G908R. For SNP 1007fs, differences between cases and controls reached significance (C allele frequency of 2.62% in cases vs 0% in controls). NOD2 is associated with CD in AA when the risk alleles were combined for R702W, G908R and 1007fs. No risk alleles were seen in West African cohort or in 1000 Genome data. Again, no differences were seen between AA cases, controls and African population with R790Q and JW1. As a whole, NOD2 is a risk in AAs, but the allele frequencies & the attributable risk is much lower in AAs compared with Caucasians. The classical NOD2 risk alleles (R702W, G908R and 1007fs) are completely absent in the West Africans individuals that we studied and our results are well supported by the “1000 genome” diversity project data (table). Taken together, our results suggest that the risk contributed by NOD2 in CD among AAs in exclusively contributed by Caucasian admixture. No Caption available. No Caption available.

Mixed origin of the current Tunisian population from the analysis of Alu and Alu/STR compound systems

During successive historical periods, Tunisia has been a crossroads of multiple civilizations and their corresponding key population movements. The aim of this study was to provide genetic information relating to the mixed origin of the Tunisian population, and to analyze its genetic relationship with other North African and Mediterranean populations. A set of 16 Alu and 3 Alu/STR compound systems has been analyzed in 268 autochthonous Tunisians from the north-center and the south of the country. Our two sampled populations showed no significant differentiation from one another in any of the three Alu/STR compound systems, whereas the analysis of the 16 Alu markers revealed a significant genetic differentiation between them. A sub-Saharan component shown by the three Alu/STR combinations is more noticeable in our north-center sample than in that of the south. The presence of two Alu/STR combinations specific to North African ancestral populations also suggests that the ancient Berber component is relatively more substantial in the north and center regions than in the south. Our Tunisian samples cluster together with other Berber samples from Morocco and Algeria, underpinning the genetic similarity among North Africans regardless of their current linguistic status (Berber or Arabic).

Genetic variation on chromosome 6 influences F cell levels in healthy individuals of African descent and HbF levels in sickle cell patients.

Fetal haemoglobin (HbF) is a major ameliorating factor in sickle cell disease. We investigated if a quantitative trait locus on chromosome 6q23 was significantly associated with HbF and F cell levels in individuals of African descent. Single nucleotide polymorphisms (SNPs) in a 24-kb intergenic region, 33-kb upstream of the HBS1L gene and 80-kb upstream of the MYB gene, were typed in 177 healthy Afro-Caribbean subjects (AC) of approximately 7% European admixture, 631 healthy Afro-Germans (AG, a group of African and German descendents located in rural Jamaica with about 20% European admixture), 87 West African and Afro-Caribbean individuals with sickle cell anaemia (HbSS), as well as 75 Northern Europeans, which served as a contrasting population. Association with a tag SNP for the locus was detected in all four groups (AC, P = 0.005, AG, P = 0.002, HbSS patients, P = 0.019, Europeans, P = 1.5×10−7). The association signal varied across the interval in the African-descended groups, while it is more uniform in Europeans. The 6q QTL for HbF traits is present in populations of African origin and is also acting in sickle cell anaemia patients. We have started to distinguish effects originating from European and African ancestral populations in our admixed study populations.

In Search of Susceptibility Genes for Type 2 Diabetes in West Africa: The Design and Results of the First Phase of the AADM Study

PURPOSE: The purpose of this study is to map type 2 diabetes susceptibility genes in West African ancestral populations of African-Americans, through an international collaboration between West African and US investigators. DESIGN AND METHODS: Affected sib-pairs (ASP) along with unaffected spouse controls are being enrolled and examined in West Africa, with two sites established in Ghana (Accra and Kumasi) and three in Nigeria (Enugu, Ibadan, and Lagos). Eligible participants are invited to study clinics to obtain detailed epidemiologic, family, and medical history information. Blood samples are drawn from each participant to measure glucose, insulin, C-peptide, total cholesterol, LDL, HDL, triglycerides, albumin, creatinine, urea, uric acid, total calcium and to detect autoantibodies to glutamic acid decarboxylase (GAD). DNA is isolated from frozen white blood cells obtained from 20 ml of EDTA whole blood samples. RESULTS: With full informed consent, 162 individuals from 78 families have been enrolled and examined since the Africa America Diabetes Mellitus (AADM) study began in June of 1997. Logistics of field examinations and specimen shipping have been successfully established. At the end of the third year of field activity (September 2000) the AADM study will have enrolled and performed comprehensive examination on 400 ASP with type 2 diabetes, for a minimum of 800 cases and 200 controls from Ghana and Nigeria. At the current participation rate, the goal of 400 sib-pairs and 200 controls will be met before the scheduled closing date. CONCLUSIONS: The AADM study will create a comprehensive epidemiologic and genetic resource that will facilitate a powerful genome-wide search for West African susceptibility genes to type 2 diabetes.