Publications by authors named "Eduardo Tarazona-Santos"

76 Publications

Tracing the Distribution of European Lactase Persistence Genotypes Along the Americas.

Front Genet 2021 22;12:671079. Epub 2021 Sep 22.

Movement Disorders Unit, Department of Neurology and Neurosurgery, Universidade Federal de São Paulo, São Paulo, Brazil.

In adulthood, the ability to digest lactose, the main sugar present in milk of mammals, is a phenotype (lactase persistence) observed in historically herder populations, mainly Northern Europeans, Eastern Africans, and Middle Eastern nomads. As the allele in the gene is the most well-characterized allele responsible for the lactase persistence phenotype, the > (rs4988235) polymorphism is commonly evaluated in lactase persistence studies. Lactase non-persistent adults may develop symptoms of lactose intolerance when consuming dairy products. In the Americas, there is no evidence of the consumption of these products until the arrival of Europeans. However, several American countries' dietary guidelines recommend consuming dairy for adequate human nutrition and health promotion. Considering the extensive use of dairy and the complex ancestry of Pan-American admixed populations, we studied the distribution of > lactase persistence genotypes and its flanking haplotypes of European origin in 7,428 individuals from several Pan-American admixed populations. We found that the allele frequency in Pan-American admixed populations is directly correlated with allele frequency of the European sources. Moreover, we did not observe any overrepresentation of European haplotypes in the > flanking region, suggesting no selective pressure after admixture in the Americas. Finally, considering the dominant effect of the allele, our results indicate that Pan-American admixed populations are likely to have higher frequency of lactose intolerance, suggesting that general dietary guidelines deserve further evaluation across the continent.
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http://dx.doi.org/10.3389/fgene.2021.671079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8493957PMC
September 2021

HLA-G 3'UTR haplotype frequencies in highland and lowland South Native American populations.

Hum Immunol 2021 Sep 22. Epub 2021 Sep 22.

Departamento de Genética, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil. Electronic address:

Human Leukocyte Antigen (HLA)-G participates in several biological processes, including reproduction, vascular remodeling, immune tolerance, and hypoxia response. HLA-G is a potential candidate gene for high altitude adaptation since its expression is modulated in both micro and macro environment under hypoxia and constant cellular stress. Besides the promoter region, the HLA-G 3'untranslated region (UTR) influences HLA-G expression patterns through several post-transcriptional mechanisms. Currently, the 3'UTR genetic diversity in terms of altitude adaptation of Native American populations is still unexplored, particularly at high altitude ecoregions. Here, we evaluated 288 Native Americans from 9 communities located in the Andes [highland (HL); ≥2,500 m (range = 2,838-4,433 m)] and 8 populations located in lowland (LL) regions [<2,500 m (range = 80-431 m); Amazonian tropical forest, Brazilian central plateau, and Chaco] of South America. In total, nine polymorphic sites and ten haplotypes were observed. The most frequent haplotypes (UTR-1, UTR-2, and UTR-3) accounted for ∼ 77% of haplotypes found in LL, while in the HL, the same haplotypes reach ∼ 93%. Also, a remarkable high frequency of putative ancestral UTR-5 haplotype was observed in LL (21.5%), while in HL UTR-2 reaches up to 47%. Further, UTR-2 frequency positively correlates with altitude-related variables, while a negative correlation for UTR-5 was observed. From an evolutionary perspective, we observed a tendency towards balancing selection in HL and LL populations thus suggesting that haplotypes of ancient and more derived alleles may have been co-opted for relatively recent adaptations such as those experienced by modern humans in the highland and lowland of South America. We also discuss how long-term balancing selection can be a reservoir of genetic variants that can be positively selected. Finally, our study provides some pieces of evidence that HLA-G 3'UTR haplotypes may have contributed to high altitude adaptation in the Andes.
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http://dx.doi.org/10.1016/j.humimm.2021.09.002DOI Listing
September 2021

Putative pathogen-selected polymorphisms in the PKLR gene are associated with mycobacterial susceptibility in Brazilian and African populations.

PLoS Negl Trop Dis 2021 08 27;15(8):e0009434. Epub 2021 Aug 27.

Laboratory of Molecular Virology, Instituto Nacional de Saúde, Maputo, Mozambique.

Pyruvate kinase (PK), encoded by the PKLR gene, is a key player in glycolysis controlling the integrity of erythrocytes. Due to Plasmodium selection, mutations for PK deficiency, which leads to hemolytic anemia, are associated with resistance to malaria in sub-Saharan Africa and with susceptibility to intracellular pathogens in experimental models. In this case-control study, we enrolled 4,555 individuals and investigated whether PKLR single nucleotide polymorphisms (SNPs) putatively selected for malaria resistance are associated with susceptibility to leprosy across Brazil (Manaus-North; Salvador-Northeast; Rondonópolis-Midwest and Rio de Janeiro-Southeast) and with tuberculosis in Mozambique. Haplotype T/G/G (rs1052176/rs4971072/rs11264359) was associated with leprosy susceptibility in Rio de Janeiro (OR = 2.46, p = 0.00001) and Salvador (OR = 1.57, p = 0.04), and with tuberculosis in Mozambique (OR = 1.52, p = 0.07). This haplotype downregulates PKLR expression in nerve and skin, accordingly to GTEx, and might subtly modulate ferritin and haptoglobin levels in serum. Furthermore, we observed genetic signatures of positive selection in the HCN3 gene (xpEHH>2 -recent selection) in Europe but not in Africa, involving 6 SNPs which are PKLR/HCN3 eQTLs. However, this evidence was not corroborated by the other tests (FST, Tajima's D and iHS). Altogether, we provide evidence that a common PKLR locus in Africans contribute to mycobacterial susceptibility in African descent populations and also highlight, for first, PKLR as a susceptibility gene for leprosy and TB.
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http://dx.doi.org/10.1371/journal.pntd.0009434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396769PMC
August 2021

Human-SARS-CoV-2 interactome and human genetic diversity: TMPRSS2-rs2070788, associated with severe influenza, and its population genetics caveats in Native Americans.

Genet Mol Biol 2021 25;44(1 Suppl 1):e20200484. Epub 2021 Aug 25.

Universidade Federal do Triângulo Mineiro, Instituto de Ciências Biológicas e Naturais, Departamento de Patologia, Genética e Evolução, Uberaba, MG, Brazil.

For human/SARS-CoV-2 interactome genes ACE2, TMPRSS2 and BSG, there is a convincing evidence of association in Asians with influenza-induced SARS for TMPRSS2-rs2070788, tag-SNP of the eQTL rs383510. This case illustrates the importance of population genetics and of sequencing data in the design of genetic association studies in different human populations: the high linkage disequilibrium (LD) between rs2070788 and rs383510 is Asian-specific. Leveraging on a combination of genotyping and sequencing data for Native Americans (neglected in genetic studies), we show that while their frequencies of the Asian tag-SNP rs2070788 is, surprisingly, the highest worldwide, it is not in LD with the eQTL rs383510, that therefore, should be directly genotyped in genetic association studies of SARS in populations with Native American ancestry.
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http://dx.doi.org/10.1590/1678-4685-GMB-2020-0484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387978PMC
August 2021

Biased pathogenic assertions of loss of function variants challenge molecular diagnosis of admixed individuals.

Am J Med Genet C Semin Med Genet 2021 09 29;187(3):357-363. Epub 2021 Jun 29.

Human Genome and Stem Cell Research Center, University of São Paulo, São Paulo, São Paulo, Brazil.

Diagnosis of individuals affected by monogenic disorders was significantly improved by next-generation sequencing targeting clinically relevant genes. Whole exomes yield a large number of variants that require several filtering steps, prioritization, and pathogenicity classification. Among the criteria recommended by ACMG, those that rely on population databases critically affect analyses of individuals with underrepresented ancestries. Population-specific allelic frequencies need consideration when characterizing potential deleteriousness of variants. An orthogonal input for classification is annotation of variants previously classified as pathogenic as a criterion that provide supporting evidence widely sourced at ClinVar. We used a whole-genome dataset from a census-based cohort of 1,171 elderly individuals from São Paulo, Brazil, highly admixed, and unaffected by severe monogenic disorders, to investigate if pathogenic assertions in ClinVar are enriched with higher proportions of European ancestry, indicating bias. Potential loss of function (pLOF) variants were filtered from 4,250 genes associated with Mendelian disorders and annotated with ClinVar assertions. Over 1,800 single nucleotide pLOF variants were included, 381 had non-benign assertions. Among carriers (N = 463), average European ancestry was significantly higher than noncarriers (N = 708; p = .011). pLOFs in genomic contexts of non-European local ancestries were nearly three times less likely to have any ClinVar entry (OR = 0.353; p <.0001). Independent pathogenicity assertions are useful for variant classification in molecular diagnosis. However, European overrepresentation of assertions can promote distortions when classifying variants in non-European individuals, even in admixed samples with a relatively high proportion of European ancestry. The investigation and deposit of clinically relevant findings of diverse populations is fundamental improve this scenario.
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http://dx.doi.org/10.1002/ajmg.c.31931DOI Listing
September 2021

Admixture/fine-mapping in Brazilians reveals a West African associated potential regulatory variant (rs114066381) with a strong female-specific effect on body mass and fat mass indexes.

Int J Obes (Lond) 2021 05 26;45(5):1017-1029. Epub 2021 Feb 26.

Cancer Biology Division, Ponce Research Institute, Ponce Health Sciences University, Ponce, Puerto Rico.

Background/objectives: Admixed populations are a resource to study the global genetic architecture of complex phenotypes, which is critical, considering that non-European populations are severely underrepresented in genomic studies. Here, we study the genetic architecture of BMI in children, young adults, and elderly individuals from the admixed population of Brazil.

Subjects/methods: Leveraging admixture in Brazilians, whose chromosomes are mosaics of fragments of Native American, European, and African origins, we used genome-wide data to perform admixture mapping/fine-mapping of body mass index (BMI) in three Brazilian population-based cohorts from Northeast (Salvador), Southeast (Bambuí), and South (Pelotas).

Results: We found significant associations with African-associated alleles in children from Salvador (PALD1 and ZMIZ1 genes), and in young adults from Pelotas (NOD2 and MTUS2 genes). More importantly, in Pelotas, rs114066381, mapped in a potential regulatory region, is significantly associated only in females (p = 2.76e-06). This variant is rare in Europeans but with frequencies of ~3% in West Africa and has a strong female-specific effect (95% CI: 2.32-5.65 kg/m per each A allele). We confirmed this sex-specific association and replicated its strong effect for an adjusted fat mass index in the same Pelotas cohort, and for BMI in another Brazilian cohort from São Paulo (Southeast Brazil). A meta-analysis confirmed the significant association. Remarkably, we observed that while the frequency of rs114066381-A allele ranges from 0.8 to 2.1% in the studied populations, it attains ~9% among women with morbid obesity from Pelotas, São Paulo, and Bambuí. The effect size of rs114066381 is at least five times higher than the FTO SNPs rs9939609 and rs1558902, already emblematic for their high effects.

Conclusions: We identified six candidate SNPs associated with BMI. rs114066381 stands out for its high effect that was replicated and its high frequency in women with morbid obesity. We demonstrate how admixed populations are a source of new relevant phenotype-associated genetic variants.
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http://dx.doi.org/10.1038/s41366-021-00761-1DOI Listing
May 2021

Trans-ethnic meta-analysis identifies new loci associated with longitudinal blood pressure traits.

Sci Rep 2021 02 18;11(1):4075. Epub 2021 Feb 18.

Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.

Genome-wide association studies (GWAS) have identified thousands of genetic loci associated with cross-sectional blood pressure (BP) traits; however, GWAS based on longitudinal BP have been underexplored. We performed ethnic-specific and trans-ethnic GWAS meta-analysis using longitudinal and cross-sectional BP data of 33,720 individuals from five cohorts in the US and one in Brazil. In addition to identifying several known loci, we identified thirteen novel loci with nine based on longitudinal and four on cross-sectional BP traits. Most of the novel loci were ethnic- or study-specific, with the majority identified in African Americans (AA). Four of these discoveries showed additional evidence of association in independent datasets, including an intergenic variant (rs4060030, p = 7.3 × 10) with reported regulatory function. We observed a high correlation between the meta-analysis results for baseline and longitudinal average BP (rho = 0.48). BP trajectory results were more correlated with those of average BP (rho = 0.35) than baseline BP(rho = 0.18). Heritability estimates trended higher for longitudinal traits than for cross-sectional traits, providing evidence for different genetic architectures. Furthermore, the longitudinal data identified up to 20% more BP known associations than did cross-sectional data. Our analyses of longitudinal BP data in diverse ethnic groups identified novel BP loci associated with BP trajectory, indicating a need for further longitudinal GWAS on BP and other age-related traits.
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http://dx.doi.org/10.1038/s41598-021-83450-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893038PMC
February 2021

Identification of New Subpopulations in Native Americans and Mestizos From Peru.

Front Microbiol 2020 14;11:601839. Epub 2020 Dec 14.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, United States.

Region-specific subpopulations have been identified. It is proposed that the hspAmerind subpopulation is being displaced from the Americans by an hpEurope population following the conquest. Our study aimed to describe the genomes and methylomes of isolates from distinct Peruvian communities: 23 strains collected from three groups of Native Americans (Asháninkas [ASHA, = 9], Shimaas [SHIM, = 5] from Amazonas, and Punos from the Andean highlands [PUNO, = 9]) and 9 modern mestizos from Lima (LIM). Closed genomes and DNA modification calls were obtained using SMRT/PacBio sequencing. We performed evolutionary analyses and evaluated genomic/epigenomic differences among strain groups. We also evaluated human genome-wide data from 74 individuals from the selected Native communities (including the 23 strains donors) to compare host and bacterial backgrounds. There were varying degrees of hspAmerind ancestry in all strains, ranging from 7% in LIM to 99% in SHIM. We identified three subpopulations corresponding to each of the Native groups and a novel hspEuropePeru which evolved in the modern mestizos. The divergence of the indigenous strains recapitulated the genetic structure of Native Americans. Phylogenetic profiling showed that Orthogroups in the indigenous strains seem to have evolved differentially toward epigenomic regulation and chromosome maintenance, whereas OGs in the modern mestizo (LIM) seem to have evolved toward virulence and adherence. The prevalence of / genotype was similar across populations ( = 0.32): 89% in ASHA, 67% in PUNO, 56% in LIM and 40% in SHIM. Both and sequences showed that LIM strains were genetically differentiated ( < 0.001) as compared to indigenous strains. We identified 642 R-M systems with 39% of the associated genes located in the core genome. We found 692 methylation motifs, including 254 population-specific sequences not previously described. In Peru, hspAmerind is not extinct, with traces found even in a heavily admixed mestizo population. Notably, our study identified three new hspAmerind subpopulations, one per Native group; and a new subpopulation among mestizos that we named hspEuropePeru. This subpopulation seems to have more virulence-related elements than hspAmerind. Purifying selection driven by variable host immune response may have shaped the evolution of Peruvian subpopulations, potentially impacting disease outcomes.
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http://dx.doi.org/10.3389/fmicb.2020.601839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767971PMC
December 2020

The genetic structure and adaptation of Andean highlanders and Amazonians are influenced by the interplay between geography and culture.

Proc Natl Acad Sci U S A 2020 12 4;117(51):32557-32565. Epub 2020 Dec 4.

Laboratorio de Biotecnología y Biología Molecular, Instituto Nacional de Salud, Lima 9, Peru;

Western South America was one of the worldwide cradles of civilization. The well-known Inca Empire was the tip of the iceberg of an evolutionary process that started 11,000 to 14,000 years ago. Genetic data from 18 Peruvian populations reveal the following: 1) The between-population homogenization of the central southern Andes and its differentiation with respect to Amazonian populations of similar latitudes do not extend northward. Instead, longitudinal gene flow between the northern coast of Peru, Andes, and Amazonia accompanied cultural and socioeconomic interactions revealed by archeology. This pattern recapitulates the environmental and cultural differentiation between the fertile north, where altitudes are lower, and the arid south, where the Andes are higher, acting as a genetic barrier between the sharply different environments of the Andes and Amazonia. 2) The genetic homogenization between the populations of the arid Andes is not only due to migrations during the Inca Empire or the subsequent colonial period. It started at least during the earlier expansion of the Wari Empire (600 to 1,000 years before present). 3) This demographic history allowed for cases of positive natural selection in the high and arid Andes vs. the low Amazon tropical forest: in the Andes, a putative enhancer in (heart and neural crest derivatives expressed 2 antisense RNA1, a noncoding gene related to cardiovascular function) and rs269868-C/Ser1067 in (dual oxidase 2, related to thyroid function and innate immunity) genes and, in the Amazon, the gene encoding for the CD45 protein, essential for antigen recognition by T and B lymphocytes in viral-host interaction.
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http://dx.doi.org/10.1073/pnas.2013773117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768732PMC
December 2020

How Ancestry Influences the Chances of Finding Unrelated Donors: An Investigation in Admixed Brazilians.

Front Immunol 2020 6;11:584950. Epub 2020 Nov 6.

Laboratory of Evolutionary Genetics, Institute of Biosciences, University of São Paulo, São Paulo, Brazil.

A match of HLA loci between patients and donors is critical for successful hematopoietic stem cell transplantation. However, the extreme polymorphism of HLA loci - an outcome of millions of years of natural selection - reduces the chances that two individuals will carry identical combinations of multilocus HLA genotypes. Further, HLA variability is not homogeneously distributed throughout the world: African populations on average have greater variability than non-Africans, reducing the chances that two unrelated African individuals are HLA identical. Here, we explore how self-identification (often equated with "ethnicity" or "race") and genetic ancestry are related to the chances of finding HLA compatible donors in a large sample from Brazil, a highly admixed country. We query REDOME, Brazil's Bone Marrow Registry, and investigate how different criteria for identifying ancestry influence the chances of finding a match. We find that individuals who self-identify as "Black" and "Mixed" on average have lower chances of finding matches than those who self-identify as "White" (up to 57% reduction). We next show that an individual's African genetic ancestry, estimated using molecular markers and quantified as the proportion of an individual's genome that traces its ancestry to Africa, is strongly associated with reduced chances of finding a match (up to 60% reduction). Finally, we document that the strongest reduction in chances of finding a match is associated with having an MHC region of exclusively African ancestry (up to 75% reduction). We apply our findings to a specific condition, for which there is a clinical indication for transplantation: sickle-cell disease. We show that the increased African ancestry in patients with this disease leads to reduced chances of finding a match, when compared to the remainder of the sample, without the condition. Our results underscore the influence of ancestry on chances of finding compatible HLA matches, and indicate that efforts guided to increasing the African component of registries are necessary.
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http://dx.doi.org/10.3389/fimmu.2020.584950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677137PMC
June 2021

Genetic admixture in Brazil.

Am J Med Genet C Semin Med Genet 2020 12 18;184(4):928-938. Epub 2020 Nov 18.

Departamento de Genética, Ecologia e Evolução, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.

We review studies from our laboratories using different molecular tools to characterize the Amerindian, European and African ancestry of Brazilians. Initially we used uniparental DNA markers to investigate the contribution of distinct Y chromosome and mitochondrial DNA lineages to present-day populations. High levels of genetic admixture and strong directional mating between European males and Amerindian and African females were unraveled. We next analyzed different types of biparental autosomal polymorphisms. Especially useful was a set of 40 insertion-deletion polymorphisms (indels) that when studied worldwide proved exquisitely sensitive in discriminating between Amerindians, Europeans and Sub-Saharan Africans. When applied to the study of Brazilians these markers confirmed extensive genomic admixture. We then studied ancestry differences in different regions by statistically controlling them to eliminate color considerations. The European ancestry was predominant in all regions studied, with proportions ranging from 60.6% in the Northeast to 77.7% in the South. We propose that the immigration of 6 million Europeans to Brazil in the 19th and 20th centuries is in large part responsible for dissipating previous ancestry dissimilarities that reflected region-specific population histories. Brazilians should be assessed individually, as 210 million human beings, and not as members of specific regions or color groups.
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http://dx.doi.org/10.1002/ajmg.c.31853DOI Listing
December 2020

Genomic Regions 10q22.2, 17q21.31, and 2p23.1 Can Contribute to a Lower Lung Function in African Descent Populations.

Genes (Basel) 2020 09 4;11(9). Epub 2020 Sep 4.

Departamento de Bio-Regulação, Instituto de Ciências da Saúde, Universidade Federal da Bahia (UFBA), Salvador 40110-902, BA, Brazil.

Accumulated evidence supports the contribution of genetic factors in modulating airway function, especially ancestry. We investigated whether genetic polymorphisms can affect lung function in a mixed Brazilian child population using the admixture mapping strategy through RFMix software version 1.5.4 (Stanford University, Stanford, CA, USA), followed by fine mapping, to identify regions whereby local African or European ancestry is associated with lung function measured by the forced expiratory volume in the first second (FEV)/forced vital capacity (FVC) ratio, an indicator of airway obstruction. The research cohort included 958 individuals aged 4 to 11 years enrolled in the SCAALA (Social Change, Asthma, Allergy in Latin America) Program. We identified that African ancestry at 17q21.31, 10q22.2, and 2p23.1 regions was associated with lower lung function measured by FEV/FVC < 1.9 × 10. In contrast, European ancestry at 17q21.31 showed an opposite effect. Fine mapping pointed out 5 single nucleotide polymorphisms (SNPs) also associated in our replication cohort (rs10999948, rs373831475, rs8068257, rs6744555, and rs1520322). Our results suggest that genomic regions associated with ancestry may contribute to differences in lung function measurements in African American children in Brazil replicated in a cohort of Brazilian adults. The analysis strategy used in this work is especially important for phenotypes, such as lung function, which has considerable disparities in terms of measurements across different populations.
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http://dx.doi.org/10.3390/genes11091047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565985PMC
September 2020

Challenges and Opportunities for Clinical Pharmacogenetic Research Studies in Resource-limited Settings: Conclusions From the Council for International Organizations of Medical Sciences-Ibero-American Network of Pharmacogenetics and Pharmacogenomics Meeting.

Clin Ther 2020 08 8;42(8):1595-1610.e5. Epub 2020 Aug 8.

INUBE Extremadura Biosanitary University Research Institute, University of Extremadura, Badajoz, Spain; University of Conscientiousness Project, Campus PHI, Acebo, Extremadura, Spain. Electronic address:

Purpose: The symposium Health and Medicines in Indigenous Populations of America was organized by the Council for International Organizations of Medical Sciences (CIOMS) Working Group on Clinical Research in Resource-Limited Settings (RLSs) and the Ibero-American Network of Pharmacogenetics and Pharmacogenomics (RIBEF). It was aimed to share and evaluate investigators' experiences on challenges and opportunities on clinical research and pharmacogenetics.

Methods: A total of 33 members from 22 countries participated in 2 sessions: RIBEF studies on population pharmacogenetics about the relationship between ancestry with relevant drug-related genetic polymorphisms and the relationship between genotype and phenotype in Native Americans (session 1) and case examples of clinical studies in RLSs from Asia (cancer), America (diabetes and women health), and Africa (malaria) in which the participants were asked to answer in free text their experiences on challenges and opportunities to solve the problems (session 2). Later, a discourse analysis grouping common themes by affinity was conducted.

Findings: The main result of session 1 was that the pharmacogenetics-related ancestry of the population should be considered when designing clinical studies in RLSs. In session 2, 21 challenges and 20 opportunities were identified. The social aspects represent the largest proportion of the challenges (43%) and opportunities (55%), and some of them seem to be common.

Implications: The main discussion points were gathered in the Declaration of Mérida/T'Hó and announced on the Parliament of Extremadura during the CIOMS-RIBEF meeting in 4 of the major Latin American autochthonous languages (Náhualth, Mayan, Miskito, and Kichwa). The declaration highlighted the following: (1) the relevance of population pharmacogenetics, (2) the sociocultural contexts (interaction with traditional medicine), and (3) the education needs of research teams for clinical research in vulnerable and autochthonous populations.
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http://dx.doi.org/10.1016/j.clinthera.2020.06.008DOI Listing
August 2020

The history behind the mosaic of the Americas.

Curr Opin Genet Dev 2020 06 10;62:72-77. Epub 2020 Jul 10.

Departamento de Genética, Ecologia e Evolução, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil. Electronic address:

Focusing on literature published in 2018-2020, we review inferences about: (i) how ancient DNA is contributing to clarify the peopling of the Americas and the dispersal of its first inhabitants, (ii) how the interplay between environmental diversity and culture has influenced the genetic structure and adaptation of Andean and Amazon populations, (iii) how genetics has contributed to our understanding of the Pre-Columbian Tupi expansion in Eastern South America, (iv) the subcontinental origins and dynamics of Post-Columbian admixture in the Americas, and finally, (v) episodes of adaptive natural selection in the American continent, particularly in the high altitudes of the Andes.
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http://dx.doi.org/10.1016/j.gde.2020.06.007DOI Listing
June 2020

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction.

Nat Commun 2020 05 21;11(1):2542. Epub 2020 May 21.

Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.
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http://dx.doi.org/10.1038/s41467-020-15706-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242331PMC
May 2020

Origins, Admixture Dynamics, and Homogenization of the African Gene Pool in the Americas.

Mol Biol Evol 2020 06;37(6):1647-1656

Instituto de Saúde Coletiva, Universidade Federal da Bahia, Salvador, BA, Brazil.

The Transatlantic Slave Trade transported more than 9 million Africans to the Americas between the early 16th and the mid-19th centuries. We performed a genome-wide analysis using 6,267 individuals from 25 populations to infer how different African groups contributed to North-, South-American, and Caribbean populations, in the context of geographic and geopolitical factors, and compared genetic data with demographic history records of the Transatlantic Slave Trade. We observed that West-Central Africa and Western Africa-associated ancestry clusters are more prevalent in northern latitudes of the Americas, whereas the South/East Africa-associated ancestry cluster is more prevalent in southern latitudes of the Americas. This pattern results from geographic and geopolitical factors leading to population differentiation. However, there is a substantial decrease in the between-population differentiation of the African gene pool within the Americas, when compared with the regions of origin from Africa, underscoring the importance of historical factors favoring admixture between individuals with different African origins in the New World. This between-population homogenization in the Americas is consistent with the excess of West-Central Africa ancestry (the most prevalent in the Americas) in the United States and Southeast-Brazil, with respect to historical-demography expectations. We also inferred that in most of the Americas, intercontinental admixture intensification occurred between 1750 and 1850, which correlates strongly with the peak of arrivals from Africa. This study contributes with a population genetics perspective to the ongoing social, cultural, and political debate regarding ancestry, admixture, and the mestizaje process in the Americas.
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http://dx.doi.org/10.1093/molbev/msaa033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253211PMC
June 2020

Genetics of cognitive trajectory in Brazilians: 15 years of follow-up from the Bambuí-Epigen Cohort Study of Aging.

Sci Rep 2019 12 2;9(1):18085. Epub 2019 Dec 2.

Fundação Oswaldo Cruz, Instituto de Pesquisas René Rachou, Belo Horizonte, Brazil.

Age-related cognitive decline (ACD) is the gradual process of decreasing of cognitive function over age. Most genetic risk factors for ACD have been identified in European populations and there are no reports in admixed Latin American individuals. We performed admixture mapping, genome-wide association analysis (GWAS), and fine-mapping to examine genetic factors associated with 15-year cognitive trajectory in 1,407 Brazilian older adults, comprising 14,956 Mini-Mental State Examination measures. Participants were enrolled as part of the Bambuí-Epigen Cohort Study of Aging. Our admixture mapping analysis identified a genomic region (3p24.2) in which increased Native American ancestry was significantly associated with faster ACD. Fine-mapping of this region identified a single nucleotide polymorphism (SNP) rs142380904 (β = -0.044, SE = 0.01, p = 7.5 × 10) associated with ACD. In addition, our GWAS identified 24 associated SNPs, most in genes previously reported to influence cognitive function. The top six associated SNPs accounted for 18.5% of the ACD variance in our data. Furthermore, our longitudinal study replicated previous GWAS hits for cognitive decline and Alzheimer's disease. Our 15-year longitudinal study identified both ancestry-specific and cosmopolitan genetic variants associated with ACD in Brazilians, highlighting the need for more trans-ancestry genomic studies, especially in underrepresented ethnic groups.
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http://dx.doi.org/10.1038/s41598-019-53988-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889148PMC
December 2019

The Genomic Impact of European Colonization of the Americas.

Curr Biol 2019 12 14;29(23):3974-3986.e4. Epub 2019 Nov 14.

Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, Pavia 27100, Italy.

The human genetic diversity of the Americas has been affected by several events of gene flow that have continued since the colonial era and the Atlantic slave trade. Moreover, multiple waves of migration followed by local admixture occurred in the last two centuries, the impact of which has been largely unexplored. Here, we compiled a genome-wide dataset of ∼12,000 individuals from twelve American countries and ∼6,000 individuals from worldwide populations and applied haplotype-based methods to investigate how historical movements from outside the New World affected (1) the genetic structure, (2) the admixture profile, (3) the demographic history, and (4) sex-biased gene-flow dynamics of the Americas. We revealed a high degree of complexity underlying the genetic contribution of European and African populations in North and South America, from both geographic and temporal perspectives, identifying previously unreported sources related to Italy, the Middle East, and to specific regions of Africa.
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http://dx.doi.org/10.1016/j.cub.2019.09.076DOI Listing
December 2019

Genomic Ancestry, CYP2D6, CYP2C9, and CYP2C19 Among Latin Americans.

Clin Pharmacol Ther 2020 01 7;107(1):257-268. Epub 2019 Oct 7.

RIBEF Ibero-American Network of Pharmacogenetics and Pharmacogenomics, Badajoz, Extremadura, Spain.

We present the distribution of CYP2D6, CYP2C9, and CYP2C19 variants and predicted phenotypes in 33 native and admixed populations from Ibero-America (n > 6,000) in the context of genetic ancestry (n = 3,387). Continental ancestries are the major determinants of frequencies of the increased-activity allele CYP2C19*17 and CYP2C19 gUMs (negatively associated with Native American ancestry), decreased-activity alleles CYP2D6*41 and CYP2C9*2 (positively associated with European ancestry), and decreased-activity alleles CYP2D6*17 and CYP2D6*29 (positively associated with African ancestry). For the rare alleles, CYP2C9*2 and CYPC19*17, European admixture accounts for their presence in Native American populations, but rare alleles CYP2D6*5 (null-activity), CYP2D6-multiplication alleles (increased activity), and CYP2C9*3 (decreased-activity) were present in the pre-Columbian Americas. The study of a broad spectrum of Native American populations from different ethno-linguistic groups show how autochthonous diversity shaped the distribution of pharmaco-alleles and give insights on the prevalence of clinically relevant phenotypes associated with drugs, such as paroxetine, tamoxifen, warfarin, and clopidogrel.
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http://dx.doi.org/10.1002/cpt.1598DOI Listing
January 2020

Reconstructed Lost Native American Populations from Eastern Brazil Are Shaped by Differential Jê/Tupi Ancestry.

Genome Biol Evol 2019 09;11(9):2593-2604

Departament de Ciències Experimentals i de la Salut, Institute of Evolutionary Biology (CSIC-UPF), Universitat Pompeu Fabra, Barcelona, Spain.

After the colonization of the Americas by Europeans and the consequent Trans-Atlantic Slave Trade, most Native American populations in eastern Brazil disappeared or went through an admixture process that configured a population composed of three main genetic components: the European, the sub-Saharan African, and the Native American. The study of the Native American genetic history is challenged by the lack of availability of genome-wide samples from Native American populations, the technical difficulties to develop ancient DNA studies, and the low proportions of the Native American component in the admixed Brazilian populations (on average 7%). We analyzed genome-wide data of 5,825 individuals from three locations of eastern Brazil: Salvador (North-East), Bambui (South-East), and Pelotas (South) and we reconstructed populations that emulate the Native American groups that were living in the 16th century around the sampling locations. This genetic reconstruction was performed after local ancestry analysis of the admixed Brazilian populations, through the rearrangement of the Native American haplotypes into reconstructed individuals with full Native American ancestry (51 reconstructed individuals in Salvador, 45 in Bambui, and 197 in Pelotas). We compared the reconstructed populations with nonadmixed Native American populations from other regions of Brazil through haplotype-based methods. Our results reveal a population structure shaped by the dichotomy of Tupi-/Jê-speaking ancestry related groups. We also show evidence of a decrease of the diversity of nonadmixed Native American groups after the European contact, in contrast with the reconstructed populations, suggesting a reservoir of the Native American genetic diversity within the admixed Brazilian population.
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http://dx.doi.org/10.1093/gbe/evz161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756188PMC
September 2019

Genetic signatures of gene flow and malaria-driven natural selection in sub-Saharan populations of the "endemic Burkitt Lymphoma belt".

PLoS Genet 2019 03 8;15(3):e1008027. Epub 2019 Mar 8.

Stanford Cancer Institute, Stanford University, Stanford, California, United States of America.

Populations in sub-Saharan Africa have historically been exposed to intense selection from chronic infection with falciparum malaria. Interestingly, populations with the highest malaria intensity can be identified by the increased occurrence of endemic Burkitt Lymphoma (eBL), a pediatric cancer that affects populations with intense malaria exposure, in the so called "eBL belt" in sub-Saharan Africa. However, the effects of intense malaria exposure and sub-Saharan populations' genetic histories remain poorly explored. To determine if historical migrations and intense malaria exposure have shaped the genetic composition of the eBL belt populations, we genotyped ~4.3 million SNPs in 1,708 individuals from Ghana and Northern Uganda, located on opposite sides of eBL belt and with ≥ 7 months/year of intense malaria exposure and published evidence of high incidence of BL. Among 35 Ghanaian tribes, we showed a predominantly West-Central African ancestry and genomic footprints of gene flow from Gambian and East African populations. In Uganda, the North West population showed a predominantly Nilotic ancestry, and the North Central population was a mixture of Nilotic and Southern Bantu ancestry, while the Southwest Ugandan population showed a predominant Southern Bantu ancestry. Our results support the hypothesis of diverse ancestral origins of the Ugandan, Kenyan and Tanzanian Great Lakes African populations, reflecting a confluence of Nilotic, Cushitic and Bantu migrations in the last 3000 years. Natural selection analyses suggest, for the first time, a strong positive selection signal in the ATP2B4 gene (rs10900588) in Northern Ugandan populations. These findings provide important baseline genomic data to facilitate disease association studies, including of eBL, in eBL belt populations.
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http://dx.doi.org/10.1371/journal.pgen.1008027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426263PMC
March 2019

African biogeographical ancestry, atopic and non-atopic asthma and atopy: A study in Latin American children.

Pediatr Pulmonol 2019 02 11;54(2):125-132. Epub 2018 Dec 11.

Institute of Collective Health, Federal University of Bahia, Salvador, Bahia, Brazil.

Background: Genetic variants underlying African ancestry have been suggested be implicated in the ethnic-racial inequalities reported for asthma and allergies.

Objectives: To investigate the association between individual African ancestry and asthma symptoms, atopic and non-atopic asthma, and atopy in children.

Methods: A cross-sectional study encompassing 1190 individuals was conducted. African biogeographic ancestry was estimated using 370 539 genome-wide SNPs. Serum levels of specific IgE were measured, and skin prick test (SPT) performed for the most common local aeroallergens. Information on asthma symptoms was obtained by applying the International Study of Allergy and Asthma in Childhood questionnaire. The associations between the proportion of individual African ancestry and the outcomes investigated were analyzed through multivariate models adjusted for socio-environmental variables, infections markers, and psychosocial factors.

Results: Each 20% increase in the proportion of African ancestry was negatively associated with SPT reactivity (OR: 0.79, 95%CI: 0.66-0.96) and positively associated with asthma symptoms in non-atopic individuals (OR: 1.40, 95%CI: 1.03-1.89). We estimated that socioeconomic status and number of infections mediated 28.4% of the effect of African ancestry on SPT reactivity, while 20.2% of the effect on non-atopic asthma was explained by socioeconomic status and behavioral problems in children.

Conclusions: The negative association observed between African ancestry and atopy is most probably explained by unobserved environmental or social factors that covariate with ancestry. For non-atopic asthma, in turn, putative genetic variants of risk underlying African ancestry may play some role.
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http://dx.doi.org/10.1002/ppul.24213DOI Listing
February 2019

Genome-wide burden and association analyses implicate copy number variations in asthma risk among children and young adults from Latin America.

Sci Rep 2018 09 27;8(1):14475. Epub 2018 Sep 27.

Institute of Collective Health, Federal University of Bahia, 40110-040, Salvador, Bahia, Brazil.

The genetic architecture of asthma was relatively well explored. However, some work remains in the field to improve our understanding on asthma genetics, especially in non-Caucasian populations and with regards to commonly neglected genetic variants, such as Copy Number Variations (CNVs). In the present study, we investigated the contribution of CNVs on asthma risk among Latin Americans. CNVs were inferred from SNP genotyping data. Genome wide burden and association analyses were conducted to evaluate the impact of CNVs on asthma outcome. We found no significant difference in the numbers of CNVs between asthmatics and non-asthmatics. Nevertheless, we found that CNVs are larger in patients then in healthy controls and that CNVs from cases intersect significantly more genes and regulatory elements. We also found that a deletion at 6p22.1 is associated with asthma symptoms in children from Salvador (Brazil) and in young adults from Pelotas (Brazil). To support our results, we conducted an in silico functional analysis and found that this deletion spans several regulatory elements, including two promoter elements active in lung cells. In conclusion, we found robust evidence that CNVs could contribute for asthma susceptibility. These results uncover a new perspective on the influence of genetic factors modulating asthma risk.
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http://dx.doi.org/10.1038/s41598-018-32837-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160443PMC
September 2018

Genomic African and Native American Ancestry and 15-Year Cognitive Trajectory: Bambui Study, Brazil.

J Am Geriatr Soc 2018 10 17;66(10):1956-1962. Epub 2018 Sep 17.

Instituto de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Brazil.

Objectives: To investigate the association between African and Native American genomic ancestry and long-term cognitive trajectories in admixed Brazilians.

Design: Population-based longitudinal study.

Setting: Bambui-Epigen (Brazil) cohort study.

Participants: Adults aged 60 and older (N=1,215) MEASUREMENTS: Participants were followed from January 1997 to December 2011. Cognitive function was assessed annually using the Mini-Mental State Examination (MMSE), totaling 12,208 measurements. We used linear mixed-effects pattern models to assess MMSE score trajectories. Ancestry was assessed using a genome-wide approach.

Results: After adjustments for covariates, the highest quintile of African ancestry was associated with poorer baseline cognitive performance (β=-0.73, 95% confidence interval (CI)=-1.36 to -0.11) but not with cognitive trajectory. Educational level modified the baseline association between highest African ancestry and cognitive performance in that the association was observed only in those with very low (<4 years) education (β=-1.13, 95% CI=-2.02 to -0.23). No association was found between Native American ancestry and baseline cognitive function or its trajectory.

Conclusion: Genomic African and Native American ancestry levels had no prognostic value for age-related cognitive decline in this admixed population.
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http://dx.doi.org/10.1111/jgs.15504DOI Listing
October 2018

Interethnic Variability in CYP2D6, CYP2C9, and CYP2C19 Genes and Predicted Drug Metabolism Phenotypes Among 6060 Ibero- and Native Americans: RIBEF-CEIBA Consortium Report on Population Pharmacogenomics.

OMICS 2018 09 11;22(9):575-588. Epub 2018 Sep 11.

1 RIBEF Ibero-American Network of Pharmacogenetics and Pharmacogenomics , Badajoz, Spain .

Pharmacogenetic variation in Latin Americans is understudied, which sets a barrier for the goal of global precision medicine. The RIBEF-CEIBA Network Consortium was established to characterize interindividual and between population variations in CYP2D6, CYP2C9, and CYP2C19 drug metabolizing enzyme genotypes, which were subsequently utilized to catalog their "predicted drug metabolism phenotypes" across Native American and Ibero American populations. Importantly, we report in this study, a total of 6060 healthy individuals from Ibero-America who were classified according to their self-reported ancestry: 1395 Native Americans, 2571 Admixed Latin Americans, 96 Afro-Latin Americans, 287 white Latin Americans (from Cuba), 1537 Iberians, and 174 Argentinean Ashkenazi Jews. Moreover, Native Americans were grouped into North-, Central-, and South Amerindians (from Mexico, Costa Rica, and Peru, respectively). All subjects were studied for the most common and functional CYP2D6, CYP2C9, and CYP2C19 allelic variants, and grouped as genotype-predicted poor or ultrarapid metabolizer phenotypes (gPMs and gUMs, respectively). Native Americans showed differences from each ethnic group in at least two alleles of CYP2D6, CYP2C9, and CYP2C19. Native Americans had higher frequencies of wild-type alleles for all genes, and lower frequency of CYP2D6*41, CYP2C9*2, and CYP2C19*17 (p < 0.05). Native Americans also showed less CYP2C19 gUMs than the rest of the population sample. In addition, differences within Native Americans (mostly North vs. South) were also found. The interethnic differences described supports the need for population-specific personalized and precision medicine programs for Native Americans. To the best of our knowledge, this is the largest study carried out in Native Americans and other Ibero-American populations analyzing CYP2D6, CYP2C9, and CYP2C19 genetic polymorphisms. Population pharmacogenomics is a nascent field of global health and warrants further research and education.
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http://dx.doi.org/10.1089/omi.2018.0114DOI Listing
September 2018

Evolutionary genomic dynamics of Peruvians before, during, and after the Inca Empire.

Proc Natl Acad Sci U S A 2018 07 26;115(28):E6526-E6535. Epub 2018 Jun 26.

Laboratorio de Biotecnología y Biología Molecular, Instituto Nacional de Salud, Lima 11, Perú;

Native Americans from the Amazon, Andes, and coastal geographic regions of South America have a rich cultural heritage but are genetically understudied, therefore leading to gaps in our knowledge of their genomic architecture and demographic history. In this study, we sequence 150 genomes to high coverage combined with an additional 130 genotype array samples from Native American and mestizo populations in Peru. The majority of our samples possess greater than 90% Native American ancestry, which makes this the most extensive Native American sequencing project to date. Demographic modeling reveals that the peopling of Peru began ∼12,000 y ago, consistent with the hypothesis of the rapid peopling of the Americas and Peruvian archeological data. We find that the Native American populations possess distinct ancestral divisions, whereas the mestizo groups were admixtures of multiple Native American communities that occurred before and during the Inca Empire and Spanish rule. In addition, the mestizo communities also show Spanish introgression largely following Peruvian Independence, nearly 300 y after Spain conquered Peru. Further, we estimate migration events between Peruvian populations from all three geographic regions with the majority of between-region migration moving from the high Andes to the low-altitude Amazon and coast. As such, we present a detailed model of the evolutionary dynamics which impacted the genomes of modern-day Peruvians and a Native American ancestry dataset that will serve as a beneficial resource to addressing the underrepresentation of Native American ancestry in sequencing studies.
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http://dx.doi.org/10.1073/pnas.1720798115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048481PMC
July 2018

EPIGEN-Brazil Initiative resources: a Latin American imputation panel and the Scientific Workflow.

Genome Res 2018 07 14;28(7):1090-1095. Epub 2018 Jun 14.

Departamento de Biologia Geral, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil.

EPIGEN-Brazil is one of the largest Latin American initiatives at the interface of human genomics, public health, and computational biology. Here, we present two resources to address two challenges to the global dissemination of precision medicine and the development of the bioinformatics know-how to support it. To address the underrepresentation of non-European individuals in human genome diversity studies, we present the EPIGEN-5M+1KGP imputation panel-the fusion of the public 1000 Genomes Project (1KGP) Phase 3 imputation panel with haplotypes derived from the EPIGEN-5M data set (a product of the genotyping of 4.3 million SNPs in 265 admixed individuals from the EPIGEN-Brazil Initiative). When we imputed a target SNPs data set (6487 admixed individuals genotyped for 2.2 million SNPs from the EPIGEN-Brazil project) with the EPIGEN-5M+1KGP panel, we gained 140,452 more SNPs in total than when using the 1KGP Phase 3 panel alone and 788,873 additional high confidence SNPs ( ≥ 0.8). Thus, the major effect of the inclusion of the EPIGEN-5M data set in this new imputation panel is not only to gain more SNPs but also to improve the quality of imputation. To address the lack of transparency and reproducibility of bioinformatics protocols, we present a conceptual Scientific Workflow in the form of a website that models the scientific process (by including publications, flowcharts, masterscripts, documents, and bioinformatics protocols), making it accessible and interactive. Its applicability is shown in the context of the development of our EPIGEN-5M+1KGP imputation panel. The Scientific Workflow also serves as a repository of bioinformatics resources.
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http://dx.doi.org/10.1101/gr.225458.117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028131PMC
July 2018

Biogeographical ancestry is associated with socioenvironmental conditions and infections in a Latin American urban population.

SSM Popul Health 2018 Apr 17;4:301-306. Epub 2018 Mar 17.

Institute of Collective Health, Federal University of Bahia, Salvador, Bahia, Brazil.

Racial inequalities are observed for different diseases and are mainly caused by differences in socioeconomic status between ethnoracial groups. Genetic factors have also been implicated, and recently, several studies have investigated the association between biogeographical ancestry (BGA) and complex diseases. However, the role of BGA as a proxy for non-genetic health determinants has been little investigated. Similarly, studies comparing the association of BGA and self-reported skin colour with these determinants are scarce. Here, we report the association of BGA and self-reported skin colour with socioenvironmental conditions and infections. We studied 1246 children living in a Brazilian urban poor area. The BGA was estimated using 370,539 genome-wide autosomal markers. Standardised questionnaires were administered to the children's guardians to evaluate socioenvironmental conditions. Infection (or pathogen exposure) was defined by the presence of positive serologic test results for IgG to seven pathogens (T, , and hepatitis A, herpes simplex, herpes zoster and Epstein-Barr viruses) and the presence of intestinal helminth eggs in stool samples (scaris and ). African ancestry was negatively associated with maternal education and household income and positively associated with infections and variables, indicating poorer housing and living conditions. The self-reported skin colour was associated with infections only. In stratified analyses, the proportion of African ancestry was associated with most of the outcomes investigated, particularly among admixed individuals. In conclusion, BGA was associated with socioenvironmental conditions and infections even in a low-income and highly admixed population, capturing differences that self-reported skin colour miss. Importantly, our findings suggest caution in interpreting significant associations between BGA and diseases as indicative of the genetic factors involved.
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http://dx.doi.org/10.1016/j.ssmph.2018.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976841PMC
April 2018

Genetic structure of pharmacogenetic biomarkers in Brazil inferred from a systematic review and population-based cohorts: a RIBEF/EPIGEN-Brazil initiative.

Pharmacogenomics J 2018 12 1;18(6):749-759. Epub 2018 May 1.

Departamento de Biologia Geral, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.

We present allele frequencies involving 39 pharmacogenetic biomarkers studied in Brazil, and their distribution on self-reported race/color categories that: (1) involve a mix of perceptions about ancestry, morphological traits, and cultural/identity issues, being social constructs pervasively used in Brazilian society and medical studies; (2) are associated with disparities in access to health services, as well as in their representation in genetic studies, and (3), as we report here, explain a larger portion of the variance of pharmaco-allele frequencies than geography. We integrated a systematic review of studies on healthy volunteers (years 1968-2017) and the analysis of allele frequencies on three population-based cohorts from northeast, southeast, and south, the most populated regions of Brazil. Cross-validation of results from these both approaches suggest that, despite methodological heterogeneity of the 120 studies conducted on 51,747 healthy volunteers, allele frequencies estimates from systematic review are reliable. We report differences in allele frequencies between color categories that persist despite the homogenizing effect of >500 years of admixture. Among clinically relevant variants: CYP2C9*2 (null), CYP3A5*3 (defective), SLCO1B1-rs4149056(C), and VKORC1-rs9923231(A) are more frequent in Whites than in Blacks. Brazilian Native Americans show lower frequencies of CYP2C9*2, CYP2C19*17 (increased activity), and higher of SLCO1B1-rs4149056(C) than other Brazilian populations. We present the most current and informative database of pharmaco-allele frequencies in Brazilian healthy volunteers.
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http://dx.doi.org/10.1038/s41397-018-0015-7DOI Listing
December 2018
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