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1.
JAMA ; 322(17): 1682-1691, 2019 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-31688885

RESUMO

Importance: Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders. Objectives: To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma. Design, Settings, and Participants: A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma. Exposures: Genetic variants associated with primary open-angle glaucoma. Main Outcomes and Measures: Presence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 × 10-8 in the discovery stage and in the meta-analysis of combined discovery and validation data. Results: A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-ß A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T>C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10-13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry. Conclusions and Relevance: In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Grupo com Ancestrais do Continente Africano/genética , Estudo de Associação Genômica Ampla , Glaucoma de Ângulo Aberto/etnologia , Glaucoma de Ângulo Aberto/genética , Polimorfismo de Nucleotídeo Único , Idoso , Peptídeos beta-Amiloides/genética , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Imuno-Histoquímica , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Fatores de Risco
3.
Braz J Med Biol Res ; 52(11): e8549, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31664304

RESUMO

The published data on the association between MCP-1 -2518A>G polymorphism and asthma susceptibility are inconclusive. Therefore, we performed a meta-analysis to estimate the impact of MCP-1 -2518A>G polymorphism on asthma susceptibility. PubMed, Web of Science, Wanfang, and China National Knowledge Infrastructure (CNKI) databases were used to identify eligible studies. The pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were used to calculate the strength of association. Sensitivity analysis was performed to evaluate the influence of individual studies on the estimates of overall effect, and funnel plots and Egger's test were used to assess publication bias. Eight publications with 1562 asthma patients and 1574 controls were finally identified. Overall, we found no significant association between MCP-1 -2518A>G polymorphism and asthma susceptibility in any of the genetic model comparisons. After stratified analysis by ethnicity, the results showed that a significant association with asthma risk was found in Caucasians in all the genetic models. However, a protective association was found in Africans under the dominant model. The present meta-analysis suggested that the MCP-1 -2518 A>G polymorphism is a risk factor for asthma in the Caucasian population, nevertheless it has a protective effect in the African population.


Assuntos
Asma/genética , Quimiocina CCL2/genética , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Polimorfismo Genético/genética , Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Europeu/genética , Frequência do Gene/genética , Humanos , Fatores de Proteção , Fatores de Risco
4.
Niger Postgrad Med J ; 26(4): 195-198, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31621657

RESUMO

Background: The presence of human leukocyte antigen (HLA) B*57:01 allele predicts hypersensitivity reaction (HSR) to abacavir (ABC), a nucleoside reverse-transcriptase inhibitor used for human immunodeficiency virus (HIV) treatment. However, the prevalence of this allele amongst Nigerians with HIV is yet to be established. We aimed to determine the prevalence of HLA-B*57:01 allele amongst Nigerians with HIV infection. Methods: We conducted a multicentre cross-sectional epidemiologic survey. Between April 2016 and April 2017, patients were enrolled across five HIV treatment facilities in Nigeria. Participants' demographic information and their history of ABC exposure were obtained, and venous blood was obtained for HLA typing. Results: One thousand five hundred and four (1504) adults were enrolled, with a mean age of 44.6 ± 10.7 years, 1078 (71.7%) were female. 1463 (97.3%) were on antiretroviral therapy. ABC use was reported by 12 (0.8%) participants and none reported HSR. Of 1500 blood samples that were processed, 1458 (97.2%) were successfully typed. Of these, 132 (9.1%) were HLA-B*57 positive using non-specific low-resolution HLA-B*5701 primer mix. On further analysis, none of the 132 samples (0%) had the HLA-B*5701 allele. Conclusion: HLA-B*5701allele is rare amongst Nigerians.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Didesoxinucleosídeos/uso terapêutico , Hipersensibilidade a Drogas/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Antígenos HLA-B/genética , Inibidores da Transcriptase Reversa/uso terapêutico , Adulto , Grupo com Ancestrais do Continente Africano/genética , Idoso , Estudos Transversais , Didesoxinucleosídeos/efeitos adversos , Hipersensibilidade a Drogas/epidemiologia , Hipersensibilidade a Drogas/genética , Feminino , Infecções por HIV/epidemiologia , Infecções por HIV/genética , Antígenos HLA-B/sangue , Antígenos HLA-B/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Nigéria/epidemiologia , Prevalência , Inibidores da Transcriptase Reversa/efeitos adversos
6.
Genome Biol ; 20(1): 149, 2019 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-31366358

RESUMO

The human reference genome is still incomplete, especially for those population-specific or individual-specific regions, which may have important functions. Here, we developed a HUman Pan-genome ANalysis (HUPAN) system to build the human pan-genome. We applied it to 185 deep sequencing and 90 assembled Han Chinese genomes and detected 29.5 Mb novel genomic sequences and at least 188 novel protein-coding genes missing in the human reference genome (GRCh38). It can be an important resource for the human genome-related biomedical studies, such as cancer genome analysis. HUPAN is freely available at http://cgm.sjtu.edu.cn/hupan/ and https://github.com/SJTU-CGM/HUPAN .


Assuntos
Genoma Humano , Software , Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Asiático/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Proteínas/genética , Análise de Sequência de DNA
7.
Hum Genet ; 138(10): 1123-1142, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31312899

RESUMO

The study of runs of homozygosity (ROH) can shed light on population demographic history and cultural practices. We present a fine-scale ROH analysis of 1679 individuals from 28 sub-Saharan African (SSA) populations along with 1384 individuals from 17 worldwide populations. Using high-density SNP coverage, we could accurately identify ROH > 300 kb using PLINK software. The genomic distribution of ROH was analysed through the identification of ROH islands and regions of heterozygosity (RHZ). The analyses showed a heterogeneous distribution of autozygosity across SSA, revealing complex demographic histories. They highlight differences between African groups and can differentiate the impact of consanguineous practices (e.g. among the Somali) from endogamy (e.g. among several Khoe and San groups). Homozygosity cold and hotspots were shown to harbour multiple protein coding genes. Studying ROH therefore not only sheds light on population history, but can also be used to study genetic variation related to adaptation and potentially to the health of extant populations.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Genética Populacional , Homozigoto , África ao Sul do Saara , Consanguinidade , Cruzamentos Genéticos , Análise de Dados , Demografia , Variação Genética , Genômica/métodos , Geografia , Humanos
8.
Hum Genet ; 138(10): 1155-1169, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31342140

RESUMO

Vitamin D inadequacy, assessed by 25-hydroxyvitamin D [25(OH)D], affects around 50% of adults in the United States and is associated with numerous adverse health outcomes. Blood 25(OH)D concentrations are influenced by genetic factors that may determine how much vitamin D intake is required to reach optimal 25(OH)D. Despite large genome-wide association studies (GWASs), only a small portion of the genetic factors contributing to differences in 25(OH)D has been discovered. Therefore, knowledge of a fuller set of genetic factors could be useful for risk prediction of 25(OH)D inadequacy, personalized vitamin D supplementation, and prevention of downstream morbidity and mortality. Using PRSice and weights from published African- and European-ancestry GWAS summary statistics, ancestry-specific polygenic scores (PGSs) were created to capture a more complete set of genetic factors in those of European (n = 9569) or African ancestry (n = 2761) from three cohort studies. The PGS for African ancestry was derived using all input SNPs (a p value cutoff of 1.0) and had an R2 of 0.3%; for European ancestry, the optimal PGS used a p value cutoff of 3.5 × 10-4 in the target/tuning dataset and had an R2 of 1.0% in the validation cohort. Those with highest genetic risk had 25(OH)D that was 2.8-3.0 ng/mL lower than those with lowest genetic risk (p = 0.0463-3.2 × 10-13), requiring an additional 467-500 IU of vitamin D intake to maintain equivalent 25(OH)D. PGSs are a powerful predictive tool that could be leveraged for personalized vitamin D supplementation to prevent the negative downstream effects of 25(OH)D inadequacy.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Europeu/genética , Genética Populacional , Padrões de Herança , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Vitamina D/análogos & derivados , Estudos de Coortes , Bases de Dados Genéticas , Suplementos Nutricionais , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Raios Ultravioleta , Vitamina D/sangue
9.
Int J Pediatr Otorhinolaryngol ; 124: 157-160, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31200317

RESUMO

INTRODUCTION: DFNB1, caused by mutations of GJB2 or GJB6, is the most prevalent genetic form of nonsyndromic (i.e., isolated) congenital deafness in countries located around the Mediterranean Sea. Because some mutations are restricted to specific ethnic-geographic groups, we studied the prevalence and spectrum of GJB2/GJB6 mutations in deaf patients originating from two different Algerian regions, Kabylie and Sahara. PATIENTS AND METHODS: Among 91 reportedly unrelated Algerian patients affected by prelingual deafness, 80 patients (41 from Kabylie and 39 from Sahara) were diagnosed with isolated deafness. All had profound deafness, except one patient with mild deafness. They were screened for the presence of GJB2 mutations by direct sequencing of the single coding exon of GJB2. Patients without mutations were then screened for the presence of the most frequent two deletions of GJB6: del(GJB6-D13S1854) and del(GJB6-D13S1830). RESULTS: Causative mutations were found in 13 and 8 patients from Kabylie and Sahara, respectively, accounting for more than a quarter of the cohort. The c.35delG, p.Gly12Valfs*2 mutation remains the most important mutation both in Kabylie (10 patients) and Sahara (7 patients). All detected patients were homozygous for this mutation. In addition, two other mutations (c.139G > T, p.Glu47* and c.167delT, p.Leu56Argfs*26) were found homozygous in one family each, and two patients were compound heterozygotes for (c.35delG p.Gly12Valfs*2/c.139G > T, p.Glu47*). No deletion of GJB6 was detected. CONCLUSION: We confirm that mutations in GJB2, mainly c.35delG, are one of the most prevalent causes of nonsyndromic congenital deafness in Algeria, whereas the del (GJB6-D13S1854) and del (GJB6-D13S1830) deletions of GJB6 contribute little, if any. Further investigation is needed to identify the cause of deafness in other patients without diagnostic.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Conexina 30/genética , Conexinas/genética , Surdez/etnologia , Surdez/genética , Mutação/genética , Adolescente , Adulto , Argélia , Criança , Pré-Escolar , Estudos de Coortes , Éxons/genética , Feminino , Homozigoto , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Prevalência , Adulto Jovem
10.
Ann Hum Biol ; 46(2): 129-139, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31163991

RESUMO

Context: Africa's role in the narrative of human evolution is indisputably emphasised in the emergence of Homo sapiens. However, once humans dispersed beyond Africa, the history of those who stayed remains vastly under-studied, lacking the proper attention the birthplace of both modern and archaic humans deserves. The sequencing of Neanderthal and Denisovan genomes has elucidated evidence of admixture between archaic and modern humans outside of Africa, but has not aided efforts in answering whether archaic admixture happened within Africa. Objectives: This article reviews the state of research for archaic introgression in African populations and discusses recent insights into this topic. Methods: Gathering published sources and recently released preprints, this review reports on the different methods developed for detecting archaic introgression. Particularly it discusses how relevant these are when implemented on African populations and what findings these studies have shown so far. Results: Methods for detecting archaic introgression have been predominantly developed and implemented on non-African populations. Recent preprints present new methods considering African populations. While a number of studies using these methods suggest archaic introgression in Africa, without an African archaic genome to validate these results, such findings remain as putative archaic introgression. Conclusion: In light of the caveats with implementing current archaic introgression detection methods in Africa, we recommend future studies to concentrate on unravelling the complicated demographic history of Africa through means of ancient DNA where possible and through more focused efforts to sequence modern DNA from more representative populations across the African continent.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , DNA Antigo/análise , Hominidae/genética , Hibridização Genética , África , Animais , Genoma Humano , Humanos
11.
PLoS Genet ; 15(6): e1008204, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31181058

RESUMO

We learn about population history and underlying evolutionary biology through patterns of genetic polymorphism. Many approaches to reconstruct evolutionary histories focus on a limited number of informative statistics describing distributions of allele frequencies or patterns of linkage disequilibrium. We show that many commonly used statistics are part of a broad family of two-locus moments whose expectation can be computed jointly and rapidly under a wide range of scenarios, including complex multi-population demographies with continuous migration and admixture events. A full inspection of these statistics reveals that widely used models of human history fail to predict simple patterns of linkage disequilibrium. To jointly capture the information contained in classical and novel statistics, we implemented a tractable likelihood-based inference framework for demographic history. Using this approach, we show that human evolutionary models that include archaic admixture in Africa, Asia, and Europe provide a much better description of patterns of genetic diversity across the human genome. We estimate that an unidentified, deeply diverged population admixed with modern humans within Africa both before and after the split of African and Eurasian populations, contributing 4 - 8% genetic ancestry to individuals in world-wide populations.


Assuntos
Evolução Molecular , Genética Populacional , Genoma Humano/genética , Hominidae/genética , África/epidemiologia , Grupo com Ancestrais do Continente Africano/genética , Animais , Ásia/epidemiologia , Europa (Continente)/epidemiologia , Fluxo Gênico/genética , Frequência do Gene , Humanos , Funções Verossimilhança , Desequilíbrio de Ligação , Modelos Genéticos , Polimorfismo Genético/genética
12.
PLoS Genet ; 15(4): e1008045, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31002671

RESUMO

Quantification of gene expression levels at the single cell level has revealed that gene expression can vary substantially even across a population of homogeneous cells. However, it is currently unclear what genomic features control variation in gene expression levels, and whether common genetic variants may impact gene expression variation. Here, we take a genome-wide approach to identify expression variance quantitative trait loci (vQTLs). To this end, we generated single cell RNA-seq (scRNA-seq) data from induced pluripotent stem cells (iPSCs) derived from 53 Yoruba individuals. We collected data for a median of 95 cells per individual and a total of 5,447 single cells, and identified 235 mean expression QTLs (eQTLs) at 10% FDR, of which 79% replicate in bulk RNA-seq data from the same individuals. We further identified 5 vQTLs at 10% FDR, but demonstrate that these can also be explained as effects on mean expression. Our study suggests that dispersion QTLs (dQTLs) which could alter the variance of expression independently of the mean can have larger fold changes, but explain less phenotypic variance than eQTLs. We estimate 4,015 individuals as a lower bound to achieve 80% power to detect the strongest dQTLs in iPSCs. These results will guide the design of future studies on understanding the genetic control of gene expression variance.


Assuntos
Células-Tronco Pluripotentes Induzidas/metabolismo , Locos de Características Quantitativas , Grupo com Ancestrais do Continente Africano/genética , Linhagem Celular , Simulação por Computador , Perfilação da Expressão Gênica , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Modelos Genéticos , Nigéria , Fenótipo , Análise de Sequência de RNA , Análise de Célula Única
13.
Genome Biol ; 20(1): 82, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31023338

RESUMO

BACKGROUND: Africa is the origin of modern humans within the past 300 thousand years. To infer the complex demographic history of African populations and adaptation to diverse environments, we sequenced the genomes of 92 individuals from 44 indigenous African populations. RESULTS: Genetic structure analyses indicate that among Africans, genetic ancestry is largely partitioned by geography and language, though we observe mixed ancestry in many individuals, consistent with both short- and long-range migration events followed by admixture. Phylogenetic analysis indicates that the San genetic lineage is basal to all modern human lineages. The San and Niger-Congo, Afroasiatic, and Nilo-Saharan lineages were substantially diverged by 160 kya (thousand years ago). In contrast, the San and Central African rainforest hunter-gatherer (CRHG), Hadza hunter-gatherer, and Sandawe hunter-gatherer lineages were diverged by ~ 120-100 kya. Niger-Congo, Nilo-Saharan, and Afroasiatic lineages diverged more recently by ~ 54-16 kya. Eastern and western CRHG lineages diverged by ~ 50-31 kya, and the western CRHG lineages diverged by ~ 18-12 kya. The San and CRHG populations maintained the largest effective population size compared to other populations prior to 60 kya. Further, we observed signatures of positive selection at genes involved in muscle development, bone synthesis, reproduction, immune function, energy metabolism, and cell signaling, which may contribute to local adaptation of African populations. CONCLUSIONS: We observe high levels of genomic variation between ethnically diverse Africans which is largely correlated with geography and language. Our study indicates ancient population substructure and local adaptation of Africans.


Assuntos
Adaptação Biológica , Grupo com Ancestrais do Continente Africano/genética , Evolução Biológica , Filogenia , Densidade Demográfica , África , Genoma Humano , Migração Humana , Humanos , Filogeografia
14.
Nat Commun ; 10(1): 1671, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30975994

RESUMO

Host and environmental factors contribute to variation in human immune responses, yet the genetic and evolutionary drivers of alternative splicing in response to infection remain largely uncharacterised. Leveraging 970 RNA-sequencing profiles of resting and stimulated monocytes from 200 individuals of African- and European-descent, we show that immune activation elicits a marked remodelling of the isoform repertoire, while increasing the levels of erroneous splicing. We identify 1,464 loci associated with variation in isoform usage (sQTLs), 9% of them being stimulation-specific, which are enriched in disease-related loci. Furthermore, we detect a longstanding increased plasticity of immune gene splicing, and show that positive selection and Neanderthal introgression have both contributed to diversify the splicing landscape of human populations. Together, these findings suggest that differential isoform usage has been an important substrate of innovation in the long-term evolution of immune responses and a more recent vehicle of population local adaptation.


Assuntos
Processamento Alternativo/imunologia , Imunidade/genética , Infecção/imunologia , Seleção Genética/imunologia , Transcriptoma/imunologia , Grupo com Ancestrais do Continente Africano/genética , Animais , Evolução Biológica , Grupo com Ancestrais do Continente Europeu/genética , Variação Genética/imunologia , Voluntários Saudáveis , Humanos , Masculino , Homem de Neandertal/genética , Polimorfismo de Nucleotídeo Único , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Locos de Características Quantitativas/imunologia , Análise de Sequência de RNA , Sequenciamento Completo do Exoma
16.
Genome Biol ; 20(1): 77, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31023378

RESUMO

BACKGROUND: Population demography and gene flow among African groups, as well as the putative archaic introgression of ancient hominins, have been poorly explored at the genome level. RESULTS: Here, we examine 15 African populations covering all major continental linguistic groups, ecosystems, and lifestyles within Africa through analysis of whole-genome sequence data of 21 individuals sequenced at deep coverage. We observe a remarkable correlation among genetic diversity and geographic distance, with the hunter-gatherer groups being more genetically differentiated and having larger effective population sizes throughout most modern-human history. Admixture signals are found between neighbor populations from both hunter-gatherer and agriculturalists groups, whereas North African individuals are closely related to Eurasian populations. Regarding archaic gene flow, we test six complex demographic models that consider recent admixture as well as archaic introgression. We identify the fingerprint of an archaic introgression event in the sub-Saharan populations included in the models (~ 4.0% in Khoisan, ~ 4.3% in Mbuti Pygmies, and ~ 5.8% in Mandenka) from an early divergent and currently extinct ghost modern human lineage. CONCLUSION: The present study represents an in-depth genomic analysis of a Pan African set of individuals, which emphasizes their complex relationships and demographic history at population level.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Fluxo Gênico , Migração Humana , África , Variação Genética , Humanos , Filogeografia , Densidade Demográfica , Sequenciamento Completo do Genoma
17.
BMC Bioinformatics ; 20(1): 116, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30845922

RESUMO

BACKGROUND: Principal component analysis (PCA) is a standard method to correct for population stratification in ancestry-specific genome-wide association studies (GWASs) and is used to cluster individuals by ancestry. Using the 1000 genomes project data, we examine how non-linear dimensionality reduction methods such as t-distributed stochastic neighbor embedding (t-SNE) or generative topographic mapping (GTM) can be used to provide improved ancestry maps by accounting for a higher percentage of explained variance in ancestry, and how they can help to estimate the number of principal components necessary to account for population stratification. GTM generates posterior probabilities of class membership which can be used to assess the probability of an individual to belong to a given population - as opposed to t-SNE, GTM can be used for both clustering and classification. RESULTS: PCA only partially identifies population clusters and does not separate most populations within a given continent, such as Japanese and Han Chinese in East Asia, or Mende and Yoruba in Africa. t-SNE and GTM, taking into account more data variance, can identify more fine-grained population clusters. GTM can be used to build probabilistic classification models, and is as efficient as support vector machine (SVM) for classifying 1000 Genomes Project populations. CONCLUSION: The main interest of probabilistic GTM maps is to attain two objectives with only one map: provide a better visualization that separates populations efficiently, and infer genetic ancestry for individuals or populations. This paper is a first application of GTM for ancestry classification models. Our code ( https://github.com/hagax8/ancestry_viz ) and interactive visualizations ( https://lovingscience.com/ancestries ) are available online.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Asiático/genética , Genética Populacional , Modelos Estatísticos , Arabidopsis/genética , Análise por Conglomerados , Estudo de Associação Genômica Ampla , Humanos , Análise de Componente Principal , Processos Estocásticos
18.
Fertil Steril ; 111(5): 1011-1019.e1, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30926125

RESUMO

OBJECTIVE: To study whether there is a difference in the prevalence of non-cavity-distorting uterine fibroids between infertile patients with polycystic ovary syndrome (PCOS) and those with unexplained infertility (UI). DESIGN: A secondary analysis of data from three randomized clinical trials. SETTING: Academic health centers. PATIENT(S): A total of 2,249 patients with normal uterine cavities. INTERVENTIONS(S): None. MAIN OUTCOME MEASURE(S): The presence or absence of non-cavity-distorting fibroids. RESULT(S): Compared with women with UI, those with PCOS were younger, had a higher body mass index, and were more likely to be Hispanic or African American, with a lower percentage of previous conception and live birth, a higher percentage of current smokers, a lower percentage of current alcohol users, and higher total testosterone, fasting insulin, and homeostasis-model-assessment insulin resistance. The prevalence of women with non-cavity-distorting uterine fibroids was lower in women with PCOS than in those with UI (6.7% vs. 12.4%); this result held after patients were divided into Black and non-Black or into three different body mass index groups. After adjustment for all the other variables in the final model, patients with PCOS had a significantly lower prevalence of fibroids than those with UI (odds ratio 0.54). No differences in the prevalence of non-cavity-distorting fibroids with any dimensions ≥4 cm or the volume of the largest fibroid was found between the two groups. CONCLUSION(S): A lower prevalence of non-cavity-distorting uterine fibroids was found in infertile women with PCOS than in those with UI.


Assuntos
Infertilidade Feminina/diagnóstico , Infertilidade Feminina/epidemiologia , Leiomioma/diagnóstico , Leiomioma/epidemiologia , Síndrome do Ovário Policístico/diagnóstico , Síndrome do Ovário Policístico/epidemiologia , Adulto , Grupo com Ancestrais do Continente Africano/genética , Método Duplo-Cego , Feminino , Humanos , Infertilidade Feminina/genética , Leiomioma/genética , Síndrome do Ovário Policístico/genética , Prevalência
19.
Gene ; 696: 186-196, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30790653

RESUMO

The COMT gene encodes for catechol-O-methyl-transferase, an enzyme playing a major role in regulation of synaptic catecholamine neurotransmitters. Investigating 4 markers of the COMT gene (rs2020917, rs4818, rs4680, rs9332377) in 6 Tunisian populations and a pool of Libyans. Our objective was to determine the distribution of allelic, genotypic and haplotypic frequencies by comparison to other populations of the 1000 genomes project and 59 populations from the Kidd Lab dataset. The allelic frequencies established for these SNPs in the North African populations are similar to those of Europeans and South Asians. Linkage disequilibrium between these SNPs and haplotypes frequencies are different between populations whose clustering in principal components analysis (PCA) according to their geographic origin was more significant using haplotypic frequencies. COMT activity prediction by haplotypes genotyping could be limited to rs4818-rs4680 micro-haplotypes. The Low activity haplotype (CG) displays the highest frequency in African populations (55%), in the 59 Kidd Lab populations we found also that Sub-Saharan Africans, Native Americans, and some East Asian and Pacific Island populations all have frequencies in the 50-81% range for (CG) where as its lowest frequency was found in Europeans (10%), this results have been also confirmed for Southwest Asians. North Africans and South Asians with intermediate frequencies have approximately similar values (20% and 25%). Europeans show the highest frequencies of haplotypes with predicted High and Medium activity in contrast to Africans. North Africans and South Asians present similar results for all the category of the COMT activity prediction by haplotypes genotyping. The high level of genetic diversity of COMT haplotypes, not only allows distinction between populations according to their history settlement, origin and ethnicity, it constitutes a basis for studies of association of the COMT gene polymorphism with pathologies, drugs response and for forensic investigation in North African populations.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Catecol O-Metiltransferase/genética , Frequência do Gene/genética , Desequilíbrio de Ligação/genética , Polimorfismo de Nucleotídeo Único/genética , Aclimatação/genética , África do Norte , Alelos , Catecol O-Metiltransferase/metabolismo , Genética Forense/métodos , Haplótipos/genética , Voluntários Saudáveis , Humanos , Farmacogenética/métodos
20.
Proc Natl Acad Sci U S A ; 116(9): 3712-3721, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30733285

RESUMO

Two coding variants in the apolipoprotein L1 (APOL1) gene (termed G1 and G2) are strongly associated with increased risk of nondiabetic kidney disease in people of recent African ancestry. The mechanisms by which the risk variants cause kidney damage, although not well-understood, are believed to involve injury to glomerular podocytes. The intracellular localization and function of APOL1 in podocytes remain unclear, with recent studies suggesting possible roles in the endoplasmic reticulum (ER), mitochondria, endosomes, lysosomes, and autophagosomes. Here, we demonstrate that APOL1 also localizes to intracellular lipid droplets (LDs). While a large fraction of risk variant APOL1 (G1 and G2) localizes to the ER, a significant proportion of wild-type APOL1 (G0) localizes to LDs. APOL1 transiently interacts with numerous organelles, including the ER, mitochondria, and endosomes. Treatment of cells that promote LD formation with oleic acid shifted the localization of G1 and G2 from the ER to LDs, with accompanying reduction of autophagic flux and cytotoxicity. Coexpression of G0 APOL1 with risk variant APOL1 enabled recruitment of G1 and G2 from the ER to LDs, accompanied by reduced cell death. The ability of G0 APOL1 to recruit risk variant APOL1 to LDs may help explain the recessive pattern of kidney disease inheritance. These studies establish APOL1 as a bona fide LD-associated protein, and reveal that recruitment of risk variant APOL1 to LDs reduces cell toxicity, autophagic flux, and cell death. Thus, interventions that divert APOL1 risk variants to LDs may serve as a novel therapeutic strategy to alleviate their cytotoxic effects.


Assuntos
Apolipoproteína L1/genética , Autofagia/genética , Nefropatias/genética , Gotículas Lipídicas/metabolismo , Grupo com Ancestrais do Continente Africano/genética , Retículo Endoplasmático/genética , Endossomos/genética , Variação Genética , Células HEK293 , Humanos , Rim/lesões , Rim/patologia , Nefropatias/fisiopatologia , Gotículas Lipídicas/patologia , Lisossomos/genética , Podócitos/metabolismo , Podócitos/patologia , Fatores de Risco
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