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1.
BMC Bioinformatics ; 22(1): 12, 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33407074

RESUMO

BACKGROUND: Multi-locus genotype data are widely used in population genetics and disease studies. In evaluating the utility of multi-locus data, the independence of markers is commonly considered in many genomic assessments. Generally, pairwise non-random associations are tested by linkage disequilibrium; however, the dependence of one panel might be triplet, quartet, or other. Therefore, a compatible and user-friendly software is necessary for testing and assessing the global linkage disequilibrium among mixed genetic data. RESULTS: This study describes a software package for testing the mutual independence of mixed genetic datasets. Mutual independence is defined as no non-random associations among all subsets of the tested panel. The new R package "mixIndependR" calculates basic genetic parameters like allele frequency, genotype frequency, heterozygosity, Hardy-Weinberg equilibrium, and linkage disequilibrium (LD) by mutual independence from population data, regardless of the type of markers, such as simple nucleotide polymorphisms, short tandem repeats, insertions and deletions, and any other genetic markers. A novel method of assessing the dependence of mixed genetic panels is developed in this study and functionally analyzed in the software package. By comparing the observed distribution of two common summary statistics (the number of heterozygous loci [K] and the number of share alleles [X]) with their expected distributions under the assumption of mutual independence, the overall independence is tested. CONCLUSION: The package "mixIndependR" is compatible to all categories of genetic markers and detects the overall non-random associations. Compared to pairwise disequilibrium, the approach described herein tends to have higher power, especially when number of markers is large. With this package, more multi-functional or stronger genetic panels can be developed, like mixed panels with different kinds of markers. In population genetics, the package "mixIndependR" makes it possible to discover more about admixture of populations, natural selection, genetic drift, and population demographics, as a more powerful method of detecting LD. Moreover, this new approach can optimize variants selection in disease studies and contribute to panel combination for treatments in multimorbidity. Application of this approach in real data is expected in the future, and this might bring a leap in the field of genetic technology. AVAILABILITY: The R package mixIndependR, is available on the Comprehensive R Archive Network (CRAN) at: https://cran.r-project.org/web/packages/mixIndependR/index.html .


Assuntos
Loci Gênicos/genética , Genômica/métodos , Software , Bases de Dados Genéticas , Genótipo , Desequilíbrio de Ligação/genética
2.
Gene ; 766: 145158, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-32949694

RESUMO

The reproductive performance (e.g. fertility) of dairy cows, which declined over past few decades due to the intense and intensive selection, needs to be improved. Previous genome-wide association study (GWAS) of female Holstein screened the Adenylate cyclase 5 (ADCY5) as the candidate gene for cow fertility. As a member of the adenylyl cyclases family, adenylate cyclase 5 (ADCY5) is famous for regulating extrapyramidal motor system related various neuropsychiatric diseases, and its genetic variant is reported to associate with lower birth and placenta weight which leads to asymmetric fetal growth restriction. It was hypothesized that ADCY5 may affect the fertility of cows by regulating the processes of ovarian development. Herein, genomic DNA from 768 ovaries samples of healthy unrelated Holstein cow were used to screen potential insertion/deletion (indel) mutations using eight pairs of primers, and we found three novel polymorphic indel variants, namely, rs385624978 (P3-D11-bp), rs433028962 (P5-I19-bp) and rs382393457 (P8-D19-bp). The minor allelic frequencies (MAF) of P3-D11-bp, P5-I19-bp and P8-D19-bp loci were 0.188, 0.365 and 0.06, respectively, and there were 7 different haplotypes. Additionally, linkage disequilibrium analysis demonstrated no linkage among them. Importantly, P3-D11-bp locus was significantly related to both ovarian width (P = 1.0E-6) and corpus luteum diameter (P = 0.015); P5-I19-bp locus had a significant relation with corpus albicans diameter (P = 0.030) and ovaries with mutational homozygous genotype produced a superior corpus albicans diameter than those with other genotypes. Briefly, three novel indel mutations of bovine ADCY5 gene were identified and two of them were uncovered to be significantly correlated with ovarian phenotypic traits or corpus luteum or albicans traits. These findings contributed to the application of molecular marker-assisted selection (MAS) in improving female fertility in cattle, which could accelerate the development of the cattle industry.


Assuntos
Adenilil Ciclases/genética , Ovário/fisiologia , Polimorfismo de Nucleotídeo Único/genética , Animais , Bovinos , Feminino , Fertilidade/genética , Frequência do Gene/genética , Estudo de Associação Genômica Ampla/métodos , Genótipo , Haplótipos/genética , Mutação INDEL/genética , Desequilíbrio de Ligação/genética , Fenótipo , Reprodução/genética
3.
Gene ; 765: 145107, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32889058

RESUMO

AIM: The Lithuanian population has outstanding rates of alcohol consumption and alcohol related mortality. Alteration of brain dopaminergic system play a role in the risk for addiction disorders. We evaluated the association of one single nucleotide polymorphism rs1800497 in the Ankyrin Repeat and Kinase Domain Containing 1 - Dopamine Receptor D2 complex (ANKK1-DRD2) and a catechol-o-methyltransferase (COMT) rs4680 single nucleotide polymorphism with the risk for alcohol use disorder and impulsiveness in Lithuanian population. Both genetic polymorphisms are known to alter brain dopaminergic activity, thus we also investigated the possible interaction effect of these polymorphisms. METHODS: The study included 329 participants recruited from the local community. Hazardous alcohol use was evaluated using the Alcohol Use Disorder Identification Test (AUDIT). Impulsiveness was measured using the Barratt Impulsiveness Scale - 11 (BIS-11). Between group differences of AUDIT and BIS-11 scores were examined stratified by genetic polymorphisms and their combinations. The independent effect of each polymorphism and their interaction for hazardous alcohol use were evaluated using adjusted logistic regression analyses. RESULTS: The ANKK1-DRD2 rs1800497 polymorphism was associated with total AUDIT score, but not with the hazardous use of alcohol, as indicated by the AUDIT test cut-off of 8. The COMT rs4680 GG genotype was associated with the hazardous use of alcohol (adjusted OR = 2.094, p = 0.029), but this association was not statistically significant after adjustment for multiple comparisons. Presence of both COMT rs4680 and ANKK1-DRD2 rs1800497 GGxCT/TT polymorphisms was associated with significantly increased risk for hazardous use of alcohol (adjusted OR = 5.016, p = 0.005). The COMT rs4680 and ANKK1-DRD2 rs1800497 genetic polymorphisms, and their combination were not associated with impulsiveness. CONCLUSIONS: Our study demonstrated that the interaction of COMT rs4680 and ANKK1-DRD2 rs1800497 genetic polymorphisms is associated with a hazardous use of alcohol.


Assuntos
Alcoolismo/genética , Catecol O-Metiltransferase/genética , Proteínas Serina-Treonina Quinases/genética , Receptores de Dopamina D2/genética , Adulto , Alcoolismo/epidemiologia , Alelos , Repetição de Anquirina/genética , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação/genética , Lituânia/epidemiologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Dopamina D2/metabolismo , Fatores de Risco
4.
Am J Hum Genet ; 108(1): 25-35, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33308443

RESUMO

Colocalization analysis has emerged as a powerful tool to uncover the overlapping of causal variants responsible for both molecular and complex disease phenotypes. The findings from colocalization analysis yield insights into the molecular pathways of complex diseases. In this paper, we conduct an in-depth investigation of the promise and limitations of the available colocalization analysis approaches. Focusing on variant-level colocalization approaches, we first establish the connections between various existing methods. We proceed to discuss the impacts of various controllable analytical factors and uncontrollable practical factors on outcomes of colocalization analysis through realistic simulations and real data examples. We identify a single analytical factor, the specification of prior enrichment levels, which can lead to severe inflation of false-positive colocalization findings. Meanwhile, the combination of many other analytical and practical factors all lead to diminished power. Consequently, we recommend the following strategies for the best practice of colocalization analysis: (1) estimating prior enrichment level from the observed data and (2) separating fine-mapping and colocalization analysis. Our analysis of 4,091 complex traits and the multi-tissue expression quantitative trait loci (eQTL) data from the GTEx (v.8) suggests that colocalizations of molecular QTLs and causal complex trait associations are widespread. However, only a small proportion can be confidently identified from currently available data due to a lack of power. Our findings set a benchmark for current and future integrative genetic association analysis applications.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Predisposição Genética para Doença/genética , Humanos , Desequilíbrio de Ligação/genética , Fenótipo
5.
Nat Commun ; 11(1): 6421, 2020 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-33339818

RESUMO

Sexual reproduction is almost ubiquitous among extant eukaryotes. As most asexual lineages are short-lived, abandoning sex is commonly regarded as an evolutionary dead end. Still, putative anciently asexual lineages challenge this view. One of the most striking examples are bdelloid rotifers, microscopic freshwater invertebrates believed to have completely abandoned sexual reproduction tens of Myr ago. Here, we compare whole genomes of 11 wild-caught individuals of the bdelloid rotifer Adineta vaga and present evidence that some patterns in its genetic variation are incompatible with strict clonality and lack of genetic exchange. These patterns include genotype proportions close to Hardy-Weinberg expectations within loci, lack of linkage disequilibrium between distant loci, incongruent haplotype phylogenies across the genome, and evidence for hybridization between divergent lineages. Analysis of triallelic sites independently corroborates these findings. Our results provide evidence for interindividual genetic exchange and recombination in A. vaga, a species previously thought to be anciently asexual.


Assuntos
Genoma , Recombinação Genética/genética , Rotíferos/genética , Alelos , Animais , Genética Populacional , Células Germinativas/metabolismo , Haplótipos/genética , Desequilíbrio de Ligação/genética , Filogenia , Sequenciamento Completo do Genoma
6.
BMC Bioinformatics ; 21(1): 491, 2020 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-33129253

RESUMO

BACKGROUND: Advances in genotyping and phenotyping techniques have enabled the acquisition of a great amount of data. Consequently, there is an interest in multivariate statistical analyses that identify genomic regions likely to contain causal mutations affecting multiple traits (i.e., pleiotropy). As the demand for multivariate analyses increases, it is imperative that optimal tools are available to assess their performance. To facilitate the testing and validation of these multivariate approaches, we developed simplePHENOTYPES, an R/CRAN package that simulates pleiotropy, partial pleiotropy, and spurious pleiotropy in a wide range of genetic architectures, including additive, dominance and epistatic models. RESULTS: We illustrate simplePHENOTYPES' ability to simulate thousands of phenotypes in less than one minute. We then provide two vignettes illustrating how to simulate sets of correlated traits in simplePHENOTYPES. Finally, we demonstrate the use of results from simplePHENOTYPES in a standard GWAS software, as well as the equivalence of simulated phenotypes from simplePHENOTYPES and other packages with similar capabilities. CONCLUSIONS: simplePHENOTYPES is a R/CRAN package that makes it possible to simulate multiple traits controlled by loci with varying degrees of pleiotropy. Its ability to interface with both commonly-used marker data formats and downstream quantitative genetics software and packages should facilitate a rigorous assessment of both existing and emerging statistical GWAS and GS approaches. simplePHENOTYPES is also available at https://github.com/samuelbfernandes/simplePHENOTYPES .


Assuntos
Simulação por Computador , Epistasia Genética , Ligação Genética , Pleiotropia Genética , Software , Frequência do Gene/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Desequilíbrio de Ligação/genética , Análise Multivariada , Fenótipo , Característica Quantitativa Herdável , Fluxo de Trabalho
7.
Nat Commun ; 11(1): 5562, 2020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-33144568

RESUMO

Cigarette smoking is the leading cause of preventable morbidity and mortality. Genetic variation contributes to initiation, regular smoking, nicotine dependence, and cessation. We present a Fagerström Test for Nicotine Dependence (FTND)-based genome-wide association study in 58,000 European or African ancestry smokers. We observe five genome-wide significant loci, including previously unreported loci MAGI2/GNAI1 (rs2714700) and TENM2 (rs1862416), and extend loci reported for other smoking traits to nicotine dependence. Using the heaviness of smoking index from UK Biobank (N = 33,791), rs2714700 is consistently associated; rs1862416 is not associated, likely reflecting nicotine dependence features not captured by the heaviness of smoking index. Both variants influence nearby gene expression (rs2714700/MAGI2-AS3 in hippocampus; rs1862416/TENM2 in lung), and expression of genes spanning nicotine dependence-associated variants is enriched in cerebellum. Nicotine dependence (SNP-based heritability = 8.6%) is genetically correlated with 18 other smoking traits (rg = 0.40-1.09) and co-morbidities. Our results highlight nicotine dependence-specific loci, emphasizing the FTND as a composite phenotype that expands genetic knowledge of smoking.


Assuntos
Predisposição Genética para Doença , Característica Quantitativa Herdável , Tabagismo/genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Padrões de Herança/genética , Desequilíbrio de Ligação/genética , Metanálise como Assunto , Anotação de Sequência Molecular , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
8.
BMC Bioinformatics ; 21(1): 461, 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33066733

RESUMO

BACKGROUND: Linkage disequilibrium (LD) analysis is broadly utilized in genetics to understand the evolutionary and demographic history and helps geneticists identify genes associated with interested inherited traits, such as diseases. There are some tools for linkage disequilibrium analysis either in a local or online way; however, there has been no such tool supporting both graphical user interface (GUI) and parallel computing. RESULTS: We developed a GUI software called LDkit for LD analysis, which supports parallel computing. The LDkit supports both variant call format (VCF) and PLINK 'ped + map' format. At the same time, users could also just analyze a subset of individuals from the whole population. The LDkit reads the data by block and then paralleled the computation process by monitoring the usage of processes. Assessment on the Human 1000 genome data showed that when paralleled with 32 threads, the running time was reduced to less than 6 minutes from ~77 minutes using the chromosome 22 dataset with 1,103,547 SNPs and 2504 individuals. CONCLUSIONS: The software LDkit can be effectively used to calculate and plot LD decay, LD block, and linkage disequilibrium analysis between a site and a given region. Most importantly, both graphical user interface (GUI) and stand-alone packages are available for users' convenience. LDkit was written in JAVA language under cross-platform support.


Assuntos
Desequilíbrio de Ligação/genética , Software , Haplótipos/genética , Humanos , Complexo Principal de Histocompatibilidade/genética , Polimorfismo de Nucleotídeo Único/genética , Interface Usuário-Computador
9.
Am J Psychiatry ; 177(10): 917-927, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32998551

RESUMO

OBJECTIVE: Death by suicide is a highly preventable yet growing worldwide health crisis. To date, there has been a lack of adequately powered genomic studies of suicide, with no sizable suicide death cohorts available for analysis. To address this limitation, the authors conducted the first comprehensive genomic analysis of suicide death using previously unpublished genotype data from a large population-ascertained cohort. METHODS: The analysis sample comprised 3,413 population-ascertained case subjects of European ancestry and 14,810 ancestrally matched control subjects. Analytical methods included principal component analysis for ancestral matching and adjusting for population stratification, linear mixed model genome-wide association testing (conditional on genetic-relatedness matrix), gene and gene set-enrichment testing, and polygenic score analyses, as well as single-nucleotide polymorphism (SNP) heritability and genetic correlation estimation using linkage disequilibrium score regression. RESULTS: Genome-wide association analysis identified two genome-wide significant loci (involving six SNPs: rs34399104, rs35518298, rs34053895, rs66828456, rs35502061, and rs35256367). Gene-based analyses implicated 22 genes on chromosomes 13, 15, 16, 17, and 19 (q<0.05). Suicide death heritability was estimated at an h2SNP value of 0.25 (SE=0.04) and a value of 0.16 (SE=0.02) when converted to a liability scale. Notably, suicide polygenic scores were significantly predictive across training and test sets. Polygenic scores for several other psychiatric disorders and psychological traits were also predictive, particularly scores for behavioral disinhibition and major depressive disorder. CONCLUSIONS: Multiple genome-wide significant loci and genes were identified and polygenic score prediction of suicide death case-control status was demonstrated, adjusting for ancestry, in independent training and test sets. Additionally, the suicide death sample was found to have increased genetic risk for behavioral disinhibition, major depressive disorder, depressive symptoms, autism spectrum disorder, psychosis, and alcohol use disorder compared with the control sample.


Assuntos
Herança Multifatorial/genética , Suicídio Consumado/psicologia , Adulto , Estudos de Casos e Controles , Feminino , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Desequilíbrio de Ligação/genética , Masculino , Polimorfismo de Nucleotídeo Único/genética , Análise de Componente Principal , Escócia/epidemiologia , Fatores Sexuais , Suicídio Consumado/prevenção & controle , Suicídio Consumado/estatística & dados numéricos , Utah/epidemiologia , Adulto Jovem
10.
PLoS One ; 15(9): e0237792, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32881892

RESUMO

BACKGROUND: Ewing sarcoma (EwS) is a rare, aggressive solid tumor of childhood, adolescence and young adulthood associated with pathognomonic EWSR1-ETS fusion oncoproteins altering transcriptional regulation. Genome-wide association studies (GWAS) have identified 6 common germline susceptibility loci but have not investigated low-frequency inherited variants with minor allele frequencies below 5% due to limited genotyped cases of this rare tumor. METHODS: We investigated the contribution of rare and low-frequency variation to EwS susceptibility in the largest EwS genome-wide association study to date (733 EwS cases and 1,346 unaffected controls of European ancestry). RESULTS: We identified two low-frequency variants, rs112837127 and rs2296730, on chromosome 20 that were associated with EwS risk (OR = 0.186 and 2.038, respectively; P-value < 5×10-8) and located near previously reported common susceptibility loci. After adjusting for the most associated common variant at the locus, only rs112837127 remained a statistically significant independent signal (OR = 0.200, P-value = 5.84×10-8). CONCLUSIONS: These findings suggest rare variation residing on common haplotypes are important contributors to EwS risk. IMPACT: Motivate future targeted sequencing studies for a comprehensive evaluation of low-frequency and rare variation around common EwS susceptibility loci.


Assuntos
Loci Gênicos , Predisposição Genética para Doença , Variação Genética , Células Germinativas/metabolismo , Sarcoma de Ewing/genética , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação/genética , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética
11.
J Vis Exp ; (161)2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32716386

RESUMO

Recently, a new implementation of a previously described method for interpreting genome-wide association study (GWAS) data using metabolic pathway analysis has been developed and released. The Pathway Association Study Tool (PAST) was developed to address concerns with user-friendliness and slow-running analyses. This new user-friendly tool has been released on Bioconductor and Github. In testing, PAST ran analyses in less than one hour that previously required twenty-four or more hours. In this article, we present the protocol for using either the Shiny application or the R console to run PAST.


Assuntos
Estudo de Associação Genômica Ampla , Redes e Vias Metabólicas , Software , Humanos , Desequilíbrio de Ligação/genética , Redes e Vias Metabólicas/genética , Polimorfismo de Nucleotídeo Único/genética
12.
Nat Commun ; 11(1): 3697, 2020 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-32728101

RESUMO

As the number of genomics datasets grows rapidly, sample mislabeling has become a high stakes issue. We present CrosscheckFingerprints (Crosscheck), a tool for quantifying sample-relatedness and detecting incorrectly paired sequencing datasets from different donors. Crosscheck outperforms similar methods and is effective even when data are sparse or from different assays. Application of Crosscheck to 8851 ENCODE ChIP-, RNA-, and DNase-seq datasets enabled us to identify and correct dozens of mislabeled samples and ambiguous metadata annotations, representing ~1% of ENCODE datasets.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Desequilíbrio de Ligação/genética , Bases de Dados de Ácidos Nucleicos , Genótipo , Células HEK293 , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Células K562 , Escore Lod , Anotação de Sequência Molecular
13.
J Bone Miner Metab ; 38(6): 868-877, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32653958

RESUMO

INTRODUCTION: Osteoporosis is a common disorder characterized by decreased bone mineral density (BMD). Interestingly, osteoporosis and obesity have several similar features, including a genetic predisposition and a common bone marrow stem cell. With aging, the composition of bone marrow shifts to adipocytes, osteoclast activity increases, and osteoblast function declines, resulting in osteoporosis. MATERIALS AND METHODS: We performed a genome-wide association study (GWAS) analysis with osteoporosis and body mass index (BMI) and did identify an association in 349 and 384 SNPs by filtering with the significant p values (p < 0.001) of BMI and osteoporosis, respectively. RESULTS: Only three of those SNPs were common (rs2326365, rs7097028, and rs11000205) between the SNPs significantly associated with BMI and/or osteoporosis in Korean Association REsource (KARE) females. Two of the three SNPs belonged to the ASCC1 gene and one to the FAM50B gene. We carried out a minor allele frequency (MAF) analysis of the rs7097028 and rs11000205 SNPs in the ASCC1 gene with a geographic genome variant browser. Both rs7097028 and rs11000205 in the ASCC1 gene were seen mostly in African and Southeast Asian populations. CONCLUSIONS: Our results suggest that the ASCC1 gene is a significant genetic factor for determining the risk for both osteoporosis and obesity in KARE postmenopausal females.


Assuntos
Proteínas de Transporte/genética , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Obesidade/genética , Osteoporose/genética , Polimorfismo de Nucleotídeo Único/genética , Pós-Menopausa/genética , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Índice de Massa Corporal , Densidade Óssea/genética , Feminino , Frequência do Gene/genética , Geografia , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , República da Coreia
14.
Nat Genet ; 52(8): 859-864, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32601477

RESUMO

Genetic correlation is a central parameter for understanding shared genetic architecture between complex traits. By using summary statistics from genome-wide association studies (GWAS), linkage disequilibrium score regression (LDSC) was developed for unbiased estimation of genetic correlations. Although easy to use, LDSC only partially utilizes LD information. By fully accounting for LD across the genome, we develop a high-definition likelihood (HDL) method to improve precision in genetic correlation estimation. Compared to LDSC, HDL reduces the variance of genetic correlation estimates by about 60%, equivalent to a 2.5-fold increase in sample size. We apply HDL and LDSC to estimate 435 genetic correlations among 30 behavioral and disease-related phenotypes measured in the UK Biobank (UKBB). In addition to 154 significant genetic correlations observed for both methods, HDL identified another 57 significant genetic correlations, compared to only another 2 significant genetic correlations identified by LDSC. HDL brings more power to genomic analyses and better reveals the underlying connections across human complex traits.


Assuntos
Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Desequilíbrio de Ligação/genética , Modelos Genéticos , Fenótipo
15.
Nat Commun ; 11(1): 2927, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32522982

RESUMO

Structural variants (SVs) and short tandem repeats (STRs) comprise a broad group of diverse DNA variants which vastly differ in their sizes and distributions across the genome. Here, we identify genomic features of SV classes and STRs that are associated with gene expression and complex traits, including their locations relative to eGenes, likelihood of being associated with multiple eGenes, associated eGene types (e.g., coding, noncoding, level of evolutionary constraint), effect sizes, linkage disequilibrium with tagging single nucleotide variants used in GWAS, and likelihood of being associated with GWAS traits. We identify a set of high-impact SVs/STRs associated with the expression of three or more eGenes via chromatin loops and show that they are highly enriched for being associated with GWAS traits. Our study provides insights into the genomic properties of structural variant classes and short tandem repeats that are associated with gene expression and human traits.


Assuntos
Repetições de Microssatélites/genética , Linhagem Celular , Variação Genética/genética , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação/genética , Herança Multifatorial , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética
16.
Nat Commun ; 11(1): 3255, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32591531

RESUMO

Mendelian randomisation (MR) analysis is an important tool to elucidate the causal relevance of environmental and biological risk factors for disease. However, causal inference is undermined if genetic variants used to instrument a risk factor also influence alternative disease-pathways (horizontal pleiotropy). Here we report how the 'no horizontal pleiotropy assumption' is strengthened when proteins are the risk factors of interest. Proteins are typically the proximal effectors of biological processes encoded in the genome. Moreover, proteins are the targets of most medicines, so MR studies of drug targets are becoming a fundamental tool in drug development. To enable such studies, we introduce a mathematical framework that contrasts MR analysis of proteins with that of risk factors located more distally in the causal chain from gene to disease. We illustrate key model decisions and introduce an analytical framework for maximising power and evaluating the robustness of analyses.


Assuntos
Sistemas de Liberação de Medicamentos , Genes , Análise da Randomização Mendeliana , Intervalos de Confiança , Doença das Coronárias/genética , Genoma Humano , Humanos , Desequilíbrio de Ligação/genética , Lipídeos/química , Modelos Genéticos , Razão de Chances , Fenômica , Polimorfismo de Nucleotídeo Único/genética , Proteínas/genética , Locos de Características Quantitativas/genética , Reprodutibilidade dos Testes
17.
Am J Hum Genet ; 107(1): 137-148, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32533945

RESUMO

Recombination rates vary significantly across the genome, and estimates of recombination rates are needed for downstream analyses such as haplotype phasing and genotype imputation. Existing methods for recombination rate estimation are limited by insufficient amounts of informative genetic data or by high computational cost. We present a method and software, called IBDrecomb, for using segments of identity by descent to infer recombination rates. IBDrecomb can be applied to sequenced population cohorts to obtain high-resolution, population-specific recombination maps. In simulated admixed data, IBDrecomb obtains higher accuracy than admixture-based estimation of recombination rates. When applied to 2,500 simulated individuals, IBDrecomb obtains similar accuracy to a linkage-disequilibrium (LD)-based method applied to 96 individuals (the largest number for which computation is tractable). Compared to LD-based maps, our IBD-based maps have the advantage of estimating recombination rates in the recent past rather than the distant past. We used IBDrecomb to generate new recombination maps for European Americans and for African Americans from TOPMed sequence data from the Framingham Heart Study (1,626 unrelated individuals) and the Jackson Heart Study (2,046 unrelated individuals), and we compare them to LD-based, admixture-based, and family-based maps.


Assuntos
Recombinação Genética/genética , Afro-Americanos/genética , Grupo com Ancestrais do Continente Europeu/genética , Genética Populacional/métodos , Genoma Humano/genética , Haplótipos/genética , Humanos , Desequilíbrio de Ligação/genética , Polimorfismo de Nucleotídeo Único/genética
18.
BMC Med Genet ; 21(1): 134, 2020 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-32560637

RESUMO

BACKGROUND: Liver cancer is one of the most common cancers in the world. The primary aim of this research was to discover the correlation between single nucleotide polymorphisms (SNPs) of the MIR155HG and liver cancer risk. METHODS: The selected SNPs in MIR155HG were genotyped utilizing the Agena MassARRAY platform. We evaluated the correlation between MIR155HG polymorphisms and Liver cancer by genetic model analysis, stratification analysis and haplotype analysis. Relative risk of Liver cancer was shown based on odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: Our results uncovered that rs12482371 and rs1893650 in the MIR155HG were associated with protection against Liver cancer. And the rs928883 was related to increase risk of Liver cancer. Furthermore, apart from rs77218221, other selected SNPs formed two LD blocks, and haplotype "GATAG" in block 2 elevated individual liver cancer risk. CONCLUSIONS: MIR155HG gene polymorphism may be correlated to Liver cancer susceptibility in Han Chinese population, particularly in males and aged ≤55 years.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Grupos Étnicos/genética , Predisposição Genética para Doença , Neoplasias Hepáticas/genética , Polimorfismo de Nucleotídeo Único/genética , RNA Longo não Codificante/genética , Fatores Etários , Estudos de Casos e Controles , Feminino , Haplótipos/genética , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Caracteres Sexuais
19.
Mol Genet Genomics ; 295(4): 855-870, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32361785

RESUMO

MicroRNAs (miRNAs) play crucial roles in all aspects of plant growth and development, but the genetic interactions of miRNAs and their target genes in woody plants are largely unknown. Here, we integrated association genetics and expression profiling to decipher the allelic variations and interactions of the Pto-MIR319 family of miRNAs and 12 putative Pto-miR319 target genes related to wood formation in 435 unrelated individuals of Populus tomentosa Carrière (Chinese white poplar). Expression pattern analysis showed that among all pairings between expressions of pre-miRNA of Pto-MIR319 members and targets, 70.0% showed negative correlation of expression levels (r = - 0.944 to 0.674, P < 0.01) in eight tissues and organs of poplar, suggesting that Pto-miR319 may participate in the regulatory network of wood formation. Single SNP-based association studies identified 137 significant associations (P < 0.01, Q < 0.1), representing 126 unique SNPs from Pto-MIR319 members and their targets, with 10 tree growth traits, revealing that these genetic factors have common roles related to wood formation. Epistasis analysis uncovered 105 significant SNP-SNP associations (P < 0.01) influencing the 10 traits, demonstrating the close genetic interactions between Pto-MIR319 family members and the 12 Pto-miR319 target genes. Notably, one common SNP, in the precursor region of Pto-MIR319e, affected the stability of Pto-MIR319e's secondary structure by altering the stem-loop structure and minimum free energy, contributing to variations in the expression of Pto-MIR319e and Pto-miR319e target genes. This study enriches the understanding of the functions of miR319 family miRNAs in poplar and exemplifies a feasible approach to exploring the genetic effects underlying miRNA-mRNA interactions related to complex traits in trees.


Assuntos
Estudos de Associação Genética , MicroRNAs/genética , Populus/genética , Madeira/genética , Alelos , Arabidopsis , Epistasia Genética/genética , Regulação da Expressão Gênica de Plantas/genética , Desequilíbrio de Ligação/genética , Polimorfismo de Nucleotídeo Único/genética , Populus/crescimento & desenvolvimento , RNA Mensageiro/genética
20.
Am J Hum Genet ; 107(1): 46-59, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32470373

RESUMO

In complex trait genetics, the ability to predict phenotype from genotype is the ultimate measure of our understanding of genetic architecture underlying the heritability of a trait. A complete understanding of the genetic basis of a trait should allow for predictive methods with accuracies approaching the trait's heritability. The highly polygenic nature of quantitative traits and most common phenotypes has motivated the development of statistical strategies focused on combining myriad individually non-significant genetic effects. Now that predictive accuracies are improving, there is a growing interest in the practical utility of such methods for predicting risk of common diseases responsive to early therapeutic intervention. However, existing methods require individual-level genotypes or depend on accurately specifying the genetic architecture underlying each disease to be predicted. Here, we propose a polygenic risk prediction method that does not require explicitly modeling any underlying genetic architecture. We start with summary statistics in the form of SNP effect sizes from a large GWAS cohort. We then remove the correlation structure across summary statistics arising due to linkage disequilibrium and apply a piecewise linear interpolation on conditional mean effects. In both simulated and real datasets, this new non-parametric shrinkage (NPS) method can reliably allow for linkage disequilibrium in summary statistics of 5 million dense genome-wide markers and consistently improves prediction accuracy. We show that NPS improves the identification of groups at high risk for breast cancer, type 2 diabetes, inflammatory bowel disease, and coronary heart disease, all of which have available early intervention or prevention treatments.


Assuntos
Herança Multifatorial/genética , Idoso , Estudos de Coortes , Diabetes Mellitus Tipo 2/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética
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