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1.
Medicine (Baltimore) ; 98(27): e16205, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31277128

RESUMO

With the advances in sequencing technologies and genome-wide association studies (GWAS), several inherited variants that increase glioma risk have been identified. Ten studies including 8818 cases and 17,551 controls were collected to conduct a meta-analysis to evaluate the associations between 6 variants in 8q24 and glioma risk. Of the 6 variants located in 8q24, 2 have strong significant associations with the risk of glioma, including rs4295627 (P = .003, odds ratio [OR] = 1.21), rs55705857 (P = 2.31 × 10, OR = 3.54). In particular, both homozygous GG (P = 1.91 × 10, OR1 = 2.01) and heterozygous GT (P = 7.75 × 10, OR2 = 1.35) genotypes of rs4295627 were associated with glioma risk. Further studies are needed to explore the role of the 8q24 variants involved in the etiology of glioma.


Assuntos
Neoplasias Encefálicas/genética , Cromossomos Humanos Par 8/genética , Estudo de Associação Genômica Ampla/métodos , Glioma/genética , Polimorfismo de Nucleotídeo Único , Alelos , Predisposição Genética para Doença , Genótipo , Humanos , Fatores de Risco
2.
BMC Plant Biol ; 19(1): 318, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311506

RESUMO

BACKGROUND: Single Nucleotide Polymorphism (SNP) array and re-sequencing technologies have different properties (e.g. calling rate, minor allele frequency profile) and drawbacks (e.g. ascertainment bias). This lead us to study their complementarity and the consequences of using them separately or combined in diversity analyses and Genome-Wide Association Studies (GWAS). We performed GWAS on three traits (grain yield, plant height and male flowering time) measured in 22 environments on a panel of 247 F1 hybrids obtained by crossing 247 diverse dent maize inbred lines with a same flint line. The 247 lines were genotyped using three genotyping technologies (Genotyping-By-Sequencing, Illumina Infinium 50 K and Affymetrix Axiom 600 K arrays). RESULTS: The effects of ascertainment bias of the 50 K and 600 K arrays were negligible for deciphering global genetic trends of diversity and for estimating relatedness in this panel. We developed an original approach based on linkage disequilibrium (LD) extent in order to determine whether SNPs significantly associated with a trait and that are physically linked should be considered as a single Quantitative Trait Locus (QTL) or several independent QTLs. Using this approach, we showed that the combination of the three technologies, which have different SNP distributions and densities, allowed us to detect more QTLs (gain in power) and potentially refine the localization of the causal polymorphisms (gain in resolution). CONCLUSIONS: Conceptually different technologies are complementary for detecting QTLs by tagging different haplotypes in association studies. Considering LD, marker density and the combination of different technologies (SNP-arrays and re-sequencing), the genotypic data available were most likely enough to well represent polymorphisms in the centromeric regions, whereas using more markers would be beneficial for telomeric regions.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Técnicas de Genotipagem , Haplótipos , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Zea mays/genética , Alelos , Biodiversidade , Cromossomos de Plantas , Marcadores Genéticos , Genoma de Planta , Desequilíbrio de Ligação , Zea mays/crescimento & desenvolvimento
3.
BMC Med Genet ; 20(1): 99, 2019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-31170924

RESUMO

BACKGROUND: Metabolic syndrome (MetS), defined as a cluster of metabolic risk factors including dyslipidemia, insulin-resistance, and elevated blood pressure, has been known as partly heritable. MetS effects the lives of many people worldwide, yet females have been reported to be more vulnerable to this cluster of risks. METHODS: To elucidate genetic variants underlying MetS specifically in females, we performed a genome-wide association study (GWAS) for MetS as well as its component traits in a total of 9932 Korean female subjects (including 2276 MetS cases and 1692 controls). To facilitate the prediction of MetS in females, we calculated a genetic risk score (GRS) combining 14 SNPs detected in our GWA analyses specific for MetS. RESULTS: GWA analyses identified 14 moderate signals (Pmeta < 5X10- 5) specific to females for MetS. In addition, two genome-wide significant female-specific associations (Pmeta < 5X10- 8) were detected for rs455489 in DSCAM for fasting plasma glucose (FPG) and for rs7115583 in SIK3 for high-density lipoprotein cholesterol (HDLC). Logistic regression analyses (adjusted for area and age) between the GRS and MetS in females indicated that the GRS was associated with increased prevalence of MetS in females (P = 5.28 × 10- 14), but not in males (P = 3.27 × 10- 1). Furthermore, in the MetS prediction models using GRS, the area under the curve (AUC) of the receiver operating characteristics (ROC) curve was higher in females (AUC = 0.85) than in males (AUC = 0.57). CONCLUSION: This study highlights new female-specific genetic variants associated with MetS and its component traits and suggests that the GRS of MetS variants is a likely useful predictor of MetS in females.


Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Síndrome Metabólica/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Predisposição Genética para Doença/etnologia , Genótipo , Humanos , Masculino , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/etnologia , Pessoa de Meia-Idade , Fenótipo , República da Coreia , Fatores de Risco , Fatores Sexuais
4.
Nat Commun ; 10(1): 2581, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31197173

RESUMO

Despite existing reports on differential DNA methylation in type 2 diabetes (T2D) and obesity, our understanding of its functional relevance remains limited. Here we show the effect of differential methylation in the early phases of T2D pathology by a blood-based epigenome-wide association study of 4808 non-diabetic Europeans in the discovery phase and 11,750 individuals in the replication. We identify CpGs in LETM1, RBM20, IRS2, MAN2A2 and the 1q25.3 region associated with fasting insulin, and in FCRL6, SLAMF1, APOBEC3H and the 15q26.1 region with fasting glucose. In silico cross-omics analyses highlight the role of differential methylation in the crosstalk between the adaptive immune system and glucose homeostasis. The differential methylation explains at least 16.9% of the association between obesity and insulin. Our study sheds light on the biological interactions between genetic variants driving differential methylation and gene expression in the early pathogenesis of T2D.


Assuntos
Metilação de DNA/fisiologia , Diabetes Mellitus Tipo 2/genética , Glucose/metabolismo , Insulina/metabolismo , Obesidade/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Simulação por Computador , Ilhas de CpG/genética , Diabetes Mellitus Tipo 2/metabolismo , Epigênese Genética/fisiologia , Epigenômica/métodos , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Homeostase/genética , Humanos , Masculino , Redes e Vias Metabólicas/genética , Pessoa de Meia-Idade , Obesidade/metabolismo , Polimorfismo de Nucleotídeo Único/fisiologia , Adulto Jovem
5.
Virchows Arch ; 475(3): 383-389, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31250201

RESUMO

Gastric hyperplastic polyps are common and generally regarded as benign lesions, whereas gastric adenocarcinomas infrequently occur from gastric hyperplastic polyps. Although gastric hyperplastic polyps have received a lot of attention because of their association with malignant transformation, it remains unclear whether gastric hyperplastic polyps are neoplastic lesions that have sporadic genetic changes similar to colorectal hyperplastic polyps. We performed genome-wide analyses of two gastric adenocarcinomas with hyperplastic polyp components. The interface between "adenocarcinoma" and "hyperplastic polyp" components was fairly sharp, and the adenocarcinoma components had copy number alterations and TP53 mutations, whereas the hyperplastic polyp components had only single nucleotide polymorphisms, which were also found in adenocarcinoma components. We did not detect any somatic changes in the hyperplastic polyp components, even in genome-wide analyses, which was in contrast to the adenocarcinoma components. However, due to the small number of cases examined herein, further genetic analyses of more cases are needed.


Assuntos
Pólipos Adenomatosos/patologia , Pólipos Intestinais/patologia , Neoplasias Gástricas/genética , Adenocarcinoma/patologia , Idoso , Idoso de 80 Anos ou mais , Transformação Celular Neoplásica/patologia , Hibridização Genômica Comparativa/métodos , Variações do Número de Cópias de DNA/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Hiperplasia , Polimorfismo de Nucleotídeo Único/genética , Pólipos/patologia , Neoplasias Gástricas/patologia , Proteína Supressora de Tumor p53/genética
6.
BMC Bioinformatics ; 20(1): 219, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31039742

RESUMO

BACKGROUND: Data from genome-wide association studies (GWASs) have been used to estimate the heritability of human complex traits in recent years. Existing methods are based on the linear mixed model, with the assumption that the genetic effects are random variables, which is opposite to the fixed effect assumption embedded in the framework of quantitative genetics theory. Moreover, heritability estimators provided by existing methods may have large standard errors, which calls for the development of reliable and accurate methods to estimate heritability. RESULTS: In this paper, we first investigate the influences of the fixed and random effect assumption on heritability estimation, and prove that these two assumptions are equivalent under mild conditions in the theoretical aspect. Second, we propose a two-stage strategy by first performing sparse regularization via cross-validated elastic net, and then applying variance estimation methods to construct reliable heritability estimations. Results on both simulated data and real data show that our strategy achieves a considerable reduction in the standard error while reserving the accuracy. CONCLUSIONS: The proposed strategy allows for a reliable and accurate heritability estimation using GWAS data. It shows the promising future that reliable estimations can still be obtained with even a relatively restricted sample size, and should be especially useful for large-scale heritability analyses in the genomics era.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Genômica/métodos , Modelos Genéticos , Humanos
7.
Gene ; 706: 181-187, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31082500

RESUMO

Systemic lupus erythematous (SEL) is a heterogeneous, systemic autoimmune disorder which is defined by its autoantibody pattern. Transcriptomic data analysis has shown pathways and immune system responses associated with SLE. Eight up-regulated genes (SOCE, MMP9, CXCL8, JUN, IL1B, NFKBIA, TNF and FOS) have been examined with four interactions among different pathways. These genes are associated with SNPs which have been identified through two datasets from SLE genome-wide association studies (GWAS). In this investigation, the GWAS results were integrated with pathway analysis of transcriptomes and several genes were detected with known SLE-related variations (TYK2, C5, SH2B, IRF5, IL2RA, STAT4, FCGR2A, IL7R, LYN, HLA-DRB and TNFAIP3). Pathway-based analysis on the Wikipathway Human Collection allowed the identification of prioritized variants in the relevant pathways, such as thymic stromal lymphopoietin (TSLP) signaling pathway linked to LYN, IL7R, STAT4 and rs7574865. Analysis of existing transcriptomes and GWAS data identified eight up-regulated candidate genes with more than four relationships among the different pathways associated with SNPs to pinpoint the relevant loci linked to SLE. The results of this investigation have expanded the number of candidate genes related to SLE and have highlighted possible pathways and GWAS-based methods for gene detection. Identification of the fundamental genes would assist in revealing the mechanisms responsible for SLE.


Assuntos
Perfilação da Expressão Gênica/métodos , Lúpus Eritematoso Sistêmico/genética , Estudos de Casos e Controles , Bases de Dados Genéticas , Ontologia Genética , Redes Reguladoras de Genes/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Fatores Reguladores de Interferon/genética , Lúpus Eritematoso Sistêmico/fisiopatologia , Polimorfismo de Nucleotídeo Único/genética , Receptores de IgG/genética , Fator de Transcrição STAT4/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética
8.
Genet Sel Evol ; 51(1): 20, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31077144

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) are widely used to identify regions of the genome that harbor genetic determinants of quantitative traits. However, the multiple-testing burden from scanning tens of millions of whole-genome sequence variants reduces the power to identify associated variants, especially if sample size is limited. In addition, factors such as inaccuracy of imputation, complex linkage disequilibrium structures, and multiple closely-located causal variants may result in an identified causative mutation not being the most significant single nucleotide polymorphism in a particular genomic region. Therefore, the use of information from different sources, particularly variant annotations, was proposed to enhance the fine-mapping of causal variants. Here, we tested whether applying significance thresholds based on variant annotation categories increases the power of GWAS compared with a flat Bonferroni multiple-testing correction. RESULTS: Whole-genome sequence variants in dairy cattle were categorized according to type and predicted impact. Then, GWAS between markers and 17 quantitative traits were analyzed for enrichment for association of each annotation category. By using annotation categories that were determined with the variants effect predictor software and datasets indicating regions of open chromatin, "low impact" variants were found to be highly enriched. Moreover, when the variants annotated as "modifier" and not located at open chromatin regions were further classified into different types of potential regulatory elements, the high impact variants, moderate impact variants, variants located in the 3' and 5' untranslated regions, and variants located in potential non-coding RNA regions exhibited relatively more enrichment. In contrast, a similar study on human GWAS data reported that enrichment of association signals was highest with high impact variants. We observed an increase in power when these variant category-based significance thresholds were applied for GWAS results on stature in Nordic Holstein cattle, as more candidate genes from previous large GWAS meta-analysis for cattle stature were confirmed. CONCLUSIONS: Use of variant category-based genome-wide significance thresholds can marginally increase the power to detect the candidate genes in cattle. With the continued improvements in annotation of the bovine genome, we anticipate that the growing usefulness of variant category-based significance thresholds will be demonstrated.


Assuntos
Bovinos/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo Genético , Animais , Estudo de Associação Genômica Ampla/normas , Anotação de Sequência Molecular , Locos de Características Quantitativas
9.
Nord J Psychiatry ; 73(4-5): 257-263, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31070508

RESUMO

Background: Prenatal maternal stress increases the risk of offspring developmental and psychological difficulties. The biological mechanisms behind these associations are mostly unknown. One explanation suggests that exposure of the fetus to maternal stress may influence DNA methylation. However, this hypothesis is largely based on animal studies, and human studies of candidate genes from single timepoints. Aim: The aim of this study was to investigate if prenatal maternal stress, in the form of maternal depressive symptoms, was associated with variation in genome-wide DNA methylation at two timepoints. Methods: One-hundred and eighty-four mother-child dyads were selected from a population of pregnant women in the Little-in-Norway study. The Edinburgh Postnatal Depression Scale (EPDS) measured maternal depressive symptoms. It was completed by the pregnant mothers between weeks 17 and 32 of gestation. DNA was obtained from infant saliva cells at two timepoints (age 6 weeks and 12 months). DNA methylation was measured in 274 samples from 6 weeks (n = 146) and 12 months (n = 128) using the Illumina Infinium HumanMethylation 450 BeadChip. Linear regression analyses of prenatal maternal depressive symptoms and infant methylation were performed at 6 weeks and 12 months separately, and for both timepoints together using a mixed model. Results: The analyses revealed no significant genome-wide association between maternal depressive symptoms and infant DNA methylation in the separate analyses and for both timepoints together. Conclusions: This sample of pregnant women and their infants living in Norway did not reveal associations between maternal depressive symptoms and infant DNA methylation.


Assuntos
Metilação de DNA/fisiologia , Depressão/psicologia , Epigenômica/métodos , Complicações na Gravidez/psicologia , Efeitos Tardios da Exposição Pré-Natal/psicologia , Adulto , Animais , Depressão/epidemiologia , Depressão/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Recém-Nascido , Estudos Longitudinais , Mães/psicologia , Noruega/epidemiologia , Gravidez , Complicações na Gravidez/epidemiologia , Complicações na Gravidez/genética , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/genética , Adulto Jovem
10.
Genet Sel Evol ; 51(1): 21, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31092189

RESUMO

BACKGROUND: Genotyping of sequence variants typically involves, as a first step, the alignment of sequencing reads to a linear reference genome. Because a linear reference genome represents only a small fraction of all the DNA sequence variation within a species, reference allele bias may occur at highly polymorphic or divergent regions of the genome. Graph-based methods facilitate the comparison of sequencing reads to a variation-aware genome graph, which incorporates a collection of non-redundant DNA sequences that segregate within a species. We compared the accuracy and sensitivity of graph-based sequence variant genotyping using the Graphtyper software to two widely-used methods, i.e., GATK and SAMtools, which rely on linear reference genomes using whole-genome sequencing data from 49 Original Braunvieh cattle. RESULTS: We discovered 21,140,196, 20,262,913, and 20,668,459 polymorphic sites using GATK, Graphtyper, and SAMtools, respectively. Comparisons between sequence variant genotypes and microarray-derived genotypes showed that Graphtyper outperformed both GATK and SAMtools in terms of genotype concordance, non-reference sensitivity, and non-reference discrepancy. The sequence variant genotypes that were obtained using Graphtyper had the smallest number of Mendelian inconsistencies between sequence-derived single nucleotide polymorphisms and indels in nine sire-son pairs. Genotype phasing and imputation using the Beagle software improved the quality of the sequence variant genotypes for all the tools evaluated, particularly for animals that were sequenced at low coverage. Following imputation, the concordance between sequence- and microarray-derived genotypes was almost identical for the three methods evaluated, i.e., 99.32, 99.46, and 99.24% for GATK, Graphtyper, and SAMtools, respectively. Variant filtration based on commonly used criteria improved genotype concordance slightly but it also decreased sensitivity. Graphtyper required considerably more computing resources than SAMtools but less than GATK. CONCLUSIONS: Sequence variant genotyping using Graphtyper is accurate, sensitive and computationally feasible in cattle. Graph-based methods enable sequence variant genotyping from variation-aware reference genomes that may incorporate cohort-specific sequence variants, which is not possible with the current implementation of state-of-the-art methods that rely on linear reference genomes.


Assuntos
Bovinos/genética , Estudo de Associação Genômica Ampla/métodos , Técnicas de Genotipagem/métodos , Polimorfismo Genético , Animais , Técnicas de Genotipagem/normas , Software
11.
Genet Sel Evol ; 51(1): 22, 2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-31132983

RESUMO

BACKGROUND: Since the 1950s, the Norwegian-Swedish Coldblooded trotter (NSCT) has been intensively selected for harness racing performance. As a result, the racing performance of the NSCT has improved remarkably; however, this improved racing performance has also been accompanied by a gradual increase in inbreeding level. Inbreeding in NSCT has historically been monitored by using traditional methods that are based on pedigree analysis, but with recent advancements in genomics, the NSCT industry has shown interest in adopting molecular approaches for the selection and maintenance of this breed. Consequently, the aims of the current study were to estimate genomic-based inbreeding coefficients, i.e. the proportion of runs of homozygosity (ROH), for a sample of NSCT individuals using high-density genotyping array data, and subsequently to compare the resulting rate of genomic-based F (FROH) to that of pedigree-based F (FPED) coefficients within the breed. RESULTS: A total of 566 raced NSCT were available for analyses. Average FROH ranged from 1.78 to 13.95%. Correlations between FROH and FPED were significant (P < 0.001) and ranged from 0.27 to 0.56, with FPED and FROH from 2000 to 2009 increasing by 1.48 and 3.15%, respectively. Comparisons of ROH between individuals yielded 1403 regions that were present in at least 95% of the sampled horses. The average percentage of a single chromosome covered in ROH ranged from 9.84 to 18.82% with chromosome 31 and 18 showing, respectively, the largest and smallest amount of homozygosity. CONCLUSIONS: Genomic inbreeding coefficients were higher than pedigree inbreeding coefficients with both methods showing a gradual increase in inbreeding level in the NSCT breed between 2000 and 2009. Opportunities exist for the NSCT industry to develop programs that provide breeders with easily interpretable feedback on regions of the genome that are suboptimal from the perspective of genetic merit or that are sensitive to inbreeding within the population. The use of molecular data to identify genomic regions that may contribute to inbreeding depression in the NSCT will likely prove to be a valuable tool for the preservation of its genetic diversity in the long term.


Assuntos
Homozigoto , Cavalos/genética , Endogamia , Locos de Características Quantitativas , Animais , Feminino , Estudo de Associação Genômica Ampla/métodos , Cavalos/fisiologia , Masculino , Linhagem , Seleção Artificial
12.
PLoS Genet ; 15(4): e1008009, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30951530

RESUMO

Recent and classical work has revealed biologically and medically significant subtypes in complex diseases and traits. However, relevant subtypes are often unknown, unmeasured, or actively debated, making automated statistical approaches to subtype definition valuable. We propose reverse GWAS (RGWAS) to identify and validate subtypes using genetics and multiple traits: while GWAS seeks the genetic basis of a given trait, RGWAS seeks to define trait subtypes with distinct genetic bases. Unlike existing approaches relying on off-the-shelf clustering methods, RGWAS uses a novel decomposition, MFMR, to model covariates, binary traits, and population structure. We use extensive simulations to show that modelling these features can be crucial for power and calibration. We validate RGWAS in practice by recovering a recently discovered stress subtype in major depression. We then show the utility of RGWAS by identifying three novel subtypes of metabolic traits. We biologically validate these metabolic subtypes with SNP-level tests and a novel polygenic test: the former recover known metabolic GxE SNPs; the latter suggests subtypes may explain substantial missing heritability. Crucially, statins, which are widely prescribed and theorized to increase diabetes risk, have opposing effects on blood glucose across metabolic subtypes, suggesting the subtypes have potential translational value.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Modelos Genéticos , Herança Multifatorial , Fenótipo , Algoritmos , Glicemia/efeitos dos fármacos , Glicemia/genética , Análise por Conglomerados , Simulação por Computador , Doença das Coronárias/sangue , Doença das Coronárias/tratamento farmacológico , Doença das Coronárias/genética , Transtorno Depressivo Maior/classificação , Transtorno Depressivo Maior/genética , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lipídeos/sangue , Polimorfismo de Nucleotídeo Único , Estado Pré-Diabético/genética , Locos de Características Quantitativas
13.
Genetics ; 211(4): 1125-1130, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30967441

RESUMO

The genetics and evolution of complex traits, including quantitative traits and disease, have been hotly debated ever since Darwin. A century ago, a paper from R.A. Fisher reconciled Mendelian and biometrical genetics in a landmark contribution that is now accepted as the main foundation stone of the field of quantitative genetics. Here, we give our perspective on Fisher's 1918 paper in the context of how and why it is relevant in today's genome era. We mostly focus on human trait variation, in part because Fisher did so too, but the conclusions are general and extend to other natural populations, and to populations undergoing artificial selection.


Assuntos
Genética/história , Estudo de Associação Genômica Ampla/métodos , Animais , Estudo de Associação Genômica Ampla/história , História do Século XX , História do Século XXI , Humanos
14.
Genetics ; 211(4): 1131-1141, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30967442

RESUMO

In this Review, we focus on the similarity of the concepts underlying prediction of estimated breeding values (EBVs) in livestock and polygenic risk scores (PRS) in humans. Our research spans both fields and so we recognize factors that are very obvious for those in one field, but less so for those in the other. Differences in family size between species is the wedge that drives the different viewpoints and approaches. Large family size achievable in nonhuman species accompanied by selection generates a smaller effective population size, increased linkage disequilibrium and a higher average genetic relationship between individuals within a population. In human genetic analyses, we select individuals unrelated in the classical sense (coefficient of relationship <0.05) to estimate heritability captured by common SNPs. In livestock data, all animals within a breed are to some extent "related," and so it is not possible to select unrelated individuals and retain a data set of sufficient size to analyze. These differences directly or indirectly impact the way data analyses are undertaken. In livestock, genetic segregation variance exposed through samplings of parental genomes within families is directly observable and taken for granted. In humans, this genomic variation is under-recognized for its contribution to variation in polygenic risk of common disease, in both those with and without family history of disease. We explore the equation that predicts the expected proportion of variance explained using PRS, and quantify how GWAS sample size is the key factor for maximizing accuracy of prediction in both humans and livestock. Last, we bring together the concepts discussed to address some frequently asked questions.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Gado/genética , Herança Multifatorial , Característica Quantitativa Herdável , Animais , Big Data , Cruzamento/métodos , Humanos
15.
Genet Sel Evol ; 51(1): 16, 2019 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-31029078

RESUMO

BACKGROUND: Large-scale phenotyping for detailed milk fatty acid (FA) composition is difficult due to expensive and time-consuming analytical techniques. Reliability of genomic prediction is often low for traits that are expensive/difficult to measure and for breeds with a small reference population size. An effective method to increase reference population size could be to combine datasets from different populations. Prediction models might also benefit from incorporation of information on the biological underpinnings of quantitative traits. Genome-wide association studies (GWAS) show that genomic regions on Bos taurus chromosomes (BTA) 14, 19 and 26 underlie substantial proportions of the genetic variation in milk FA traits. Genomic prediction models that incorporate such results could enable improved prediction accuracy in spite of limited reference population sizes. In this study, we combine gas chromatography quantified FA samples from the Chinese, Danish and Dutch Holstein populations and implement a genomic feature best linear unbiased prediction (GFBLUP) model that incorporates variants on BTA14, 19 and 26 as genomic features for which random genetic effects are estimated separately. Prediction reliabilities were compared to those estimated with traditional GBLUP models. RESULTS: Predictions using a multi-population reference and a traditional GBLUP model resulted in average gains in prediction reliability of 10% points in the Dutch, 8% points in the Danish and 1% point in the Chinese populations compared to predictions based on population-specific references. Compared to the traditional GBLUP, implementation of the GFBLUP model with a multi-population reference led to further increases in prediction reliability of up to 38% points in the Dutch, 23% points in the Danish and 13% points in the Chinese populations. Prediction reliabilities from the GFBLUP model were moderate to high across the FA traits analyzed. CONCLUSIONS: Our study shows that it is possible to predict genetic merits for milk FA traits with reasonable accuracy by combining related populations of a breed and using models that incorporate GWAS results. Our findings indicate that international collaborations that facilitate access to multi-population datasets could be highly beneficial to the implementation of genomic selection for detailed milk composition traits.


Assuntos
Bovinos/genética , Estudo de Associação Genômica Ampla/métodos , Leite/química , Animais , Cruzamento , Ácidos Graxos/análise , Testes Genéticos/métodos , Variação Genética/genética , Genética Populacional/métodos , Genômica/métodos , Genótipo , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas , Reprodutibilidade dos Testes
16.
Hum Genet ; 138(6): 547-561, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30968250

RESUMO

Air pollution is recognized as causal factor for cardiovascular disease (CVD) and is associated with multiple CVD risk factors. Substantial research effort has been invested in understanding the linkages between genetic variation and CVD risk, resulting in over 50 CVD-associated genetic loci. More recently, gene-air pollution interaction studies have quantified the contribution of genetic variation to inter-individual heterogeneity in air pollution health risks, and aided in elucidating mechanisms of air pollution exposure health risks. Here, we perform a comprehensive review of gene-air pollution interaction studies for CVD, as well as risk factors and emerging CVD biomarkers. The literature review revealed that most published interaction studies have been candidate gene studies, causing observed interactions to cluster in a few genes related to detoxification (GSTM1 and GSTT1), inflammation (IL-6), iron processing (HFE), and microRNA processing (GEMIN4 and DGCR8). There have been a few genome-wide interaction studies with results indicating that interactions extend beyond commonly considered genetic loci. Gene-air pollution interactions are observed for exposure periods ranging from hours to years and a variety of air pollutants including particulate matter, gaseous pollutants, and pollutant sources such as traffic. Though the existing evidence for the existence of relevant gene-air pollution interactions for CVD outcomes is substantial, it could be strengthened by improved replication and meta-analyses as well as functional validation.


Assuntos
Poluição do Ar , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/genética , Exposição Ambiental/efeitos adversos , Interação Gene-Ambiente , Saúde Ambiental/métodos , Predisposição Genética para Doença/etiologia , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Medição de Risco/métodos , Fatores de Risco
17.
Hum Genet ; 138(6): 601-611, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30968251

RESUMO

Facial shape differences are one of the most significant phenotypes in humans. It is affected largely by skull shape. However, research into the genetic basis of the craniofacial morphology has rarely been reported. The present study aimed to identify genetic variants influencing craniofacial morphology in northern Han Chinese through whole-exome sequencing (WES). Phenotypic data of the volunteers' faces and skulls were obtained through three-dimensional CT scan of the skull. A total of 48 phenotypes (35 facial and 13 cranial phenotypes) were used for the bioinformatics analysis. Four genetic loci were identified affecting the craniofacial shapes. The four candidate genes are RGPD3, IGSF3, SLC28A3, and USP40. Four single-nucleotide polymorphism (SNP) site mutations in RGPD3, IGSF3, and USP40 were significantly associated with the skull shape (p < 1×10-6), and three SNP site mutations in RGPD3, IGSF3, and SLC28A3 were significantly associated with the facial shape (p < 1×10-6). The rs62152530 site mutation in the RGPD3 gene may be closely associated with the nasal length, ear length, and alar width. The rs647711 site mutation in the IGSF3 gene may be closely associated with the nasal length, mandibular width, and width between the mental foramina. The rs10868138 site mutation in the SLC28A3 gene may be associated with the nasal length, alar width, width between tragus, and width between the mental foramina. The rs1048603 and rs838543 site mutations in the USP40 gene may be closely associated with the pyriform aperture width. Our findings provide useful genetic information for the determination of face morphology.


Assuntos
Ossos Faciais/metabolismo , Loci Gênicos/genética , Polimorfismo de Nucleotídeo Único , Crânio/metabolismo , Sequenciamento Completo do Exoma/métodos , Grupo com Ancestrais do Continente Asiático/genética , Sequência de Bases , China , Anormalidades Craniofaciais/etnologia , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/patologia , Ossos Faciais/anatomia & histologia , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Crânio/anatomia & histologia
18.
Hum Genet ; 138(6): 681-689, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31025105

RESUMO

In human society, the facial surface is visible and recognizable based on the facial shape variation which represents a set of highly polygenic and correlated complex traits. Understanding the genetic basis underlying facial shape traits has important implications in population genetics, developmental biology, and forensic science. A number of single nucleotide polymorphisms (SNPs) are associated with human facial shape variation, mostly in European populations. To bridge the gap between European and Asian populations in term of the genetic basis of facial shape variation, we examined the effect of these SNPs in a European-Asian admixed Eurasian population which included a total of 612 individuals. The coordinates of 17 facial landmarks were derived from high resolution 3dMD facial images, and 136 Euclidean distances between all pairs of landmarks were quantitatively derived. DNA samples were genotyped using the Illumina Infinium Global Screening Array and imputed using the 1000 Genomes reference panel. Genetic association between 125 previously reported facial shape-associated SNPs and 136 facial shape phenotypes was tested using linear regression. As a result, a total of eight SNPs from different loci demonstrated significant association with one or more facial shape traits after adjusting for multiple testing (significance threshold p < 1.28 × 10-3), together explaining up to 6.47% of sex-, age-, and BMI-adjusted facial phenotype variance. These included EDAR rs3827760, LYPLAL1 rs5781117, PRDM16 rs4648379, PAX3 rs7559271, DKK1 rs1194708, TNFSF12 rs80067372, CACNA2D3 rs56063440, and SUPT3H rs227833. Notably, the EDAR rs3827760 and LYPLAL1 rs5781117 SNPs displayed significant association with eight and seven facial phenotypes, respectively (2.39 × 10-5 < p < 1.28 × 10-3). The majority of these SNPs showed a distinct allele frequency between European and East Asian reference panels from the 1000 Genomes Project. These results showed the details of above eight genes influence facial shape variation in a Eurasian population.


Assuntos
Face/anatomia & histologia , Genética Populacional , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Grupo com Ancestrais do Continente Asiático/etnologia , China , Grupo com Ancestrais do Continente Europeu/etnologia , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Adulto Jovem
19.
Med Sci Monit ; 25: 2452-2478, 2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30945699

RESUMO

BACKGROUND As an important aspect of tumor heterogeneity, genetic variation may influence susceptibility and prognosis in different types of cancer. By exploring the prognostic value of genetic variation, this study aimed to establish a model for predicting postoperative survival and assessing the impact of variation on clinical outcomes in patients with hepatocellular carcinoma (HCC). MATERIAL AND METHODS A genome-wide association study of 367 patients with HCC was conducted to identify single nucleotide polymorphisms (SNPs) associated with prognosis. Identified predictors were further evaluated in 758 patients. Two prognostic models were established using Cox proportional hazards regression and Nomogram strategy, and validated in another 316 patients. The effect of the SNP rs2431 was analyzed in detail. RESULTS A prognostic model including 5 SNPs (rs10893585, rs2431, rs34675408, rs6078460, and rs6766361) was established and exhibited high predictive accuracy for HCC prognosis. The panel combined with tumor node metastasis (TNM) stage resulted in a significantly higher c-index (0.723) than the individual c-index values. Stratified by the Nomogram prediction model, the median overall survival for the low-risk and high-risk groups were 100.1 versus 30.8 months (P<0.001) in the training set and 82.2 versus 22.5 months (P<0.001) in the validation set. A closer examination of rs2431 revealed that it may regulate the expression of FNDC3B by disrupting a microRNA-binding site. CONCLUSIONS This study established prediction models based on genetic factors alone or in combination with TNM stage for postoperative survival in patients with HCC, and identified FNDC3B as a potential therapeutic target for combating HCC metastasis.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidade , Testes Genéticos/métodos , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Linhagem Celular Tumoral , China , Feminino , Fibronectinas/genética , Fibronectinas/metabolismo , Estudo de Associação Genômica Ampla/métodos , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Nomogramas , Polimorfismo de Nucleotídeo Único/genética , Período Pós-Operatório , Prognóstico , Fatores de Risco
20.
Respir Res ; 20(1): 64, 2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940143

RESUMO

BACKGROUND: A growing number of studies clearly demonstrate a substantial association between chronic obstructive pulmonary disease (COPD) and cardiovascular diseases (CVD), although little is known about the shared genetics that contribute to this association. METHODS: We conducted a large-scale cross-trait genome-wide association study to investigate genetic overlap between COPD (Ncase = 12,550, Ncontrol = 46,368) from the International COPD Genetics Consortium and four primary cardiac traits: resting heart rate (RHR) (N = 458,969), high blood pressure (HBP) (Ncase = 144,793, Ncontrol = 313,761), coronary artery disease (CAD)(Ncase = 60,801, Ncontrol = 123,504), and stroke (Ncase = 40,585, Ncontrol = 406,111) from UK Biobank, CARDIoGRAMplusC4D Consortium, and International Stroke Genetics Consortium data. RESULTS: RHR and HBP had modest genetic correlation, and CAD had borderline evidence with COPD at a genome-wide level. We found evidence of local genetic correlation with particular regions of the genome. Cross-trait meta-analysis of COPD identified 21 loci jointly associated with RHR, 22 loci with HBP, and 3 loci with CAD. Functional analysis revealed that shared genes were enriched in smoking-related pathways and in cardiovascular, nervous, and immune system tissues. An examination of smoking-related genetic variants identified SNPs located in 15q25.1 region associated with cigarettes per day, with effects on RHR and CAD. A Mendelian randomization analysis showed a significant positive causal effect of COPD on RHR (causal estimate = 0.1374, P = 0.008). CONCLUSION: In a set of large-scale GWAS, we identify evidence of shared genetics between COPD and cardiac traits.


Assuntos
Doenças Cardiovasculares/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único/genética , Doença Pulmonar Obstrutiva Crônica/genética , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Bases de Dados Genéticas/tendências , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Característica Quantitativa Herdável
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