Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 418
Filtrar
1.
Mol Genet Genomic Med ; : e1267, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32478482

RESUMO

Sarcopenia is a complex polygenic disease, and its molecular mechanism is still unclear. Whole lean body mass (WLBM) is a heritable trait predicting sarcopenia. To identify genomic loci underlying, we performed a whole-exome sequencing (WES) of WLBM variation with high sequencing depth (more than 40*) in 101 Chinese subjects. We then replicated in the major findings in the large-scale UK Biobank (UKB) cohort (N = 217,822) for WLBM. The results of four single-nucleotide polymorphisms (SNPs) were significant both in the discovery stage and replication stage: SNP rs740681 (discovery p = 1.66 × 10-6 , replication p = .05), rs2272303 (discovery p = 3.20 × 10-4 , replication p = 3.10 × 10-4 ), rs11170413 (discovery p = 3.99 × 10-4 , replication p = 2.90 × 10-4 ), and rs2272302 (discovery p = 9.13 × 10-4 , replication p = 3.10 × 10-4 ). We combined p values of the significant SNPs. Functional annotations highlighted two candidate genes, including FZR1 and SOAT2, that may exert pleiotropic effects to the development of body mass. Our findings provide useful insights that further enhance our understanding of genetic interplay in sarcopenia.

2.
J Clin Endocrinol Metab ; 105(8)2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32483604

RESUMO

PURPOSE: Menopause is a crucial physiological transition during a woman's life, and it occurs with growing risks of health issues like osteoporosis. To identify postmenopausal osteoporosis-related genes, we performed transcriptome-wide expression analyses for human peripheral blood monocytes (PBMs) using Affymetrix 1.0 ST arrays in 40 Caucasian postmenopausal women with discordant bone mineral density (BMD) levels. METHODS: We performed multiscale embedded gene coexpression network analysis (MEGENA) to study functionally orchestrating clusters of differentially expressed genes in the form of functional networks. Gene sets net correlations analysis (GSNCA) was applied to assess how the coexpression structure of a predefined gene set differs in high and low BMD groups. Bayesian network (BN) analysis was used to identify important regulation patterns between potential risk genes for osteoporosis. A small interfering ribonucleic acid (siRNA)-based gene silencing in vitro experiment was performed to validate the findings from BN analysis. RESULT: MEGENA showed that the "T cell receptor signaling pathway" and the "osteoclast differentiation pathway" were significantly enriched in the identified compact network, which is significantly correlated with BMD variation. GSNCA revealed that the coexpression structure of the "Signaling by TGF-beta receptor complex pathway" is significantly different between the 2 BMD discordant groups; the hub genes in the postmenopausal low and high BMD group are FURIN and SMAD3 respectively. With siRNA in vitro experiments, we confirmed the regulation relationship of TGFBR2-SMAD7 and TGFBR1-SMURF2. MAIN CONCLUSION: The present study suggests that biological signals involved in monocyte recruitment, monocyte/macrophage lineage development, osteoclast formation, and osteoclast differentiation might function together in PBMs that contribute to the pathogenesis of postmenopausal osteoporosis.

3.
Mol Genet Genomics ; 2020 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-32474671

RESUMO

Genome-wide association studies (GWASs) have identified more than 20 genetic loci as risk predictors associated with stroke. However, these studies were generally performed for single-trait and failed to consider the pleiotropic effects of these risk genes among the multiple risk factors for stroke. In this study, we applied a novel metaCCA method followed by gene-based VEGAS2 analysis to identify the risk genes for stroke that may overlap between seven correlated risk factors (including atrial fibrillation, hypertension, coronary artery disease, heart failure, diabetes, body mass index, and total cholesterol level) by integrating seven corresponding GWAS data. We detected 20 potential pleiotropic genes that may be associated with multiple risk factors of stroke. Furthermore, using gene-to-trait pathway analysis, we suggested six potential risk genes (FUT8, GMIP, PLA2G6, PDE3A, SMARCA4, SKAPT) that may affect ischemic or hemorrhage stroke through multiple intermediate factors such as MAPK family. These findings provide novel insight into the genetic determinants contributing to the concurrent development of biological conditions that may influence stroke susceptibility, and also indicate some potential therapeutic targets that can be further studied for the prevention of cerebrovascular disease.

4.
Eur J Hum Genet ; 2020 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-32457519

RESUMO

DNA sequencing is a widely used tool in genetic association study. Sequencing cost remains a major concern in sequencing-based study, although the application of next generation sequencing has dramatically decreased the sequencing cost and increased the efficiency. The choice of sequencing depth and the sequencing sample size will largely determine the final study investment and performance. Many studies have been conducted to find a cost-effective design of sequencing depth that can achieve certain sequencing accuracy using minimal sequencing cost. The strategies previously studied can be classified into two groups: (1) single-stage to sequence all the samples using either high (>~30×) or low (<~10×) sequencing depth; and (2) two-stage to sequence an affordable number of individuals at a high-coverage followed by a large sample of low-coverage sequencing. However, limited studies examined the performance of the medium-coverage (10-30×) sequencing depth for a genetic association study, where the optimum sequencing depth may exist. In this study, using a published simulation framework, we comprehensively compared the medium-coverage sequencing (MCS) to the single- and two-stage high/low-coverage sequencing in terms of the power and type I error of the variant discovery and association testing. We found, given certain sequencing effort, MCS yielded a comparable discovery power and better type I error control compared with the best (highest power) scenarios using other high- and low-coverage single-stage or two-stage designs. However, MCS was not as competent as other designs with respect to the association power, especially for the rare variants and when the sequencing investment was limited.

5.
Public Health Nutr ; : 1-11, 2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-32389160

RESUMO

OBJECTIVE: To assess the prevalence and to identify the associated factors of malnutrition among elderly Chinese with physical functional dependency. DESIGN: Face-to-face interviews using standardised questionnaires were conducted to collect demographic information, health-related issues and psychosocial status. Physical function was measured by the Barthel Index (BI), and nutrition status was assessed by the Mini Nutritional Assessment-Short Form. Multivariate binary logistic regression was used to assess associated factors of malnutrition. SETTING: China. PARTICIPANTS: A total of 2323 participants (aged ≥ 60 years) with physical functional dependency in five provinces in China were enrolled using a multistage cluster sampling scheme. RESULTS: The prevalence of malnutrition was 17·9 % (95 % CI 16·3, 19·4). Multivariable binary logistic regression revealed the independent risk factors of poor nutrition status were being female, older age, lower educational status, poor hearing, poor physical functional status, lack of hobbies, low religious participation, poor social support, lack of social participation and changes in social participation. The study found that the most significant independent risk factor for malnutrition was complete physical functional dependence (OR 4·46, 95 % CI 2·92, 6·82). CONCLUSIONS: The findings of the study confirm that malnutrition and the risk of malnutrition are prevalent in Chinese older adults with physical functional dependency. In addition to demographic and physical health-related factors, psychosocial factors, which are often overlooked, are independently associated with nutrition status in Chinese older adults with physical functional dependency. A holistic approach should be adopted to screen for malnutrition and develop health promotion interventions in this vulnerable population.

6.
Hum Genet ; 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32239398

RESUMO

Aiming to uncover a shared genetic basis of abdominal obesity and osteoporosis, we performed a bivariate GWAS meta-analysis of femoral neck BMD (FNK-BMD) and trunk fat mass adjusted by trunk lean mass (TFMadj) in 11,496 subjects from 6 samples, followed by in silico replication in the large-scale UK Biobank (UKB) cohort. A series of functional investigations were conducted on the identified variants. Bivariate GWAS meta-analysis identified two novel pleiotropic loci 12q15 (lead SNP rs73134637, p = 3.45 × 10-7) and 10p14 (lead SNP rs2892347, p = 2.63 × 10-7) that were suggestively associated and that were replicated in the analyses of related traits in the UKB sample (osteoporosis p = 0.06 and 0.02, BMI p = 0.03 and 4.61 × 10-3, N up to 499,520). Cis-eQTL analysis demonstrated that allele C at rs73134637 was positively associated with IFNG expression in whole blood (N = 369, p = 0.04), and allele A at rs11254759 (10p14, p = 9.49 × 10-7) was negatively associated with PRKCQ expression in visceral adipose tissue (N = 313, p = 0.04) and in lymphocytes (N = 117, p = 0.03). As a proof-of-principle experiment, the function of rs11254759, which is 235 kb 5'-upstream from PRKCQ gene, was investigated by the dual-luciferase reporter assay, which clearly showed that the haplotype carrying rs11254759 regulated PRKCQ expression by upregulating PRKCQ promoter activity (p = 4.60 × 10-7) in an allelic specific manner. Mouse model analysis showed that heterozygous PRKCQ deficient mice presented decreased fat mass compared to wild-type control mice (p = 3.30 × 10-3). Mendelian randomization analysis demonstrated that both FNK-BMD and TFMadj were causally associated with fracture risk (p = 1.26 × 10-23 and 1.18 × 10-11). Our findings may provide useful insights into the genetic association between osteoporosis and abdominal obesity.

7.
Mol Genet Genomics ; 295(3): 607-619, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32162118

RESUMO

Genome-wide association studies (GWASs) have identified hundreds of single nucleotide polymorphisms (SNPs) associated with type 2 diabetes (T2D) and coronary artery disease (CAD), respectively. Nevertheless, these studies were generally performed for single-trait/disease and failed to assess the pleiotropic role of the identified variants. To identify novel functional loci and the pleiotropic relationship between CAD and T2D, the targeted cFDR analysis on CpG-SNPs was performed by integrating two independent large and multi-centered GWASs with summary statistics of T2D (26,676 cases and 132,532 controls) and CAD (60,801 cases and 123,504 controls). Applying the cFDR significance threshold of 0.05, we observed a pleiotropic enrichment between T2D and CAD by incorporating pleiotropic effects into a conditional analysis framework. We identified 79 novel CpG-SNPs for T2D, 61 novel CpG-SNPs for CAD, and 18 novel pleiotropic loci for both traits. Among these novel CpG-SNPs, 33 of them were annotated as methylation quantitative trait locus (meQTL) in whole blood, and ten of them showed expression QTL (eQTL), meQTL, and metabolic QTL (metaQTL) effects simultaneously. To the best of our knowledge, we performed the first targeted cFDR analysis on CpG-SNPs, and our findings provided novel insights into the shared biological mechanisms and overlapped genetic heritability between T2D and CAD.


Assuntos
Doença da Artéria Coronariana/genética , Ilhas de CpG , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Locos de Características Quantitativas , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Redes Reguladoras de Genes , Pleiotropia Genética , Estudo de Associação Genômica Ampla , Humanos , Fenótipo , Mapas de Interação de Proteínas
8.
Sci Rep ; 10(1): 4293, 2020 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-32152362

RESUMO

Whole body lean mass (WBLM) is a heritable trait predicting sarcopenia. To identify genomic locus underlying WBLM, we performed a genome-wide association study of fat-adjusted WBLM in the Framingham Heart Study (FHS, N = 6,004), and replicated in the Kansas City Osteoporosis Study (KCOS, N = 2,207). We identified a novel locus 3p27.1 that was associated with WBLM (lead SNP rs3732593 P = 7.19 × 10-8) in the discovery FHS sample, and the lead SNP was successfully replicated in the KCOS sample (one-sided P = 0.04). Bioinformatics analysis found that this SNP and its adjacent SNPs had the function of regulating enhancer activity in skeletal muscle myoblasts cells, further confirming the regulation of WBLM by this locus. Our finding provides new insight into the genetics of WBLM and enhance our understanding of sarcopenia.

9.
Sci Rep ; 10(1): 5057, 2020 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-32193455

RESUMO

Sarcopenia is characterized by low skeletal muscle, a complex trait with high heritability. With the dramatically increasing prevalence of obesity, obesity and sarcopenia occur simultaneously, a condition known as sarcopenic obesity. Fat mass and obesity-associated (FTO) gene is a candidate gene of obesity. To identify associations between lean mass and FTO gene, we performed a genome-wide association study (GWAS) of lean mass index (LMI) in 2207 unrelated Caucasian subjects and replicated major findings in two replication samples including 6,004 unrelated Caucasian and 38,292 unrelated Caucasian. We found 29 single nucleotide polymorphisms (SNPs) in FTO significantly associated with sarcopenia (combined p-values ranging from 5.92 × 10-12 to 1.69 × 10-9). Potential biological functions of SNPs were analyzed by HaploReg v4.1, RegulomeDB, GTEx, IMPC and STRING. Our results provide suggestive evidence that FTO gene is associated with lean mass.

10.
Aging (Albany NY) ; 12(4): 3340-3353, 2020 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-32062614

RESUMO

Previous Mendelian randomization (MR) studies have yielded a conflicting causal relationship between sarcopenia and coronary artery disease (CAD), and lack the association of CAD with sarcopenia. We performed a bi-directional MR approach to clarify the causality and causal direction between sarcopenia-related traits and CAD. In stage 1 analysis, estimates of inverse variance weighting (IVW) and several sensitivity analyses were obtained by applying genetic variants that predict sarcopenia-related traits to CAD. Conversely, we also applied genetic variants that predict CAD to sarcopenia-related traits in stage 2 analyses. IVW analysis showed that higher handgrip strength reduces risk for CAD: A 1-kilogram (kg) increase in genetically determined left handgrip strength reduced odds of CAD by 36% [odds ratio (OR) = 0.64, 95% confidence interval (CI) 0.498 - 0.821, p = 4.56E-04], and right handgrip strength reduced odds of CAD by 41.1% (OR = 0.599, 95% CI 0.476 - 0.753, p = 1.10E-05). However, genetically predicted CAD did not show any causal association with handgrip strength, and no significant causal relationship was detected between genetically instrumented body lean mass and CAD. Our results suggest that decreased muscle strength but not decreased muscle mass leads to the increased risk of CAD in sarcopenia.

11.
Epigenetics ; 15(6-7): 728-749, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31975641

RESUMO

A major challenge in translating findings from genome-wide association studies (GWAS) to biological mechanisms is pinpointing functional variants because only a very small percentage of variants associated with a given trait actually impact the trait. We used an extensive epigenetics, transcriptomics, and genetics analysis of the TBX15/WARS2 neighbourhood to prioritize this region's best-candidate causal variants for the genetic risk of osteoporosis (estimated bone density, eBMD) and obesity (waist-hip ratio or waist circumference adjusted for body mass index). TBX15 encodes a transcription factor that is important in bone development and adipose biology. Manual curation of 692 GWAS-derived variants gave eight strong candidates for causal SNPs that modulate TBX15 transcription in subcutaneous adipose tissue (SAT) or osteoblasts, which highly and specifically express this gene. None of these SNPs were prioritized by Bayesian fine-mapping. The eight regulatory causal SNPs were in enhancer or promoter chromatin seen preferentially in SAT or osteoblasts at TBX15 intron-1 or upstream. They overlap strongly predicted, allele-specific transcription factor binding sites. Our analysis suggests that these SNPs act independently of two missense SNPs in TBX15. Remarkably, five of the regulatory SNPs were associated with eBMD and obesity and had the same trait-increasing allele for both. We found that WARS2 obesity-related SNPs can be ascribed to high linkage disequilibrium with TBX15 intron-1 SNPs. Our findings from GWAS index, proxy, and imputed SNPs suggest that a few SNPs, including three in a 0.7-kb cluster, act as causal regulatory variants to fine-tune TBX15 expression and, thereby, affect both obesity and osteoporosis risk.

12.
Commun Biol ; 3(1): 39, 2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31969651

RESUMO

Osteoporosis is a highly prevalent chronic aging-related disease that frequently is only detected after fracture. We hypothesized that aminobutyric acids could serve as biomarkers for osteoporosis. We developed a quick, accurate, and sensitive screening method for aminobutyric acid isomers and enantiomers yielding correlations with bone mineral density (BMD) and osteoporotic fracture. In serum, γ-aminobutyric acid (GABA) and (R)-3-aminoisobutyric acid (D-BAIBA) have positive associations with physical activity in young lean women. D-BAIBA positively associated with hip BMD in older individuals without osteoporosis/osteopenia. Lower levels of GABA were observed in 60-80 year old women with osteoporotic fractures. Single nucleotide polymorphisms in seven genes related to these metabolites associated with BMD and osteoporosis. In peripheral blood monocytes, dihydropyrimidine dehydrogenase, an enzyme essential to D-BAIBA generation, exhibited positive association with physical activity and hip BMD. Along with their signaling roles, BAIBA and GABA might serve as biomarkers for diagnosis and treatments of osteoporosis.

14.
Nat Rev Endocrinol ; 16(2): 91-103, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31792439

RESUMO

Osteoporosis is a highly prevalent disorder characterized by low bone mineral density and an increased risk of fracture, termed osteoporotic fracture. Notably, bone mineral density, osteoporosis and osteoporotic fracture are highly heritable; however, determining the genetic architecture, and especially the underlying genomic and molecular mechanisms, of osteoporosis in vivo in humans is still challenging. In addition to susceptibility loci identified in genome-wide association studies, advances in various omics technologies, including genomics, transcriptomics, epigenomics, proteomics and metabolomics, have all been applied to dissect the pathogenesis of osteoporosis. However, each technology individually cannot capture the entire view of the disease pathology and thus fails to comprehensively identify the underlying pathological molecular mechanisms, especially the regulatory and signalling mechanisms. A change to the status quo calls for integrative multi-omics and inter-omics analyses with approaches in 'systems genetics and genomics'. In this Review, we highlight findings from genome-wide association studies and studies using various omics technologies individually to identify mechanisms of osteoporosis. Furthermore, we summarize current studies of data integration to understand, diagnose and inform the treatment of osteoporosis. The integration of multiple technologies will provide a road map to illuminate the complex pathogenesis of osteoporosis, especially from molecular functional aspects, in vivo in humans.


Assuntos
Densidade Óssea/fisiologia , Estudo de Associação Genômica Ampla/métodos , Osteoporose/genética , Osteoporose/metabolismo , Epigenômica/métodos , Fraturas Ósseas/genética , Fraturas Ósseas/metabolismo , Fraturas Ósseas/prevenção & controle , Genômica/métodos , Humanos , Metabolômica/métodos , Osteoporose/epidemiologia , Proteômica/métodos
15.
Skelet Muscle ; 9(1): 28, 2019 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-31757224

RESUMO

BACKGROUND: Low lean body mass is the most important predictor of sarcopenia with strong genetic background. The aim of this study was to uncover genetic factors underlying lean mass development. MATERIALS AND METHODS: We performed a genome-wide association study (GWAS) of fat-adjusted leg lean mass in the Framingham Heart Study (FHS, N = 6587), and replicated in the Women's Health Initiative-African American sub-sample (WHI-AA, N = 847) and the Kansas City Osteoporosis Study (KCOS, N = 2219). We also cross-validated significant variants in the publicly available body mass index (BMI) summary results (N ~ 700,000). We then performed a series of functional investigations on the identified variants. RESULTS: Four correlated SNPs at 6p21.1 were identified at the genome-wide significance (GWS, α = 5.0 × 10-8) level in the discovery FHS sample (rs551145, rs524533, rs571770, and rs545970, p = 3.40-9.77 × 10-9), and were successfully replicated in both the WHI-AA and the KCOS samples (one-sided p = 1.61 × 10-3-0.04). They were further cross-validated by the large-scale BMI summary results (p = 7.0-9.8 × 10-3). Cis-eQTL analyses associated these SNPs with the NFKBIE gene expression. Electrophoresis mobility shift assay (EMSA) in mouse C2C12 myoblast cells implied that rs524533 and rs571770 were bound to an unknown transcription factor in an allelic specific manner, while rs551145 and rs545970 did not. Dual-luciferase reporter assay revealed that both rs524533 and rs571770 downregulated luciferase expression by repressing promoter activity. Moreover, the regulation pattern was allelic specific, strengthening the evidence towards their differential regulatory effects. CONCLUSIONS: Through a large-scale GWAS followed by a series of functional investigations, we identified 2 correlated functional variants at 6p21.1 associated with leg lean mass. Our findings not only enhanced our understanding of molecular basis of lean mass development but also provided useful candidate genes for further functional studies.


Assuntos
Cromossomos Humanos Par 6/genética , Polimorfismo de Nucleotídeo Único , Sarcopenia/genética , Magreza/genética , Idoso , Animais , Índice de Massa Corporal , Linhagem Celular , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Proteínas I-kappa B/genética , Desequilíbrio de Ligação , Masculino , Camundongos , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas/genética , Locos de Características Quantitativas , Sarcopenia/patologia , Magreza/patologia
16.
J Bioinform Comput Biol ; 17(4): 1950028, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31617462

RESUMO

The kernel canonical correlation analysis based U-statistic (KCCU) is being used to detect nonlinear gene-gene co-associations. Estimating the variance of the KCCU is however computationally intensive. In addition, the kernel canonical correlation analysis (kernel CCA) is not robust to contaminated data. Using a robust kernel mean element and a robust kernel (cross)-covariance operator potentially enables the use of a robust kernel CCA, which is studied in this paper. We first propose an influence function-based estimator for the variance of the KCCU. We then present a non-parametric robust KCCU, which is designed for dealing with contaminated data. The robust KCCU is less sensitive to noise than KCCU. We investigate the proposed method using both synthesized and real data from the Mind Clinical Imaging Consortium (MCIC). We show through simulation studies that the power of the proposed methods is a monotonically increasing function of sample size, and the robust test statistics bring incremental gains in power. To demonstrate the advantage of the robust kernel CCA, we study MCIC data among 22,442 candidate Schizophrenia genes for gene-gene co-associations. We select 768 genes with strong evidence for shedding light on gene-gene interaction networks for Schizophrenia. By performing gene ontology enrichment analysis, pathway analysis, gene-gene network and other studies, the proposed robust methods can find undiscovered genes in addition to significant gene pairs, and demonstrate superior performance over several of current approaches.

17.
Sci Rep ; 9(1): 12311, 2019 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-31444391

RESUMO

It has been reported that geographical variation influences bone mineral density (BMD), obesity, and sarcopenia related traits in other countries. However, there is lack of similar studies in the US population. In this study, we compared data from three US study cohorts to evaluate geographical variations of BMD and body composition. BMD, fat mass and lean mass were collected from Dual-energy X-ray absorptiometry machine. ANCOVA and Chi-square tests were used to compare the differences between BMDs, obesity and sarcopenia related traits from different regional sites (Omaha, Kansas City and Baton Rouge/New Orleans). Eta-squared was used to measure the effect sizes of these differences. A total of 11,315 Caucasians from our previous three study cohorts were compared. There was no significant geographical difference in BMD for males or females under the criteria of p-values < 0.05 and effect size η2 > 0.01. There were significant geographical differences with medium effect size (p-value < 0.001, 0.01 < η2 < 0.14) for whole body fat mass percentage and index of low muscle mass. For Caucasians in the United States, there is no significant geographical effect found on BMD. The obesity and sarcopenia related traits are significantly different between the three study cohorts.

18.
Sci Rep ; 9(1): 10863, 2019 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-31350445

RESUMO

Differential network analysis investigates how the network of connected genes changes from one condition to another and has become a prevalent tool to provide a deeper and more comprehensive understanding of the molecular etiology of complex diseases. Based on the asymptotically normal estimation of large Gaussian graphical model (GGM) in the high-dimensional setting, we developed a computationally efficient test for differential network analysis through testing the equality of two precision matrices, which summarize the conditional dependence network structures of the genes. Additionally, we applied a multiple testing procedure to infer the differential network structure with false discovery rate (FDR) control. Through extensive simulation studies with different combinations of parameters including sample size, number of vertices, level of heterogeneity and graph structure, we demonstrated that our method performed much better than the current available methods in terms of accuracy and computational time. In real data analysis on lung adenocarcinoma, we revealed a differential network with 3503 nodes and 2550 edges, which consisted of 50 clusters with an FDR threshold at 0.05. Many of the top gene pairs in the differential network have been reported relevant to human cancers. Our method represents a powerful tool of network analysis for high-dimensional biological data.

19.
Biol Reprod ; 101(2): 457-465, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31162612

RESUMO

Zona pellucida (ZP), which enwraps the oocyte during folliculogenesis, initially forms in the primary follicle and plays an important role in female fertility. Here, we investigated a mouse strain ("mutant mice" for short) carrying two types of ZP defects in folliculogenesis, i.e., ZP thinned (but intact) and ZP cracked, caused by targeted mutation in the Zp1 gene. Using this mutant mouse strain and wild-type mouse as control, we studied the effects of the ZP defects on the development of oocytes and granulosa cells during folliculogenesis. For each ZP defect, we examined the morphology of transzonal projections and apoptosis of granulosa cells in the corresponding growing follicles, as well as the morphology of corresponding ovulated eggs and their abilities to develop into viable individuals. Our results suggested that ZP integrity rather than thickness or porosity is crucial for preventing the ectopia of granulosa cells, maintaining adequate routine bilateral signaling between oocyte and surrounding granulosa cells, and thus for ensuring the survival of granulosa cells and the establishment of the full developmental competence of oocytes. This is the first study to elucidate the effects of different degrees of ZP defects caused by the same gene mutation, on the apoptosis of granulosa cells and developmental competence of oocytes, and to explore the potential mechanisms underlying these effects.

20.
J Hum Genet ; 64(8): 781-787, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31165785

RESUMO

Genome-wide association studies (GWASs) have identified >20 genetic loci associated with human intelligence. However, due to correlations between the trait-associated SNPs, only a few of the loci are confirmed to have a true biological effect. In order to distinguish the SNPs that have a causal effect on human intelligence, we must eliminate the noise from the high degree of linkage disequilibrium that persists throughout the genome. In this study, we apply a novel PAINTOR fine-mapping method, which uses a Bayesian approach to determine the SNPs with the highest probability of causality. This technique incorporates the GWAS summary statistics, linkage disequilibrium structure, and functional annotations to compute the posterior probability of causality for all SNPs in the GWAS-associated regions. We found five SNPs (rs6002620, rs41352752, rs6568547, rs138592330, and rs28371699) with a high probability of causality, three of which have posterior probabilities >0.60. The SNP rs6002620 (NDUFA6), which is involved in mitochondrial function, has the highest likelihood of causality. These findings provide important insight into the genetic determinants contributing to human intelligence.


Assuntos
Mapeamento Cromossômico , Variação Genética , Inteligência/genética , Modelos Genéticos , Locos de Características Quantitativas , Característica Quantitativa Herdável , Algoritmos , Biologia Computacional/métodos , Interpretação Estatística de Dados , Bases de Dados Genéticas , Estudo de Associação Genômica Ampla , Humanos , Anotação de Sequência Molecular , Polimorfismo de Nucleotídeo Único
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA