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1.
Menopause ; 2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34313616

RESUMO

OBJECTIVE: To examine the contribution of skeletal mass index (SMI) as a mediator in the relationship between menarcheal age and hip/spine bone mineral density (BMD) in premenopausal women by race/ethnicity. METHODS: The data of 4,329 participants (age ≥ 18; mean age=35.7 ±â€Š9.5) of Whites (n = 2,543), African Americans (n = 1,236), and Asians (n = 550) enrolled from October 2011 to January 2019 from the Louisiana Osteoporosis Study were analyzed. After adjustment for physiological and behavioral factors, multivariable linear regression analyses were conducted to evaluate each component of the proposed mediation models, and mediation was verified by the bootstrapping resampling approach. RESULTS: Premenopausal women with early menarcheal age tended to have higher SMI and BMD than women with normal menarcheal age among all races/ethnicities included. Women with late menarcheal age were, however, more likely to have a lower SMI than their counterparts with normal menarcheal age (r = -0.212, 95% CI = [-0.321 to -0.103] for White women; r = -0.181, 95% CI = [-0.410 to -0.008] for African-American women; r = -0.174, 95% CI = [-0.343 to -0.006] for Asian women). Similar results were found for both spine and hip BMD. SMI fully mediated the difference in BMD due to different menarcheal ages among Whites, African Americans, and Asian women with early menarcheal age; however, no mediating effects were observed for Asian women with late menarcheal age. CONCLUSIONS: SMI, as a full mediator, affected the relationship between menarcheal age and BMD among premenopausal women, and the mediating effects varied by race/ethnicity. To prevent or slow down the loss of hip/spine BMD and the development of osteoporosis, measures aiming at minimizing the risk for muscle mass loss should be recommended, especially for White and African-American women with late menarcheal age.

2.
J Biomed Inform ; 120: 103854, 2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34237438

RESUMO

In recent years, a comprehensive study of complex disease with multi-view datasets (e.g., multi-omics and imaging scans) has been a focus and forefront in biomedical research. State-of-the-art biomedical technologies are enabling us to collect multi-view biomedical datasets for the study of complex diseases. While all the views of data tend to explore complementary information of disease, analysis of multi-view data with complex interactions is challenging for a deeper and holistic understanding of biological systems. In this paper, we propose a novel generalized kernel machine approach to identify higher-order composite effects in multi-view biomedical datasets (GKMAHCE). This generalized semi-parametric (a mixed-effect linear model) approach includes the marginal and joint Hadamard product of features from different views of data. The proposed kernel machine approach considers multi-view data as predictor variables to allow a more thorough and comprehensive modeling of a complex trait. We applied GKMAHCE approach to both synthesized datasets and real multi-view datasets from adolescent brain development and osteoporosis study. Our experiments demonstrate that the proposed method can effectively identify higher-order composite effects and suggest that corresponding features (genes, region of interests, and chemical taxonomies) function in a concerted effort. We show that the proposed method is more generalizable than existing ones. To promote reproducible research, the source code of the proposed method is available at.

3.
Bone ; 153: 116106, 2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34252604

RESUMO

Transcriptome-wide association studies (TWAS) systematically investigate the association of genetically predicted gene expression with disease risk, providing an effective approach to identify novel susceptibility genes. Osteoporosis is the most common metabolic bone disease, associated with reduced bone mineral density (BMD) and increased risk of osteoporotic fractures, whereas genetic factors explain approximately 70% of the variance in phenotypes associated with bone. BMD is commonly assessed using dual-energy X-ray absorptiometry (DXA) to obtain measurements (g/cm2) of areal BMD. However, quantitative computed tomography (QCT) measured 3D volumetric BMD (vBMD) (g/cm3) has important advantages compared with DXA since it can evaluate cortical and trabecular microstructural features of bone quality, which can be used to directly predict fracture risk. Here, we performed the first TWAS for volumetric BMD (vBMD) by integrating genome-wide association studies (GWAS) data from two independent cohorts, namely the Framingham Heart Study (FHS, n = 3298) and the Osteoporotic Fractures in Men (MrOS, n = 4641), with tissue-specific gene expression data from the Genotype-Tissue Expression (GTEx) project. We first used stratified linkage disequilibrium (LD) score regression approach to identify 12 vBMD-relevant tissues, for which vBMD heritability is enriched in tissue-specific genes of the given tissue. Focusing on these tissues, we subsequently leveraged GTEx expression reference panels to predict tissue-specific gene expression levels based on the genotype data from FHS and MrOS. The associations between predicted gene expression levels and vBMD variation were then tested by MultiXcan, an innovative TWAS method that integrates information available across multiple tissues. We identified 70 significant genes associated with vBMD, including some previously identified osteoporosis-related genes such as LYRM2 and NME8, as well as some novel loci such as DNAAF2 and SPAG16. Our findings provide novel insights into the pathophysiological mechanisms of osteoporosis and highlight several novel vBMD-associated genes that warrant further investigation.

4.
Aging (Albany NY) ; 13(11): 15595-15619, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34111027

RESUMO

The homeostasis of bone metabolism depends on the coupling and precise regulation of various types of cells in bone tissue. However, the communication and interaction between bone tissue cells at the single-cell level remains poorly understood. Thus, we performed single-cell RNA sequencing (scRNA-seq) on the primary human femoral head tissue cells (FHTCs). Nine cell types were identified in 26,574 primary human FHTCs, including granulocytes, T cells, monocytes, B cells, red blood cells, osteoblastic lineage cells, endothelial cells, endothelial progenitor cells (EPCs) and plasmacytoid dendritic cells. We identified serine protease 23 (PRSS23) and matrix remodeling associated protein 8 (MXRA8) as novel bone metabolism-related genes. Additionally, we found that several subtypes of monocytes, T cells and B cells were related to bone metabolism. Cell-cell communication analysis showed that collagen, chemokine, transforming growth factor and their ligands have significant roles in the crosstalks between FHTCs. In particular, EPCs communicated with osteoblastic lineage cells closely via the "COL2A1-ITGB1" interaction pair. Collectively, this study provided an initial characterization of the cellular composition of the human FHTCs and the complex crosstalks between them at the single-cell level. It is a unique starting resource for in-depth insights into bone metabolism.


Assuntos
Cabeça do Fêmur/metabolismo , Análise de Sequência de RNA , Análise de Célula Única , Linfócitos B/metabolismo , Linhagem da Célula/genética , Perfilação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Monócitos/metabolismo , Osteoblastos/citologia , Osteoblastos/metabolismo , Linfócitos T/metabolismo
5.
Ann Hum Genet ; 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34115876

RESUMO

Bone mineral density (BMD) and whole-body lean mass (WBLM) are two important phenotypes of osteoporosis and sarcopenia. Previous studies have shown that BMD and lean mass were phenotypically and genetically correlated. To identify the novel common genetic factors shared between BMD and WBLM, we performed the conditional false discovery rate (cFDR) analysis using summary data of the genome-wide association study of femoral neck BMD (n = 53,236) and WBLM (n = 38,292) from the Genetic Factors for Osteoporosis Consortium (GEFOS). We identified eight pleiotropic Single Nucleotide Polymorphism (SNPs) (PLCL1 rs11684176 and rs2880389, JAZF1 rs198, ADAMTSL3 rs10906982, RFTN2/MARS2 rs7340470, SH3GL3 rs1896797, ST7L rs10776755, ANKRD44/SF3B1 rs11888760) significantly associated with femoral neck BMD and WBLM (ccFDR < 0.05). Bayesian fine-mapping analysis showed that rs11888760, rs198, and rs1896797 were the possible functional variants in the ANKRD44/SF3B1, JAZF1i, and SH3GL3 loci, respectively. Functional annotation suggested that rs11888760 was likely to comprise a DNA regulatory element and linked to the expression of RFTN2 and PLCL1. PLCL1 showed differential expression in laryngeal posterior cricoarytenoid muscle between rats of 6 months and 30 months of age. Our findings, together with PLCL1's potential functional relevance to bone and skeletal muscle function, suggested that rs11888760 was the possible pleiotropic functional variants appearing to coregulate both bone and muscle metabolism through regulating the expression of PLCL1. The findings enhanced our knowledge of genetic associations between BMD and lean mass and provide a rationale for subsequent functional studies of the implicated genes in the pathophysiology of diseases, such as osteoporosis and sarcopenia.

6.
Brief Bioinform ; 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33975333

RESUMO

Neuropeptides (NPs) are the most versatile neurotransmitters in the immune systems that regulate various central anxious hormones. An efficient and effective bioinformatics tool for rapid and accurate large-scale identification of NPs is critical in immunoinformatics, which is indispensable for basic research and drug development. Although a few NP prediction tools have been developed, it is mandatory to improve their NPs' prediction performances. In this study, we have developed a machine learning-based meta-predictor called NeuroPred-FRL by employing the feature representation learning approach. First, we generated 66 optimal baseline models by employing 11 different encodings, six different classifiers and a two-step feature selection approach. The predicted probability scores of NPs based on the 66 baseline models were combined to be deemed as the input feature vector. Second, in order to enhance the feature representation ability, we applied the two-step feature selection approach to optimize the 66-D probability feature vector and then inputted the optimal one into a random forest classifier for the final meta-model (NeuroPred-FRL) construction. Benchmarking experiments based on both cross-validation and independent tests indicate that the NeuroPred-FRL achieves a superior prediction performance of NPs compared with the other state-of-the-art predictors. We believe that the proposed NeuroPred-FRL can serve as a powerful tool for large-scale identification of NPs, facilitating the characterization of their functional mechanisms and expediting their applications in clinical therapy. Moreover, we interpreted some model mechanisms of NeuroPred-FRL by leveraging the robust SHapley Additive exPlanation algorithm.

7.
Aging (Albany NY) ; 13(7): 10619-10658, 2021 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-33835050

RESUMO

Genome-wide association studies (GWASs) have identified hundreds of genetic loci for type 2 diabetes (T2D) and birth weight (BW); however, a large proportion of the total trait heritability remains unexplained. The previous studies were generally focused on individual traits and largely failed to identify the majority of the variants that play key functional roles in the etiology of the disease. Here, we aim to identify novel functional loci for T2D, BW and the pleiotropic variants shared between them by performing a targeted conditional false discovery rate (cFDR) analysis that integrates two independent GWASs with summary statistics for T2D (n = 26,676 cases and 132,532 controls) and BW (n = 153,781) which entails greater statistical power than individual trait analyses. In this analysis, we considered CpG-SNPs, which are SNPs that may influence DNA methylation status, and are therefore considered to be functionally important. We identified 103 novel CpG-SNPs for T2D, 182 novel CpG-SNPs for BW (cFDR < 0.05), and 52 novel pleiotropic loci for both (conjunction cFDR [ccFDR] < 0.05). Among the identified novel CpG-SNPs, 33 were annotated as methylation quantitative trait loci (meQTLs) in whole blood, and 145 displayed at least some effects on meQTL, metabolic QTL (metaQTL), and/or expression QTL (eQTL). These findings may provide further insights into the shared biological mechanisms and functional genetic determinants that overlap between T2D and BW, thereby providing novel potential targets for treatment/intervention development.


Assuntos
Ilhas de CpG/genética , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença/genética , Recém-Nascido de Baixo Peso , Polimorfismo de Nucleotídeo Único/genética , Metilação de DNA/genética , Estudo de Associação Genômica Ampla , Humanos , Locos de Características Quantitativas
8.
Front Immunol ; 12: 643894, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33889153

RESUMO

Strong relationships have been found between appendicular lean mass (ALM) and bone mineral density (BMD). It may be due to a shared genetic basis, termed pleiotropy. By leveraging the pleiotropy with BMD, the aim of this study was to detect more potential genetic variants for ALM. Using the conditional false discovery rate (cFDR) methodology, a combined analysis of the summary statistics of two large independent genome wide association studies (GWAS) of ALM (n = 73,420) and BMD (n = 10,414) was conducted. Strong pleiotropic enrichment and 26 novel potential pleiotropic SNPs were found for ALM and BMD. We identified 156 SNPs for ALM (cFDR <0.05), of which 74 were replicates of previous GWASs and 82 were novel SNPs potentially-associated with ALM. Eleven genes annotated by 31 novel SNPs (13 pleiotropic and 18 ALM specific) were partially validated in a gene expression assay. Functional enrichment analysis indicated that genes corresponding to the novel potential SNPs were enriched in GO terms and/or KEGG pathways that played important roles in muscle development and/or BMD metabolism (adjP <0.05). In protein-protein interaction analysis, rich interactions were demonstrated among the proteins produced by the corresponding genes. In conclusion, the present study, as in other recent studies we have conducted, demonstrated superior efficiency and reliability of the cFDR methodology for enhanced detection of trait-associated genetic variants. Our findings shed novel insight into the genetic variability of ALM in addition to the shared genetic basis underlying ALM and BMD.

9.
J Clin Endocrinol Metab ; 106(8): e3159-e3177, 2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-33693744

RESUMO

CONTEXT: Although metabolic profiles appear to play an important role in menopausal bone loss, the functional mechanisms by which metabolites influence bone mineral density (BMD) during menopause are largely unknown. OBJECTIVE: We aimed to systematically identify metabolites associated with BMD variation and their potential functional mechanisms in peri- and postmenopausal women. DESIGN AND METHODS: We performed serum metabolomic profiling and whole-genome sequencing for 517 perimenopausal (16%) and early postmenopausal (84%) women aged 41 to 64 years in this cross-sectional study. Partial least squares regression and general linear regression analysis were applied to identify BMD-associated metabolites, and weighted gene co-expression network analysis was performed to construct co-functional metabolite modules. Furthermore, we performed Mendelian randomization analysis to identify causal relationships between BMD-associated metabolites and BMD variation. Finally, we explored the effects of a novel prominent BMD-associated metabolite on bone metabolism through both in vivo/in vitro experiments. RESULTS: Twenty metabolites and a co-functional metabolite module (consisting of fatty acids) were significantly associated with BMD variation. We found dodecanoic acid (DA), within the identified module causally decreased total hip BMD. Subsequently, the in vivo experiments might support that dietary supplementation with DA could promote bone loss, as well as increase the osteoblast and osteoclast numbers in normal/ovariectomized mice. Dodecanoic acid treatment differentially promoted osteoblast and osteoclast differentiation, especially for osteoclast differentiation at higher concentrations in vitro (eg,10, 100 µM). CONCLUSIONS: This study sheds light on metabolomic profiles associated with postmenopausal osteoporosis risk, highlighting the potential importance of fatty acids, as exemplified by DA, in regulating BMD.

10.
Calcif Tissue Int ; 109(1): 17-31, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33740106

RESUMO

Genome-wide association studies (GWASs) have identified hundreds of genetic loci for osteoporosis (OP) and rheumatoid arthritis (RA), individually, however, a large proportion of the total trait heritability remains unexplained. Previous studies demonstrated that these two diseases may share some common genetic determination and risk factors, but they were generally focused on individual trait and failed to identify the common variants that play key functional roles in the etiology of these two diseases. Here, we performed a conditional false discovery rate (cFDR) analysis to identify novel pleiotropic variants shared between them by integrating two independent GWASs with summary statistics for total body bone mineral density (TB-BMD, a major risk factor for osteoporosis) (n = 66,628) and RA (n = 58,284). A fine-mapping approach was also applied to identify the most probable causal variants with biological effects on both TB-BMD and RA. As a result, we found 47 independent pleiotropic SNPs shared between TB-BMD and RA, and 40 of them were validated in heel ultrasound estimated BMD (eBMD), femoral neck BMD (FN-BMD) or lumbar spine (LS-BMD). We detected one SNP (rs13299616) was novel and not identified by previous BMD or RA-related studies. Combined with fine-mapping and GWAS-eQTL colocalization analyses, our results suggested that locus 1p13.2 (including PTPN22, MAGI3, PHTF1, and RSBN1) was an important region to regulate TB-BMD and RA simultaneously. These findings provide new insights into the shared biological mechanisms and functional genetic determinants between OP and RA, and novel potential targets for treatment development.

11.
J Hypertens ; 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33758158

RESUMO

OBJECTIVE: We carried out sensitivity analyses on gut microbiota metagenomic sequencing, untargeted metabolome, targeted metabolome for short-chain fatty acids (SCFAs) and human whole genome sequencing from 402 early postmenopausal Chinese women to search for early omics-biomarkers and gain novel insights into the potential mechanisms of BP regulation in postmenopausal women. METHODS: Clusters of co-abundant gut bacterial species and serum untargeted metabolites were identified by weighted gene co-expression network analysis (WGCNA). Partial least square analysis and joint analysis were performed to detect BP-associated omics-variables. Partial Pearson correlation was conducted to identify the interactions of microbe--host for host BP variation. Mendelian randomization analysis and causal inference test were used to examine causal relationships among gut microbiota, metabolites and BP variation. RESULTS: In the present study, 651 bacterial species and 296 metabolites were binned into 53 and 26 co-abundance clusters by WGCNA, respectively. Then, we totally identified four gut bacterial species, one host metabolites and two SCFAs that were significantly associated with both SBP and DBP. Moreover, we found that gut microbiota would play important roles in host metabolic activity. Finally, our results revealed that increased Bacteroides fragilis could elevate BP via decreased caproic acid, and phenylacetylglutamine mediated the causal relationships of both B. fragilis and Clostridium sp.CAG.226 on DBP variation. CONCLUSION: Multi-omics datasets integration has the potential to capture complementary effect and their interactions for BP variation, revealed the potential pathogenesis of BP variation and may be useful for studying other complex diseases/traits.

12.
Biol Reprod ; 104(6): 1282-1291, 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-33709118

RESUMO

Zona pellucida (ZP), which is composed of at most four extracellular glycoproteins (ZP1, ZP2, ZP3, and ZP4) in mammals, shelters the oocytes and is vital in female fertility. Several studies have identified the indispensable roles of ZP1-3 in maintaining normal female fertility. However, the understanding of ZP4 is still very poor because only one study on ZP4-associated infertility performed in rabbits has been reported up to date. Here we investigated the function of mammalian Zp4 by creating a knockout (KO) rat strain (Zp4-/- rat) using CRISPR-Cas9-mediated DNA-editing method. The influence of Zp4 KO on ZP morphology and some pivotal processes of reproduction, including oogenesis, ovulation, fertilization, and pup production, were studied using periodic acid-Schiff's staining, superovulation, in vitro fertilization, and natural mating. The ZP morphology in Zp4-/- rats was normal, and none of these pivotal processes was affected. This study renewed the knowledge of mammalian Zp4 by suggesting that Zp4 was completely dispensable for female fertility.

14.
J Cell Mol Med ; 25(6): 2851-2860, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33599396

RESUMO

Although previous studies have explored the gene expression profiles of human oocytes and granulosa cells by single-cell RNA sequencing (scRNA-seq), the dynamic regulatory network at a single-cell resolution during folliculogenesis remains largely unknown. We identified 10 functional modules by WGCNA, four of which were significantly correlated with primary/antral oocyte and antral/pre-ovulatory granulosa cells. Functional enrichment analysis showed that the brown module, which was correlated with antral oocyte, was enriched in oocyte differentiation, and two core subnetworks identified by MCODE were involved in cell cycle (blue subnetwork) and oogenesis (red subnetwork). The cell-specific network (CSN) analysis demonstrated a distinct gene network structure associated with the antral follicular stage, which was notably different from other developmental stages. To our knowledge, this is the first study to explore gene functions during folliculogenesis at single-cell network level. We uncovered two potential gene subnetworks, which may play an important role in oocyte function beginning at the antral stage, and further established their rewiring process at intra-network/whole transcriptome level. The findings provide crucial insights from a novel network perspective to be further explored in functional mechanistic studies.

15.
Bioinformatics ; 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33523132

RESUMO

MOTIVATION: Transcriptome-wide association studies (TWAS) have successfully facilitated the discovery of novel genetic risk loci for many complex traits, including late-onset Alzheimer's disease (AD). However, most existing TWAS methods rely only on gene expression and ignore epigenetic modification (i.e., DNA methylation) and functional regulatory information (i.e., enhancer-promoter interactions), both of which contribute significantly to the genetic basis of AD. RESULTS: We develop a novel gene-level association testing method that integrates genetically regulated DNA methylation and enhancer-target gene pairs with genome-wide association study (GWAS) summary results. Through simulations, we show that our approach, referred to as the CMO (cross methylome omnibus) test, yielded well controlled type I error rates and achieved much higher statistical power than competing methods under a wide range of scenarios. Furthermore, compared with TWAS, CMO identified an average of 124% more associations when analyzing several brain imaging-related GWAS results. By analyzing to date the largest AD GWAS of 71,880 cases and 383,378 controls, CMO identified six novel loci for AD, which have been ignored by competing methods. AVAILABILITY: Software: https://github.com/ChongWuLab/CMO. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

16.
Biol Reprod ; 104(6): 1262-1270, 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-33624742

RESUMO

The zona pellucida (ZP) plays vital roles in reproductive processes including oogenesis, fertilization, and preimplantation development. Both human and rat ZP consist of four glycoproteins, called ZP1, ZP2, ZP3, and ZP4. Our previous research reported a novel Zp1 mutation in cases of human infertility, associated with an abnormal phenotype involving the absence of the ZP. Here, we developed a homologous rat strain to investigate the pathogenic effect. The ovaries of homozygous (Zp1MT/MT) females possessed both growing and fully grown oocytes; the oocytes completely lacked a ZP, but ZP1 was detectable inside the cytoplasm. Only 1-2 eggs were recovered from oviducts of superovulated Zp1MT/MT females, while an average of 21 eggs were recovered from superovulated Zp1WT/WT per female. The eggs of Zp1MT/MT females were not surrounded by a ZP and lost their fertilization capacity in vitro. Zp1MT/MT females mated with wild-type males failed to become pregnant. Studies in 293T cells showed that mutant Zp1 resulted in a truncated ZP1 protein, which might be intracellularly sequestered and interacted with wild-type ZP3 or ZP4. Our results suggest that the Zp1 point mutation led to infertility and loss of the ZP in oocytes in rats.

17.
J Hum Genet ; 66(3): 251-260, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32929176

RESUMO

Bone mineral density (BMD) and lean body mass (LBM) not only have a considerable heritability each, but also are genetically correlated. However, common genetic determinants shared by both traits are largely unknown. In the present study, we performed a bivariate genome-wide association study (GWAS) meta-analysis of hip BMD and trunk lean mass (TLM) in 11,335 subjects from 6 samples, and performed replication in estimated heel BMD and TLM in 215,234 UK Biobank (UKB) participants. We identified 2 loci that nearly attained the genome-wide significance (GWS, p < 5.0 × 10-8) level in the discovery GWAS meta-analysis and that were successfully replicated in the UKB sample: 11p15.2 (lead SNP rs12800228, discovery p = 2.88 × 10-7, replication p = 1.95 × 10-4) and 18q21.32 (rs489693, discovery p = 1.67 × 10-7, replication p = 1.17 × 10-3). The above 2 pleiotropic loci may play a pleiotropic role for hip BMD and TLM development. So our findings provide useful insights that further enhance our understanding of genetic interplay between BMD and LBM.

18.
Mol Genet Genomics ; 296(1): 55-65, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32970232

RESUMO

Both bone mineral density (BMD) and lean body mass (LBM) are important physiological measures with strong genetic determination. Besides, BMD and LBM might have common genetic factors. Aiming to identify pleiotropic genomic loci underlying BMD and LBM, we performed bivariate genome-wide association study meta-analyses of femoral neck bone mineral density and LBM at arms and legs, and replicated in the large-scale UK Biobank cohort sample. Combining the results from discovery meta-analysis and replication sample, we identified three genomic loci at the genome-wide significance level (p < 5.0 × 10-8): 2p23.2 (lead SNP rs4477866, discovery p = 3.47 × 10-8, replication p = 1.03 × 10-4), 16q12.2 (rs1421085, discovery p = 2.04 × 10-9, replication p = 6.47 × 10-14) and 18q21.32 (rs11152213, discovery p = 3.47 × 10-8, replication p = 6.69 × 10-6). Our findings not only provide useful insights into lean mass and bone mass development, but also enhance our understanding of the potential genetic correlation between BMD and LBM.


Assuntos
Colo do Fêmur/metabolismo , Loci Gênicos , Pleiotropia Genética , Predisposição Genética para Doença , Osteoporose/genética , Sarcopenia/genética , Grupo com Ancestrais do Continente Africano , Grupo com Ancestrais do Continente Asiático , Índice de Massa Corporal , Densidade Óssea , Grupo com Ancestrais do Continente Europeu , Feminino , Colo do Fêmur/patologia , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/etnologia , Osteoporose/metabolismo , Osteoporose/patologia , Polimorfismo de Nucleotídeo Único , Sarcopenia/etnologia , Sarcopenia/metabolismo , Sarcopenia/patologia , Magreza/genética , Magreza/metabolismo
19.
Public Health Nutr ; 24(6): 1404-1414, 2021 Apr.
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.

20.
J Hum Genet ; 66(3): 297-306, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32948839

RESUMO

Metabolic syndrome is a cluster of symptoms including excessive body fat and insulin resistance which may lead to obesity and type 2 diabetes (T2D). The physiological and pathological cross-talk between T2D and obesity is crucial and complex, meanwhile, the genetic connection between T2D and obesity is largely unknown. The purpose of this study is to identify pleiotropic SNPs and genes between these two associated conditions by applying genetic analysis incorporating pleiotropy and annotation (GPA) on two large genome-wide association studies (GWAS) data sets: a body mass index (BMI) data set containing 339,224 subjects and a T2D data set containing 110,452 subjects. In all, 5182 SNPs showed pleiotropy in both T2D and obesity. After further prioritization based on suggested local false discovery rates (FDR) by the GPA model, 2146 SNPs corresponding to 217 unique genes are significantly associated with both traits (FDR < 0.2), among which 187 are newly identified pleiotropic genes compare with original GWAS in individual traits. Subsequently, gene enrichment and pathway analyses highlighted several pleiotropic SNPs including rs849135 (FDR = 0.0002), rs2119812 (FDR = 0.0018), rs4506565 (FDR = 1.23E-08), rs1558902 (7.23E-10) and corresponding genes JAZF1, SYN2, TCF7L2, FTO which may play crucial rol5es in the etiology of both T2D and obesity. Additional evidences from expression data analysis of pleiotropic genes strongly supports that the pleiotropic genes including JAZF1 (p = 1.39E-05 and p = 2.13E-05), SYN2 (p = 5.49E-03 and p = 5.27E-04), CDKN2C (p = 1.99E-12 and p = 6.27E-11), RABGAP1 (p = 3.08E-03 and p = 7.46E-03), and UBE2E2 (p = 1.83E-04 and p = 8.22E-03) play crucial roles in both obesity and T2D pathogenesis. Pleiotropic analysis integrated with functional network identified several novel and causal SNPs and genes involved in both BMI and T2D which may be ignored in single GWAS.

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