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1.
Artigo em Inglês | MEDLINE | ID: mdl-32390946

RESUMO

Aiming to identify more genomic loci associated with bone mineral density (BMD), we conducted a joint association analysis of 2 genome-wide association study (GWAS) by the integrative association method multi-trait analysis of GWAS (MTAG). The first one is the single GWAS of estimated heel BMD (eBMD) in the UK biobank (UKB) cohort (N = 426,824), and the second one is the GWAS meta-analysis of total body BMD (TB-BMD) in 66,628 participants from 30 studies. Approximate conditional association analysis was performed in the identified novel loci to identify secondary association signal. Statistical fine-mapping was conducted to prioritize plausible credible risk variants (CRVs). Candidate genes were prioritized based on the analyses of cis- expression quantitative trait locus (cis-eQTL) and cis-protein QTL (cis-pQTL) information as well as the functional category of the SNP. By integrating the information carried in over 490,000 participants, this largest joint analysis of BMD GWAS identified 12 novel genomic loci at the genome-wide significance level (GWS, p = 5.0 × 10-8), nine of which were for eBMD and four were for TB-BMD, explaining an additional 0.11 and 0.23% heritability for the two traits, respectively. These loci include 1p33 (lead SNP rs10493130, peBMD = 3.19 × 10-8), 5q13.2 (rs4703589, peBMD = 4.78 × 10-8), 5q31.3 (rs9324887, pTB-BMD = 1.36 × 10-9), 6p21.32 (rs6905837, peBMD = 3.32 × 10-8), 6q14.1 (rs10806234, peBMD = 2.63 × 10-8), 7q21.11 (rs10806234, pTB-BMD = 3.37 × 10-8), 8q24.12 (rs11995866, peBMD = 6.72 × 10-9), 12p13.31 (rs1639122, peBMD = 4.43 × 10-8), 12p12.1 (rs58489179, peBMD = 4.74 × 10-8), 12q24.23 (rs75499226, peBMD = 1.44 × 10-8), 19q13.31 (rs7255083, pTB-BMD = 2.18 × 10-8) and 22q11.23 (rs13056137, pTB-BMD = 2.54 × 10-8). All lead SNPs in these 12 loci are nominally significant in both original studies as well as consistent in effect direction between them, providing solid evidence of replication. Approximate conditional analysis identified one secondary signal in 5q13.2 (rs11738874, pconditional = 5.06 × 10-9). Statistical fine-mapping analysis prioritized 269 CRVs. A total of 65 candidate genes were prioritized, including those with known biological function to bone development (such as FGF1, COL11A2 and DEPTOR). Our findings provide novel insights into a better understanding of the genetic mechanism underlying bone development as well as candidate genes for future functional investigation.

2.
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.

3.
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.

4.
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.

5.
J Transl Med ; 18(1): 105, 2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32111256

RESUMO

Following publication of the original article [1], the authors reported an error in one of the author names. In this Correction the incorrect and correct author names are listed.

7.
J Transl Med ; 18(1): 30, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31952517

RESUMO

OBJECTIVE: The purpose of the present study was to evaluate the effectiveness of probiotics on type II diabetes mellitus (T2DM). METHODS: We performed a comprehensive search on PubMed, Web of Science, China National Knowledge Infrastructure, Chinese Scientific Journal Databases, Wan Fang database and China biology medicine disc for relevant studies published before June 2019. Glycated hemoglobin A1c (HbA1c), homeostasis model assessment of insulin resistance (HOMA-IR) and fasting blood glucose (FBG) were used as indicators for T2DM. Inverse-variance weighted mean difference (WMD) with 95% confidence interval (CI) was calculated for the mean HbA1c, FBG and HOMA-IR changes from baseline. RESULTS: 15 randomized controlled trials (RCT) with a total of 902 participants were included into the meta-analysis. Considering the clinical heterogeneity caused by variation of dosage and duration of probiotic treatment, random-effects model was used to estimate the pooled WMD. Significantly greater reduction in HbA1c% (WMD = - 0.24, 95% CI [- 0.44, - 0.04], p = 0.02), FBG (WMD = - 0.44 mmol/L, 95% CI [- 0.74, - 0.15], p = 0.003) and HOMA-IR (WMD = - 1.07, 95% CI [- 1.58, - 0.56], p < 0.00001) were observed in probiotics treated group. Further sensitivity analysis verified the reliability and stability of our results. CONCLUSION: The results of our meta-analysis indicated that probiotics treatment may reduce HbA1c, FBG and insulin resistance level in T2DM patients. More clinical data and research into the mechanism of probiotics are needed to clarify the role of probiotics in T2DM.

8.
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
9.
Front Genet ; 10: 947, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31681408

RESUMO

As an important trait at birth, infant head circumference (HC) is associated with a variety of intelligence- and mental-related conditions. Despite being dominated by genetics, the mechanism underlying the variation of HC is poorly understood. Aiming to uncover the genetic basis of HC, we performed a genome-wide joint association analysis by integrating the genome-wide association summary statistics of HC with that of its two related traits, birth length and birth weight, using a recently developed integrative method, multitrait analysis of genome-wide association (MTAG), and performed in silico replication in an independent sample of intracranial volume (N = 26,577). We then conducted a series of bioinformatic investigations on the identified loci. Combining the evidence from both the MTAG analysis and the in silico replication, we identified three novel loci at the genome-wide significance level (α = 5.0 × 10-8): 3q23 [lead single nucleotide polymorphism (SNP) rs9846396, p MTAG = 3.35 × 10-8, p replication = 0.01], 7p15.3 (rs12534093, p MTAG = 2.00 × 10-8, p replication = 0.004), and 9q33.3 (rs7048271 p MTAG = 9.23 × 10-10, p replication = 1.14 × 10-4). Each of the three lead SNPs was associated with at least one of eight brain-related traits including intelligence and educational attainment. Credible risk variants, defined as those SNPs located within 500 kb of the lead SNP and with p values within two orders of magnitude of the lead SNP, were enriched in DNase I hypersensitive site region in brain. Nine candidate genes were prioritized at the three novel loci using multiple sources of information. Gene set enrichment analysis identified one associated pathway GO:0048009, which participates in the development of nervous system. Our findings provide useful insights into the genetic basis of HC and the relationship between brain growth and mental health.

10.
Bone ; 127: 37-43, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31158506

RESUMO

The level of serum lipids is associated with bone mineral density (BMD), an important skeletal trait. Yet the causality has not been determined. Here we performed a Mendelian randomization (MR) analysis to test potential causal links between BMD and lipid profile, i.e., low-density lipoprotein cholesterol (LDC-c), total cholesterol (TC), triglyceride (TG) and high-density lipoprotein cholesterol (HDL-c). We observed causal effect of LDL-c, TC and TG to BMD, and reversely the effect of BMD to HDL-c. We further explored the effect of body mass index (BMI) in these causalities and found that the effect of LDL-c, TC and TG to BMD is independent of BMI. Our findings provided useful information in the clinical relevance of blood lipids on BMD variation and osteoporosis risk.

11.
Int J Obes (Lond) ; 43(12): 2480-2490, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-30944420

RESUMO

OBJECTIVES: Aiming to uncover the genetic basis of abdominal obesity, we performed a genome-wide association study (GWAS) meta-analysis of trunk fat mass adjusted by trunk lean mass (TFMadj) and followed by a series of functional investigations. SUBJECTS: A total of 11,569 subjects from six samples were included into the GWAS meta-analysis. METHODS: Meta-analysis was performed by a weighted fixed-effects model. In silico replication analysis was performed in the UK-Biobank (UKB) sample (N = 331,093) and in the GIANT study (N up to 110,204). Cis-expression QTL (cis-eQTL) analysis, dual-luciferase reporter assay and electrophoresis mobility shift assay (EMSA) were conducted to examine the functional relevance of the identified SNPs. At last, differential gene expression analysis (DGEA) was performed. RESULTS: We identified an independent SNP rs12409479 at 1p21 (MAF = 0.07, p = 7.26 × 10-10), whose association was replicated by the analysis of TFM in the UKB sample (one-sided p = 3.39 × 10-3), and was cross-validated by the analyses of BMI (one-sided p = 0.03) and WHRadj (one-sided p = 0.04) in the GIANT study. Cis-eQTL analysis demonstrated that allele A at rs12409479 was positively associated with PTBP2 expression level in subcutaneous adipose tissue (N = 385, p = 4.15 × 10-3). Dual-luciferase reporter assay showed that the region repressed PTBP2 gene expression by downregulating PTBP2 promoter activity (p < 0.001), and allele A at rs12409479 induced higher luciferase activity than allele G did (p = 4.15 × 10-3). EMSA experiment implied that allele A was more capable of binding to unknown transcription factors than allele G. Lastly, DGEA showed that the level of PTBP2 expression was higher in individuals with obesity than in individuals without obesity (N = 20 and 11, p = 0.04 and 9.22 × 10-3), suggesting a regulatory role in obesity development. CONCLUSIONS: Taken together, we hypothesize a regulating path from rs12409479 to trunk fat mass development through its allelic specific regulation of PTBP2 gene expression, thus providing some novel insight into the genetic basis of abdominal obesity.

12.
J Bone Miner Res ; 34(6): 1086-1094, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30690781

RESUMO

Bone mineral density (BMD) at various skeletal sites have shared genetic determinants. In the present study, aiming to identify shared loci associated with BMD, we conducted a joint association study of a genomewide association study (GWAS) and a meta-analysis of BMD at different skeletal sites: (i) a single GWAS of heel BMD in 142,487 individuals from the UK Biobank, and (ii) a meta-analysis of 30 GWASs of total body (TB) BMD in 66,628 individuals from the Genetic Factors for Osteoporosis (GEFOS) Consortium. The genetic correlation coefficient of the two traits was estimated to be 0.57. We performed joint association analysis with a recently developed statistical method multi-trait analysis of GWAS (MTAG) to account for trait heterogeneity and sample overlap. The joint association analysis combining samples of up to 209,115 individuals identified 18 novel loci associated with BMD at the genomewide significance level (α = 5.0 × 10-8 ), explaining an additional 0.43% and 0.60% of heel-BMD and TB-BMD heritability, respectively. The vast majority of the identified lead SNPs or their proxies exerted local expression quantitative trait loci (cis-eQTL) activity. Credible risk variants, defined as those SNPs located within 500 kilobases (kb) of the lead SNP and with p values within two orders of magnitude of the lead SNP, were enriched in transcription factor binding sites (p = 3.58 × 10-4 ) and coding regions (p = 5.71 × 10-4 ). Fifty-six candidate genes were prioritized at these novel loci using multiple sources of information, including several genes being previously reported to play a role in bone biology but not reported in previous GWASs (PPARG, FBN2, DEF6, TNFRSF19, and NFE2L1). One newly identified gene, SCMH1, was shown to upregulate the expression of several bone biomarkers, including alkaline phosphatase (ALP), collagen type 1 (COL-I), osteocalcin (OCN), osteopontin (OPN), and runt-related transcription factor 2 (RUNX2), in mouse osteoblastic MC3T3-E1 cells, highlighting its regulatory role in bone formation. Our results may provide useful candidate genes for future functional investigations. © 2019 American Society for Bone and Mineral Research.

13.
Front Microbiol ; 9: 1683, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30093893

RESUMO

The metagenomics sequencing data provide valuable resources for investigating the associations between the microbiome and host environmental/clinical factors and the dynamic changes of microbial abundance over time. The distinct properties of microbiome measurements include varied total sequence reads across samples, over-dispersion and zero-inflation. Additionally, microbiome studies usually collect samples longitudinally, which introduces time-dependent and correlation structures among the samples and thus further complicates the analysis and interpretation of microbiome count data. In this article, we propose negative binomial mixed models (NBMMs) for longitudinal microbiome studies. The proposed NBMMs can efficiently handle over-dispersion and varying total reads, and can account for the dynamic trend and correlation among longitudinal samples. We develop an efficient and stable algorithm to fit the NBMMs. We evaluate and demonstrate the NBMMs method via extensive simulation studies and application to a longitudinal microbiome data. The results show that the proposed method has desirable properties and outperform the previously used methods in terms of flexible framework for modeling correlation structures and detecting dynamic effects. We have developed an R package NBZIMM to implement the proposed method, which is freely available from the public GitHub repository http://github.com//nyiuab//NBZIMM and provides a useful tool for analyzing longitudinal microbiome data.

14.
Diabetes Res Clin Pract ; 141: 256-263, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29733871

RESUMO

AIMS: To investigate whether microbial dysbiosis is associated with T1D in Chinese population and to explore relationships between the composition of gut microbiome and clinical data. METHODS: In this study, we recruited 10 healthy and 12 T1D Han Chinese subjects between the ages of 12 to 33. Fecal samples were collected for DNA extraction and 16S rRNA sequencing, followed by analyses of the gut microbiota composition. RESULTS: Bacterial communities differed between healthy and T1D subjects. At the phylum level, Bacteroidetes and Firmicutes are the dominant phyla in T1D patients and healthy controls, respectively. The linear discriminant analysis (LDA) effect size (LEfSe) algorithm detected 28 bacterial taxonomic clades showing statistically differences (13 increased and 15 decreased) in T1D patients. Association analyses of clinical data and microbial community abundance demonstrated that abundances of Faecalibacterium were negatively correlated with HbA1c levels (Z = -2.614, P = 0.017). The numbers of detected anti-islet cell autoantibodies were positively correlated with Bacteriodes (Z = 2.531, P = 0.011) and Bilophila (Z = 2.477, P = 0.013) abundances, while negatively correlated with abundances of Streptococcus (Z = -2.041, P = 0.041) and Ruminococcaceae (Z = -2.23, P = 0.026). CONCLUSIONS: These results suggest that Han Chinese T1D patients possess distinctly different gut microbiota, compared to healthy subjects, characterized by increased Bacteroidetes/Firmicutes ratio, negative correlation of Faecalibacterium abundance with HbA1c, and positive correlation of Bacteroides abundance with the presence of autoantibodies.


Assuntos
Autoanticorpos/metabolismo , Diabetes Mellitus Tipo 1/fisiopatologia , Fezes/microbiologia , Microbioma Gastrointestinal/fisiologia , Adulto , Grupo com Ancestrais do Continente Asiático , Feminino , Humanos , Masculino , Adulto Jovem
15.
Bone ; 110: 378-385, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29499414

RESUMO

In the present study, aiming to identify loci associated with osteoporosis, we conducted a joint association study of 2 independent genome-wide association meta-analyses of femoral neck and lumbar spine bone mineral densities (BMDs): 1) an in-house study of 6 samples involving 7484 subjects, and 2) the GEFOS-seq study of 7 samples involving 32,965 subjects. The in-house samples were imputed by the 1000 genomes project phase 3 reference panel. SNP-based association test was applied to 7,998,108 autosomal SNPs in each meta-analysis, and for each SNP the 2 association signals were then combined for joint analysis and for mutual replication. Combining the evidence from both studies, we identified 2 novel loci associated with BMDs at the genome-wide significance level (α=5.0×10-8): 20p12.1 (rs73100693 p=2.65×10-8, closest gene MACROD2) and 20q13.33 (rs2380128 p=3.44×10-8, OSBPL2). We also replicated 7 loci that were reported by two recent studies on heel and total body BMD. Our findings provide useful insights that enhance our understanding of bone development, osteoporosis and fracture pathogenesis.


Assuntos
Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 13/genética , Estudo de Associação Genômica Ampla/métodos , Osteoporose/genética , Densidade Óssea/genética , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética
17.
Sci Rep ; 7: 45025, 2017 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-28322352

RESUMO

Lean body mass (LBM) is a complex trait for human health. To identify genomic loci underlying LBM, we performed a gene-based genome-wide association study of lean mass index (LMI) in 1000 unrelated Caucasian subjects, and replicated in 2283 unrelated Caucasians subjects. Gene-based association analyses highlighted the significant associations of three genes UQCR, TCF3 and MBD3 in one single locus 19p13.3 (discovery p = 6.10 × 10-5, 1.65 × 10-4 and 1.10 × 10-4; replication p = 2.21 × 10-3, 1.84 × 10-3 and 6.95 × 10-3; combined p = 2.26 × 10-6, 4.86 × 10-6 and 1.15 × 10-5, respectively). These results, together with the known functional relevance of the three genes to LMI, suggested that the 19p13.3 region containing UQCR, TCF3 and MBD3 genes was a novel locus underlying lean mass variation.


Assuntos
Composição Corporal/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 19 , Estudo de Associação Genômica Ampla , Magreza/genética , Adulto , Idoso , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único
18.
Obesity (Silver Spring) ; 25(4): 757-764, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28224759

RESUMO

OBJECTIVE: Body fat mass (BFM) is more homogeneous and accurate than body total mass in measuring obesity but has rarely been studied. Aiming to uncover the genetic basis of fat-induced obesity, a genome-wide association meta-analysis of BFM, after adjustment by body lean mass, was performed in the European population. METHODS: Three samples of European ancestry were included in the meta-analysis: the Framingham Heart Study (N = 6,004), the Kansas City osteoporosis study (N = 2,207), and the Omaha osteoporosis study (N = 968). RESULTS: At the genome-wide significance level (α = 5.0×10-8 ), a cluster of 10 single-nucleotide polymorphisms (SNPs) at chromosomal region 20p11 that were associated with BFM (lead SNP rs2069126, P = 1.82×10-9 , closest gene SLC24A3) was identified in 9,179 subjects. One of the top SNPs, rs6046308 (P = 3.74×10-8 ), was found to be nominally significant for body fat percentage in another independent study (P = 0.03, N = 75,888) and was reported to transregulate the expression of the MPZ gene at 1q23.3 (unadjusted P = 9.78×10-6 , N = 1,490). Differential gene expression analysis demonstrated that SLC24A3 and CFAP61 at the identified locus were differentially expressed in tissues of people with versus without obesity (P = 3.40×10-5 and 8.72×10-4 , N = 126 and 70), implying their potential role in fat development. CONCLUSIONS: These results may provide new insights into the biological mechanism that underlies fat-induced obesity pathology.


Assuntos
Tecido Adiposo , Cromossomos Humanos Par 20 , Grupo com Ancestrais do Continente Europeu/genética , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Índice de Massa Corporal , Feminino , Estudo de Associação Genômica Ampla , Genômica , Humanos , Masculino , Pessoa de Meia-Idade
19.
J Bone Miner Metab ; 35(6): 649-658, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28012008

RESUMO

Several studies indicated bone mineral density (BMD) and alcohol intake might share common genetic factors. The study aimed to explore potential SNPs/genes related to both phenotypes in US Caucasians at the genome-wide level. A bivariate genome-wide association study (GWAS) was performed in 2069 unrelated participants. Regular drinking was graded as 1, 2, 3, 4, 5, or 6, representing drinking alcohol never, less than once, once or twice, three to six times, seven to ten times, or more than ten times per week respectively. Hip, spine, and whole body BMDs were measured. The bivariate GWAS was conducted on the basis of a bivariate linear regression model. Sex-stratified association analyses were performed in the male and female subgroups. In males, the most significant association signal was detected in SNP rs685395 in DYNC2H1 with bivariate spine BMD and alcohol drinking (P = 1.94 × 10-8). SNP rs685395 and five other SNPs, rs657752, rs614902, rs682851, rs626330, and rs689295, located in the same haplotype block in DYNC2H1 were the top ten most significant SNPs in the bivariate GWAS in males. Additionally, two SNPs in GRIK4 in males and three SNPs in OPRM1 in females were suggestively associated with BMDs (of the hip, spine, and whole body) and alcohol drinking. Nine SNPs in IL1RN were only suggestively associated with female whole body BMD and alcohol drinking. Our study indicated that DYNC2H1 may contribute to the genetic mechanisms of both spine BMD and alcohol drinking in male Caucasians. Moreover, our study suggested potential pleiotropic roles of OPRM1 and IL1RN in females and GRIK4 in males underlying variation of both BMD and alcohol drinking.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Densidade Óssea/genética , Grupo com Ancestrais do Continente Europeu/genética , Pleiotropia Genética , Estudo de Associação Genômica Ampla , Adulto , Feminino , Haplótipos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
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