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1.
Artigo em Inglês | MEDLINE | ID: mdl-34050765

RESUMO

BACKGROUND: Age at natural menopause (ANM) is an important index for women's health. Either early or late ANM is associated with a series of adverse outcomes later in life. Despite being an inheritable trait, its genetic determinant has not yet been fully understood. METHODS: Aiming to better characterize the genetic architecture of ANM, we conducted genome-wide association study (GWAS) meta-analyses in European-specific as well as trans-ancestry samples by using GWAS summary statistics from the following 3 large studies: the Reproductive Genetics Consortium (ReproGen, N=69,626), the UK Biobank cohort (UKBB, N=111,593) and the BioBank Japan Project (BBJ, N=43,861), followed by a series of bioinformatical assessments and functional annotations. RESULTS: By integrating the summary statistics from the 3 GWAS of up to 225,200 participants, this largest meta-analysis identified 49 novel loci and 3 secondary signals that were associated with ANM at the genome-wide significance level (P<5×10 -8). No population specificity or heterogeneity was observed at most of the associated loci. Functional annotations prioritized 90 candidate genes at the newly identified loci. Among the 26 traits that were genetically correlated with ANM, hormone replacement therapy (HRT) exerted a causal relationship, implying a causal pattern by which HRT was determined by ANM. CONCLUSION: Our findings improved our understanding of the etiology of female menopause, as well as shed light on potential new therapies for abnormal menopause.

3.
J Nutr ; 151(6): 1401-1406, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33768223

RESUMO

BACKGROUND: Although recent studies have revealed an association between the composition of the gut microbiota and obesity, whether specific gut microbiota cause obesity has not been determined. OBJECTIVES: The aim of this study is to determine the causal relationship between specific gut microbiota and abdominal obesity. Based on genome-wide association study (GWAS) summary statistics, we performed a 2-sample Mendelian randomization (MR) analysis to evaluate whether the gut microbiota affects abdominal obesity. METHODS: Gut microbiota GWAS in 1126 twin pairs (age range, 18-89 years; 89% were females) from the TwinsUK study were used as exposure data. The primary outcome tested was trunk fat mass (TFM) GWAS in 492,805 participants (age range, 40-69 years; 54% were females) from the UK Biobank. The gut microbiota were classified at family, genus, and species levels. A feature was defined as a distinct family, genus, or species. MR analysis was mainly performed by an inverse variance-weighted test or Wald ratio test, depending on the number of instrumental variables (IVs) involved. A sensitivity analysis was performed on significant results by a weighted median test and a weighted genetic risk score (GRS) analysis. RESULTS: Results of MR analyses provided evidence of a causal association between 3 microbiota features and TFM, including 1 family [Lachnosiraceae; P = 0.02; ß = 0.001 (SEE, 4.28 × 10-4)], 1 genus [Bifidobacterium; P = 5.0 × 10-9; ß = -0.08 (SEE, 0.14)], and 1 species [Prausnitzii; P = 0.03; ß = -0.007 (SEE, 0.003)]. Both the weighted median test and GRS analysis successfully validated the association of the genetically predicted family, Lachnosiraceae (Pweighted median = 0.03; PGRS = 0.004). CONCLUSIONS: Our findings provided evidence of a causal association between gut microbiota and TFM in UK adults and identified specific bacteria taxa that may regulate the fat metabolism, thus offering new direction for the treatment of obesity.

4.
Commun Biol ; 3(1): 608, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33097823

RESUMO

Appendicular lean mass (ALM) is a heritable trait associated with loss of lean muscle mass and strength, or sarcopenia, but its genetic determinants are largely unknown. Here we conducted a genome-wide association study (GWAS) with 450,243 UK Biobank participants to uncover its genetic architecture. A total of 1059 conditionally independent variants from 799 loci were identified at the genome-wide significance level (p < 5 × 10-9), all of which were also significant at p < 5 × 10-5 in both sexes. These variants explained ~15.5% of the phenotypic variance, accounting for more than one quarter of the total ~50% GWAS-attributable heritability. There was no difference in genetic effect between sexes or among different age strata. Heritability was enriched in certain functional categories, such as conserved and coding regions, and in tissues related to the musculoskeletal system. Polygenic risk score prediction well distinguished participants with high and low ALM. The findings are important not only for lean mass but also for other complex diseases, such as type 2 diabetes, as ALM is shown to be a protective factor for type 2 diabetes.

5.
Mol Genet Genomics ; 2020 Sep 24.
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.

6.
Bone ; : 115652, 2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-32971307

RESUMO

Recent studies have demonstrated the important role played by gut microbiota in regulating bone development, but the evidence of such causal relationship is still sparse in human population. The aim of this study is to assess the causal relationship from gut microbiota to bone development and to identify specific causal bacteria taxa via a Mendelian randomization (MR) approach. A genome-wide association study (GWAS) summary statistic based two-sample MR analysis was performed. Summary statistics of microbiome GWAS (MGWAS) in 1126 twin pairs of the TwinsUK study was used as discovery sample, and the MGWAS in 984 Dutch participants from the LifeLines-DEEP cohort was used as replication sample. Estimated heel bone mineral density (eBMD) GWAS in 426,824 participants from the UK biobank (UKB) cohort was used as outcome. Bacteria were grouped into taxa features at both order and family levels. In the discovery sample, a total of 25 bacteria features including 9 orders and 16 families were analyzed. Fourteen features (5 orders + 9 families) were nominally significant, including 5 orders (Bacteroidales, Clostridiales, Lactobacillales, Pasteurellales and Verrucomicrobiales) and 9 families (Bacteroidaceae, Clostridiaceae, Lachnospiraceae, Mogibacteriaceae, Pasteurellaceae, Porphyromonadaceae, Streptococcaceae, Verrucomicrobiaceae and Veillonellaceae). One order Clostridiales and its child taxon, family Lachnospiraceae, were successfully replicated in the replication sample (Clostridiales Pdiscovery = 3.32 × 10-3Preplication = 7.29 × 10-3; Lachnospiraceae Pdiscovery = 0.03 Preplication = 7.29 × 10-3). Our findings provided evidence of causal relationship from microbiota to bone development, as well as identified specific bacteria taxa that regulated bone mass variation, thus providing new insights into the microbiota mediated bone development mechanism.

7.
J Hum Genet ; 2020 Sep 14.
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.

8.
Eur J Hum Genet ; 2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963334

RESUMO

Osteoporosis and obesity are two severe complex diseases threatening public health worldwide. Both diseases are under strong genetic determinants as well as genetically correlated. Aiming to identify pleiotropic genes underlying obesity and osteoporosis, we performed a bivariate genome-wide association (GWA) meta-analysis of hip bone mineral density (BMD) and total body fat mass (TBFM) in 12,981 participants from seven samples, and followed by in silico replication in the UK biobank (UKB) cohort sample (N = 217,822). Combining the results from discovery meta-analysis and replication sample, we identified one novel locus, 17q21.31 (lead SNP rs12150327, NC_000017.11:g.44956910G > A, discovery bivariate P = 4.83 × 10-9, replication P = 5.75 × 10-5) at the genome-wide significance level (ɑ = 5.0 × 10-8), which may have pleiotropic effects to both hip BMD and TBFM. Functional annotations highlighted several candidate genes, including KIF18B, C1QL1, and PRPF19 that may exert pleiotropic effects to the development of both body mass and bone mass. Our findings can improve our understanding of the etiology of osteoporosis and obesity, as well as shed light on potential new therapies.

9.
Int J Obes (Lond) ; 44(10): 2113-2123, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32719433

RESUMO

BACKGROUND: Fat mass and lean mass are two biggest components of body mass. Both fat mass and lean mass are under strong genetic determinants and are correlated. METHODS: We performed a bivariate genome-wide association meta-analysis of (lean adjusted) leg fat mass and (fat adjusted) leg lean mass in 12,517 subjects from 6 samples, and followed by in silico replication in large-scale UK biobank cohort sample (N = 370 097). RESULTS: We identified four loci that were significant at the genome-wide significance (GWS, α = 5.0 × 10-8) level at the discovery meta-analysis, and successfully replicated in the replication sample: 2q36.3 (rs1024137, pdiscovery = 3.32 × 10-8, preplication = 4.07 × 10-13), 5q13.1 (rs4976033, pdiscovery = 1.93 × 10-9, preplication = 6.35 × 10-7), 12q24.31 (rs4765528, pdiscovery = 7.19 × 10-12, preplication = 1.88 × 10-11) and 18q21.32 (rs371326986, pdiscovery = 9.04 × 10-9, preplication = 2.35 × 10-95). The above four pleiotropic loci may play a pleiotropic role for fat mass and lean mass development. CONCLUSIONS: Our findings further enhance the understanding of the genetic association between fat mass and lean mass and provide a new theoretical basis for their understanding.

10.
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.

11.
Hum Genet ; 139(8): 1023-1035, 2020 Aug.
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.


Assuntos
Pleiotropia Genética/genética , Interferon gama/genética , Obesidade Abdominal/genética , Osteoporose/genética , Proteína Quinase C-theta/genética , Locos de Características Quantitativas/genética , Animais , Índice de Massa Corporal , Estudos de Coortes , Feminino , Colo do Fêmur/fisiologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Análise da Randomização Mendeliana , Camundongos , Camundongos Knockout , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética
12.
Sci Rep ; 10(1): 4293, 2020 03 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.


Assuntos
Composição Corporal , Cromossomos Humanos Par 3/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Sarcopenia/genética , Sarcopenia/patologia , Magreza/genética , Feminino , Loci Gênicos , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo
13.
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.

14.
Sci Rep ; 10(1): 5057, 2020 03 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.

16.
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.

17.
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.

18.
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
19.
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.


Assuntos
Densidade Óssea/genética , Lipídeos/sangue , Análise da Randomização Mendeliana , Índice de Massa Corporal , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação/genética , Polimorfismo de Nucleotídeo Único/genética , Análise de Regressão
20.
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.


Assuntos
Cromossomos Humanos Par 1/genética , Obesidade Abdominal/genética , Polimorfismo de Nucleotídeo Único/genética , Idoso , Índice de Massa Corporal , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/análise , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteína de Ligação a Regiões Ricas em Polipirimidinas/análise , Proteína de Ligação a Regiões Ricas em Polipirimidinas/genética , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo
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