Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 69
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Bone Miner Res ; 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31525280

RESUMO

Novel anabolic drug targets are needed to treat osteoporosis. Having established a large national cohort with unexplained high bone mass (HBM), we aimed to identify a novel monogenic cause of HBM and provide insight into a regulatory pathway potentially amenable to therapeutic intervention. We investigated a pedigree with unexplained HBM in whom previous sequencing had excluded known causes of monogenic HBM. Whole exome sequencing identified a rare (minor allele frequency 0.0023), highly evolutionarily conserved missense mutation in SMAD9 (c.65T>C, p.Leu22Pro) segregating with HBM in this autosomal dominant family. The same mutation was identified in another two unrelated individuals both with HBM. In silico protein modeling predicts the mutation severely disrupts the MH1 DNA-binding domain of SMAD9. Affected individuals have bone mineral density (BMD) Z-scores +3 to +5, mandible enlargement, a broad frame, torus palatinus/mandibularis, pes planus, increased shoe size, and a tendency to sink when swimming. Peripheral quantitative computed tomography (pQCT) measurement demonstrates increased trabecular volumetric BMD and increased cortical thickness conferring greater predicted bone strength; bone turnover markers are low/normal. Notably, fractures and nerve compression are not found. Both genome-wide and gene-based association testing involving estimated BMD measured at the heel in 362,924 white British subjects from the UK Biobank Study showed strong associations with SMAD9 (PGWAS = 6 × 10-16 ; PGENE = 8 × 10-17 ). Furthermore, we found Smad9 to be highly expressed in both murine cortical bone-derived osteocytes and skeletal elements of zebrafish larvae. Our findings support SMAD9 as a novel HBM gene and a potential novel osteoanabolic target for osteoporosis therapeutics. SMAD9 is thought to inhibit bone morphogenetic protein (BMP)-dependent target gene transcription to reduce osteoblast activity. Thus, we hypothesize SMAD9 c.65T>C is a loss-of-function mutation reducing BMP inhibition. Lowering SMAD9 as a potential novel anabolic mechanism for osteoporosis therapeutics warrants further investigation. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

3.
J Bone Miner Res ; 34(7): 1306-1313, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30882941

RESUMO

Observations that insulin and adiponectin levels are related to cortical bone size in adolescents, independently of body composition, suggest factors related to fat metabolism directly influence skeletal development. To explore this question, we examined associations between a metabolic screen focusing on fat metabolism, and peripheral quantitative computed tomography (pQCT) measures of the mid-tibia, in 15-year-olds from the Avon Longitudinal Study of Parents and Children. Metabolic profiles were generated by proton nuclear magnetic resonance spectroscopy, from blood samples obtained at the same time as pQCT scans. Ordinary least squares linear regression was used to investigate relationships between metabolic measures and periosteal circumference (PC), cortical thickness (CT), and cortical bone mineral density (BMDC ). Metabolic profiles yielded 22 independent components following principal component analysis (PCA), giving a Bonferroni-adjusted threshold for statistical significance of p = 0.002. Data were available in 1121 subjects (487 males), mean age 15 years. Several metabolites related to lipid and cholesterol metabolism were associated with PC, CT, and BMDC after adjustment for age, sex, and Tanner stage. After additional adjustment for height, fat, and lean mass, only the association between citrate and BMDC remained below the Bonferroni-significant threshold (ß = -0.14 [-0.18, -0.09]) (ß represents a standardized coefficient). Citrate also showed evidence of association with PC (ß = 0.06 [0.03, 0.10]) and strength strain index (SSI; ß = 0.04 [0.01, 0.08]). Subsequently, we investigated whether these relationships were explained by increased bone resorption. Citrate was strongly related to serum ß-C-telopeptides of type I collagen (ß-CTX) (ß = 0.20 [0.16, 0.23]). After additional adjustment for ß-CTX the above associations between citrate and BMDC (ß = -0.04 [-0.08, 0.01]), PC (ß = 0.03 [-0.01, 0.07]) and SSI (ß = 0.03 [-0.01, 0.07]) were no longer observed. We conclude that in adolescents, circulating levels of citrate are inversely related to BMDC and positively related to PC, reflecting associations with higher bone turnover. Further studies are justified to elucidate possible contributions of citrate, a constituent of bone matrix, to bone resorption and cortical density. © 2019 American Society for Bone and Mineral Research.

4.
Nat Genet ; 51(2): 258-266, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30598549

RESUMO

Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with estimated BMD (eBMD), in ~1.2 million individuals. We then identified target genes enriched for genes known to influence bone density and strength (maximum odds ratio (OR) = 58, P = 1 × 10-75) from cell-specific features, including chromatin conformation and accessible chromatin sites. We next performed rapid-throughput skeletal phenotyping of 126 knockout mice with disruptions in predicted target genes and found an increased abnormal skeletal phenotype frequency compared to 526 unselected lines (P < 0.0001). In-depth analysis of one gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This genetic atlas provides evidence linking associated SNPs to causal genes, offers new insight into osteoporosis pathophysiology, and highlights opportunities for drug development.


Assuntos
Densidade Óssea/genética , Predisposição Genética para Doença/genética , Osteoporose/genética , Adulto , Idoso , Animais , Feminino , Fraturas Ósseas/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
5.
Am J Hum Genet ; 103(5): 691-706, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30388399

RESUMO

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

6.
Bone ; 114: 62-71, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29883787

RESUMO

BACKGROUND: Generalised high bone mass (HBM), associated with features of a mild skeletal dysplasia, has a prevalence of 0.18% in a UK DXA-scanned adult population. We hypothesized that the genetic component of extreme HBM includes contributions from common variants of small effect and rarer variants of large effect, both enriched in an extreme phenotype cohort. METHODS: We performed a genome-wide association study (GWAS) of adults with either extreme high or low BMD. Adults included individuals with unexplained extreme HBM (n = 240) from the UK with BMD Z-scores ≥+3.2, high BMD females from the Anglo-Australasian Osteoporosis Genetics Consortium (AOGC) (n = 1055) with Z-scores +1.5 to +4.0 and low BMD females also part of AOGC (n = 900), with Z-scores -1.5 to -4.0. Following imputation, we tested association between 6,379,332 SNPs and total hip and lumbar spine BMD Z-scores. For potential target genes, we assessed expression in human osteoblasts and murine osteocytes. RESULTS: We observed significant enrichment for associations with established BMD-associated loci, particularly those known to regulate endochondral ossification and Wnt signalling, suggesting that part of the genetic contribution to unexplained HBM is polygenic. Further, we identified associations exceeding genome-wide significance between BMD and four loci: two established BMD-associated loci (5q14.3 containing MEF2C and 1p36.12 containing WNT4) and two novel loci: 5p13.3 containing NPR3 (rs9292469; minor allele frequency [MAF] = 0.33%) associated with lumbar spine BMD and 11p15.2 containing SPON1 (rs2697825; MAF = 0.17%) associated with total hip BMD. Mouse models with mutations in either Npr3 or Spon1 have been reported, both have altered skeletal phenotypes, providing in vivo validation that these genes are physiologically important in bone. NRP3 regulates endochondral ossification and skeletal growth, whilst SPON1 modulates TGF-ß regulated BMP-driven osteoblast differentiation. Rs9292469 (downstream of NPR3) also showed some evidence for association with forearm BMD in the independent GEFOS sample (n = 32,965). We found Spon1 was highly expressed in murine osteocytes from the tibiae, femora, humeri and calvaria, whereas Npr3 expression was more variable. CONCLUSION: We report the most extreme-truncate GWAS of BMD performed to date. Our findings, suggest potentially new anabolic bone regulatory pathways that warrant further study.

7.
Hum Mol Genet ; 27(11): 2025-2038, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29659830

RESUMO

The ratio of the length of the index finger to that of the ring finger (2D:4D) is sexually dimorphic and is commonly used as a non-invasive biomarker of prenatal androgen exposure. Most association studies of 2D:4D ratio with a diverse range of sex-specific traits have typically involved small sample sizes and have been difficult to replicate, raising questions around the utility and precise meaning of the measure. In the largest genome-wide association meta-analysis of 2D:4D ratio to date (N = 15 661, with replication N = 75 821), we identified 11 loci (9 novel) explaining 3.8% of the variance in mean 2D:4D ratio. We also found weak evidence for association (ß = 0.06; P = 0.02) between 2D:4D ratio and sensitivity to testosterone [length of the CAG microsatellite repeat in the androgen receptor (AR) gene] in females only. Furthermore, genetic variants associated with (adult) testosterone levels and/or sex hormone-binding globulin were not associated with 2D:4D ratio in our sample. Although we were unable to find strong evidence from our genetic study to support the hypothesis that 2D:4D ratio is a direct biomarker of prenatal exposure to androgens in healthy individuals, our findings do not explicitly exclude this possibility, and pathways involving testosterone may become apparent as the size of the discovery sample increases further. Our findings provide new insight into the underlying biology shaping 2D:4D variation in the general population.

8.
Am J Hum Genet ; 102(1): 88-102, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29304378

RESUMO

Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course.

9.
Nat Genet ; 49(10): 1468-1475, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28869591

RESUMO

Osteoporosis is a common disease diagnosed primarily by measurement of bone mineral density (BMD). We undertook a genome-wide association study (GWAS) in 142,487 individuals from the UK Biobank to identify loci associated with BMD as estimated by quantitative ultrasound of the heel. We identified 307 conditionally independent single-nucleotide polymorphisms (SNPs) that attained genome-wide significance at 203 loci, explaining approximately 12% of the phenotypic variance. These included 153 previously unreported loci, and several rare variants with large effect sizes. To investigate the underlying mechanisms, we undertook (1) bioinformatic, functional genomic annotation and human osteoblast expression studies; (2) gene-function prediction; (3) skeletal phenotyping of 120 knockout mice with deletions of genes adjacent to lead independent SNPs; and (4) analysis of gene expression in mouse osteoblasts, osteocytes and osteoclasts. The results implicate GPC6 as a novel determinant of BMD, and also identify abnormal skeletal phenotypes in knockout mice associated with a further 100 prioritized genes.


Assuntos
Densidade Óssea/genética , Calcâneo/patologia , Estudo de Associação Genômica Ampla , Osteoporose/genética , Polimorfismo de Nucleotídeo Único , Animais , Modelos Animais de Doenças , Feminino , Fêmur/química , Perfilação da Expressão Gênica , Glipicanas/deficiência , Glipicanas/genética , Glipicanas/fisiologia , Transtornos do Crescimento/genética , Humanos , Masculino , Camundongos , Camundongos Knockout , Anotação de Sequência Molecular , Osteoblastos/metabolismo , Osteocondrodisplasias/congênito , Osteocondrodisplasias/genética , Osteoclastos/metabolismo , Osteócitos/metabolismo , Osteoporose/patologia , Fenótipo
10.
Hum Mol Genet ; 26(19): 3850-3858, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28934396

RESUMO

Osteoarthritis (OA) is a common complex disease with high public health burden and no curative therapy. High bone mineral density (BMD) is associated with an increased risk of developing OA, suggesting a shared underlying biology. Here, we performed the first systematic overlap analysis of OA and BMD on a genome wide scale. We used summary statistics from the GEFOS consortium for lumbar spine (n = 31,800) and femoral neck (n = 32,961) BMD, and from the arcOGEN consortium for three OA phenotypes (hip, ncases=3,498; knee, ncases=3,266; hip and/or knee, ncases=7,410; ncontrols=11,009). Performing LD score regression we found a significant genetic correlation between the combined OA phenotype (hip and/or knee) and lumbar spine BMD (rg=0.18, P = 2.23 × 10-2), which may be driven by the presence of spinal osteophytes. We identified 143 variants with evidence for cross-phenotype association which we took forward for replication in independent large-scale OA datasets, and subsequent meta-analysis with arcOGEN for a total sample size of up to 23,425 cases and 236,814 controls. We found robustly replicating evidence for association with OA at rs12901071 (OR 1.08 95% CI 1.05-1.11, Pmeta=3.12 × 10-10), an intronic variant in the SMAD3 gene, which is known to play a role in bone remodeling and cartilage maintenance. We were able to confirm expression of SMAD3 in intact and degraded cartilage of the knee and hip. Our findings provide the first systematic evaluation of pleiotropy between OA and BMD, highlight genes with biological relevance to both traits, and establish a robust new OA genetic risk locus at SMAD3.


Assuntos
Densidade Óssea/genética , Osteoartrite/genética , Proteína Smad3/genética , Bases de Dados de Ácidos Nucleicos , Colo do Fêmur/química , Colo do Fêmur/fisiologia , Estudos de Associação Genética/métodos , Pleiotropia Genética/genética , Humanos , Vértebras Lombares/fisiologia , Osteoartrite/etiologia , Osteoartrite do Quadril/genética , Osteoartrite do Joelho/genética , Fatores de Risco , Proteína Smad3/metabolismo
11.
Nat Commun ; 8(1): 121, 2017 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-28743860

RESUMO

Bone mineral density is known to be a heritable, polygenic trait whereas genetic variants contributing to lean mass variation remain largely unknown. We estimated the shared SNP heritability and performed a bivariate GWAS meta-analysis of total-body lean mass (TB-LM) and total-body less head bone mineral density (TBLH-BMD) regions in 10,414 children. The estimated SNP heritability is 43% (95% CI: 34-52%) for TBLH-BMD, and 39% (95% CI: 30-48%) for TB-LM, with a shared genetic component of 43% (95% CI: 29-56%). We identify variants with pleiotropic effects in eight loci, including seven established bone mineral density loci: WNT4, GALNT3, MEPE, CPED1/WNT16, TNFSF11, RIN3, and PPP6R3/LRP5. Variants in the TOM1L2/SREBF1 locus exert opposing effects TB-LM and TBLH-BMD, and have a stronger association with the former trait. We show that SREBF1 is expressed in murine and human osteoblasts, as well as in human muscle tissue. This is the first bivariate GWAS meta-analysis to demonstrate genetic factors with pleiotropic effects on bone mineral density and lean mass.Bone mineral density and lean skeletal mass are heritable traits. Here, Medina-Gomez and colleagues perform bivariate GWAS analyses of total body lean mass and bone mass density in children, and show genetic loci with pleiotropic effects on both traits.


Assuntos
Proteínas de Transporte/genética , Pleiotropia Genética , Estudo de Associação Genômica Ampla/métodos , Metanálise como Assunto , Desenvolvimento Musculoesquelético/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Peso Corporal , Densidade Óssea , Criança , Feminino , Expressão Gênica , Humanos , Masculino , Análise Multivariada , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética
12.
Nat Genet ; 49(8): 1255-1260, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28628106

RESUMO

Preeclampsia, which affects approximately 5% of pregnancies, is a leading cause of maternal and perinatal death. The causes of preeclampsia remain unclear, but there is evidence for inherited susceptibility. Genome-wide association studies (GWAS) have not identified maternal sequence variants of genome-wide significance that replicate in independent data sets. We report the first GWAS of offspring from preeclamptic pregnancies and discovery of the first genome-wide significant susceptibility locus (rs4769613; P = 5.4 × 10-11) in 4,380 cases and 310,238 controls. This locus is near the FLT1 gene encoding Fms-like tyrosine kinase 1, providing biological support, as a placental isoform of this protein (sFlt-1) is implicated in the pathology of preeclampsia. The association was strongest in offspring from pregnancies in which preeclampsia developed during late gestation and offspring birth weights exceeded the tenth centile. An additional nearby variant, rs12050029, associated with preeclampsia independently of rs4769613. The newly discovered locus may enhance understanding of the pathophysiology of preeclampsia and its subtypes.


Assuntos
Feto , Predisposição Genética para Doença , Pré-Eclâmpsia/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Estudos de Coortes , Feminino , Seguimentos , Genoma Humano , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Gravidez , Proteínas da Gravidez/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue
13.
Bioinformatics ; 33(2): 272-279, 2017 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-27663502

RESUMO

MOTIVATION: LD score regression is a reliable and efficient method of using genome-wide association study (GWAS) summary-level results data to estimate the SNP heritability of complex traits and diseases, partition this heritability into functional categories, and estimate the genetic correlation between different phenotypes. Because the method relies on summary level results data, LD score regression is computationally tractable even for very large sample sizes. However, publicly available GWAS summary-level data are typically stored in different databases and have different formats, making it difficult to apply LD score regression to estimate genetic correlations across many different traits simultaneously. RESULTS: In this manuscript, we describe LD Hub - a centralized database of summary-level GWAS results for 173 diseases/traits from different publicly available resources/consortia and a web interface that automates the LD score regression analysis pipeline. To demonstrate functionality and validate our software, we replicated previously reported LD score regression analyses of 49 traits/diseases using LD Hub; and estimated SNP heritability and the genetic correlation across the different phenotypes. We also present new results obtained by uploading a recent atopic dermatitis GWAS meta-analysis to examine the genetic correlation between the condition and other potentially related traits. In response to the growing availability of publicly accessible GWAS summary-level results data, our database and the accompanying web interface will ensure maximal uptake of the LD score regression methodology, provide a useful database for the public dissemination of GWAS results, and provide a method for easily screening hundreds of traits for overlapping genetic aetiologies. AVAILABILITY AND IMPLEMENTATION: The web interface and instructions for using LD Hub are available at http://ldsc.broadinstitute.org/ CONTACT: jie.zheng@bristol.ac.ukSupplementary information: Supplementary data are available at Bioinformatics online.


Assuntos
Bases de Dados de Ácidos Nucleicos , Doenças Genéticas Inatas/genética , Estudo de Associação Genômica Ampla/métodos , Desequilíbrio de Ligação , Fenótipo , Polimorfismo de Nucleotídeo Único , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Tamanho da Amostra , Software
14.
J Am Acad Child Adolesc Psychiatry ; 55(10): 896-905.e6, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27663945

RESUMO

OBJECTIVE: The aims of this study were to elucidate the influence of common genetic variants on childhood attention-deficit/hyperactivity disorder (ADHD) symptoms, to identify genetic variants that explain its high heritability, and to investigate the genetic overlap of ADHD symptom scores with ADHD diagnosis. METHOD: Within the EArly Genetics and Lifecourse Epidemiology (EAGLE) consortium, genome-wide single nucleotide polymorphisms (SNPs) and ADHD symptom scores were available for 17,666 children (<13 years of age) from nine population-based cohorts. SNP-based heritability was estimated in data from the three largest cohorts. Meta-analysis based on genome-wide association (GWA) analyses with SNPs was followed by gene-based association tests, and the overlap in results with a meta-analysis in the Psychiatric Genomics Consortium (PGC) case-control ADHD study was investigated. RESULTS: SNP-based heritability ranged from 5% to 34%, indicating that variation in common genetic variants influences ADHD symptom scores. The meta-analysis did not detect genome-wide significant SNPs, but three genes, lying close to each other with SNPs in high linkage disequilibrium (LD), showed a gene-wide significant association (p values between 1.46 × 10(-6) and 2.66 × 10(-6)). One gene, WASL, is involved in neuronal development. Both SNP- and gene-based analyses indicated overlap with the PGC meta-analysis results with the genetic correlation estimated at 0.96. CONCLUSION: The SNP-based heritability for ADHD symptom scores indicates a polygenic architecture, and genes involved in neurite outgrowth are possibly involved. Continuous and dichotomous measures of ADHD appear to assess a genetically common phenotype. A next step is to combine data from population-based and case-control cohorts in genetic association studies to increase sample size and to improve statistical power for identifying genetic variants.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Estudos de Casos e Controles , Criança , Estudos de Coortes , Feminino , Genética Populacional/métodos , Estudo de Associação Genômica Ampla , Humanos , Masculino
15.
Bonekey Rep ; 5: 796, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27257477

RESUMO

Peak bone mass, the maximum amount of bone accrued at the end of the growth period, is an important predictor of future risk of osteoporosis and fracture. Hence, the contribution of genetic factors influencing bone accrual is of considerable interest to the osteoporosis research community. In this article, we review evidence that genetic factors play an important role in bone growth, describe the genetic loci implicated so far and briefly discuss lessons learned from the application of genome-wide association studies. Moreover, we attempt to make the case for genetic investigations of bone mineral density in paediatric and young adult populations, describing their potential to increase our knowledge of the process of bone metabolism throughout the life course, and in turn, identify novel targets for the pharmacological treatment of osteoporosis.

17.
Int J Epidemiol ; 45(5): 1560-1572, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27215616

RESUMO

BACKGROUND: Lean mass is positively associated with bone mineral density (BMD). However, the relationship between adiposity and BMD is more controversial. In particular, it is unclear if the observational association between the two reflects a causal effect of fat mass on BMD. Previous Mendelian randomization (MR) studies using variants in the FTO and MC4R genes as genetic instruments for adiposity have suggested that fat mass does indeed causally influence BMD. However, it is possible that these genetic variants pleiotropically influence lean mass and affect BMD through pathways independent of adiposity, invalidating one of the core assumptions of MR and complicating interpretation of the analysis. METHODS: To investigate whether adiposity causally affects BMD, we investigated the relationship between fat mass and BMD at the skull (SK), upper limbs (UL) and lower limbs (LL), spine (SP) and pelvis (PE), using 32 body mass index (BMI)-associated SNPs, including a variant near ADCY3 that was strongly associated with fat but not lean mass in our sample. Dual-energy X-ray absorptiometry (DXA) scans and genetic data were available for 5221 subjects (mean age 9.9 years) from the Avon Longitudinal Study of Parents and Children. We performed a series of MR analyses involving single BMI-associated SNPs and allelic scores of these SNPs. We used new extensions of the MR method including MR Egger regression and multivariable MR, which are more robust to possible confounding effects due to horizontal pleiotropy and, in the case of multivariable MR, specifically account for the effect of lean mass in the analysis. Bidirectional Mendelian randomization analysis was also performed to examine whether BMD causally affected BMI and adiposity. RESULTS: Observationally, fat mass was strongly positively related to BMD at all sites, but more weakly at the skull. Instrumental variables (IV) analyses using an allelic score of BMI SNPs suggested that fat mass was causally related to LL-BMD, UL-BMD, SP-BMD and PE-BMD but not SK-BMD. Multivariable MR, Egger regression and IV analyses involving the ADCY3 variant suggested a positive causal effect of adiposity on all sites except the skull, and that an effect was present even after taking lean mass into account. Finally, IV analyses using BMD allelic scores showed no evidence of reverse causality between BMD and fat mass. CONCLUSIONS: Our results suggest that adiposity is causally related to increased BMD at all sites except the skull, perhaps reflecting positive effects of loading on bone formation at weighted but not unweighted sites. In contrast, we found no evidence for BMD causally affecting BMI or measures of adiposity. Our results illustrate how MR can be used profitably to investigate clinical questions relevant to osteoporosis.


Assuntos
Adiposidade/genética , Densidade Óssea/genética , Osso e Ossos/diagnóstico por imagem , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Absorciometria de Fóton , Adenilil Ciclases/genética , Índice de Massa Corporal , Criança , Estudos Transversais , Inglaterra , Feminino , Humanos , Estudos Longitudinais , Masculino , Análise Multivariada , Osteoporose/genética
19.
Am J Med Genet B Neuropsychiatr Genet ; 171(5): 562-72, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26087016

RESUMO

Individual differences in aggressive behavior emerge in early childhood and predict persisting behavioral problems and disorders. Studies of antisocial and severe aggression in adulthood indicate substantial underlying biology. However, little attention has been given to genome-wide approaches of aggressive behavior in children. We analyzed data from nine population-based studies and assessed aggressive behavior using well-validated parent-reported questionnaires. This is the largest sample exploring children's aggressive behavior to date (N = 18,988), with measures in two developmental stages (N = 15,668 early childhood and N = 16,311 middle childhood/early adolescence). First, we estimated the additive genetic variance of children's aggressive behavior based on genome-wide SNP information, using genome-wide complex trait analysis (GCTA). Second, genetic associations within each study were assessed using a quasi-Poisson regression approach, capturing the highly right-skewed distribution of aggressive behavior. Third, we performed meta-analyses of genome-wide associations for both the total age-mixed sample and the two developmental stages. Finally, we performed a gene-based test using the summary statistics of the total sample. GCTA quantified variance tagged by common SNPs (10-54%). The meta-analysis of the total sample identified one region in chromosome 2 (2p12) at near genome-wide significance (top SNP rs11126630, P = 5.30 × 10(-8) ). The separate meta-analyses of the two developmental stages revealed suggestive evidence of association at the same locus. The gene-based analysis indicated association of variation within AVPR1A with aggressive behavior. We conclude that common variants at 2p12 show suggestive evidence for association with childhood aggression. Replication of these initial findings is needed, and further studies should clarify its biological meaning. © 2015 Wiley Periodicals, Inc.


Assuntos
Agressão/fisiologia , Adolescente , Agressão/psicologia , Comportamento , Criança , Feminino , Estudos de Associação Genética/métodos , Predisposição Genética para Doença/genética , Variação Genética , Genética Comportamental/métodos , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Receptores de Vasopressinas/genética , Receptores de Vasopressinas/fisiologia , Inquéritos e Questionários
20.
Nat Commun ; 6: 8658, 2015 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-26635082

RESUMO

Lung function measures are used in the diagnosis of chronic obstructive pulmonary disease. In 38,199 European ancestry individuals, we studied genome-wide association of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC with 1000 Genomes Project (phase 1)-imputed genotypes and followed up top associations in 54,550 Europeans. We identify 14 novel loci (P<5 × 10(-8)) in or near ENSA, RNU5F-1, KCNS3, AK097794, ASTN2, LHX3, CCDC91, TBX3, TRIP11, RIN3, TEKT5, LTBP4, MN1 and AP1S2, and two novel signals at known loci NPNT and GPR126, providing a basis for new understanding of the genetic determinants of these traits and pulmonary diseases in which they are altered.


Assuntos
Estudo de Associação Genômica Ampla , Pneumopatias/genética , Pulmão/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Volume Expiratório Forçado , Humanos , Pneumopatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA