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1.
Hum Mol Genet ; 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-33517400

RESUMO

Interleukin-6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery, and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed-effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on Chromosome (Chr) 2q14, (pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.

2.
Nat Commun ; 11(1): 5976, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33239696

RESUMO

Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia.

3.
Nat Hum Behav ; 2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-32989287

RESUMO

Handedness has been extensively studied because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and the International Handedness Consortium, we conducted a genome-wide association meta-analysis of handedness (N = 1,766,671). We found 41 loci associated (P < 5 × 10-8) with left-handedness and 7 associated with ambidexterity. Tissue-enrichment analysis implicated the CNS in the aetiology of handedness. Pathways including regulation of microtubules and brain morphology were also highlighted. We found suggestive positive genetic correlations between left-handedness and neuropsychiatric traits, including schizophrenia and bipolar disorder. Furthermore, the genetic correlation between left-handedness and ambidexterity is low (rG = 0.26), which implies that these traits are largely influenced by different genetic mechanisms. Our findings suggest that handedness is highly polygenic and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders.

4.
J Bone Miner Res ; 35(9): 1626-1633, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32777102

RESUMO

The development of high-throughput genotyping technologies and large biobank collections, complemented with rapid methodological advances in statistical genetics, has enabled hypothesis-free genome-wide association studies (GWAS), which have identified hundreds of genetic variants across many loci associated with musculoskeletal conditions. Similarly, basic scientists have valuable molecular cellular and animal data based on musculoskeletal disease that would be enhanced by being able to determine the human translation of their findings. By integrating these large-scale human genomic musculoskeletal datasets with complementary evidence from model organisms, new and existing genetic loci can be statistically fine-mapped to plausibly causal variants, candidate genes, and biological pathways. Genes and pathways identified using this approach can be further prioritized as drug targets, including side-effect profiling and the potential for new indications. To bring together these big data, and to realize the vision of creating a knowledge portal, the International Federation of Musculoskeletal Research Societies (IFMRS) established a working group to collaborate with scientists from the Broad Institute to create the Musculoskeletal Knowledge Portal (MSK-KP)(http://mskkp.org/). The MSK consolidates omics datasets from humans, cellular experiments, and model organisms into a central repository that can be accessed by researchers. The vision of the MSK-KP is to enable better understanding of the biological mechanisms underlying musculoskeletal disease and apply this knowledge to identify and develop new disease interventions. © 2020 American Society for Bone and Mineral Research (ASBMR).

5.
PLoS Med ; 17(7): e1003152, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32614825

RESUMO

BACKGROUND: Since screening programs identify only a small proportion of the population as eligible for an intervention, genomic prediction of heritable risk factors could decrease the number needing to be screened by removing individuals at low genetic risk. We therefore tested whether a polygenic risk score for heel quantitative ultrasound speed of sound (SOS)-a heritable risk factor for osteoporotic fracture-can identify low-risk individuals who can safely be excluded from a fracture risk screening program. METHODS AND FINDINGS: A polygenic risk score for SOS was trained and selected in 2 separate subsets of UK Biobank (comprising 341,449 and 5,335 individuals). The top-performing prediction model was termed "gSOS", and its utility in fracture risk screening was tested in 5 validation cohorts using the National Osteoporosis Guideline Group clinical guidelines (N = 10,522 eligible participants). All individuals were genome-wide genotyped and had measured fracture risk factors. Across the 5 cohorts, the average age ranged from 57 to 75 years, and 54% of studied individuals were women. The main outcomes were the sensitivity and specificity to correctly identify individuals requiring treatment with and without genetic prescreening. The reference standard was a bone mineral density (BMD)-based Fracture Risk Assessment Tool (FRAX) score. The secondary outcomes were the proportions of the screened population requiring clinical-risk-factor-based FRAX (CRF-FRAX) screening and BMD-based FRAX (BMD-FRAX) screening. gSOS was strongly correlated with measured SOS (r2 = 23.2%, 95% CI 22.7% to 23.7%). Without genetic prescreening, guideline recommendations achieved a sensitivity and specificity for correct treatment assignment of 99.6% and 97.1%, respectively, in the validation cohorts. However, 81% of the population required CRF-FRAX tests, and 37% required BMD-FRAX tests to achieve this accuracy. Using gSOS in prescreening and limiting further assessment to those with a low gSOS resulted in small changes to the sensitivity and specificity (93.4% and 98.5%, respectively), but the proportions of individuals requiring CRF-FRAX tests and BMD-FRAX tests were reduced by 37% and 41%, respectively. Study limitations include a reliance on cohorts of predominantly European ethnicity and use of a proxy of fracture risk. CONCLUSIONS: Our results suggest that the use of a polygenic risk score in fracture risk screening could decrease the number of individuals requiring screening tests, including BMD measurement, while maintaining a high sensitivity and specificity to identify individuals who should be recommended an intervention.


Assuntos
Programas de Rastreamento/métodos , Herança Multifatorial , Fraturas por Osteoporose/genética , Fraturas por Osteoporose/prevenção & controle , Medição de Risco/métodos , Idoso , Densidade Óssea , Calcâneo/diagnóstico por imagem , Estudos de Coortes , Bases de Dados Genéticas , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Calcanhar/diagnóstico por imagem , Humanos , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Osteoporose/genética , Fatores de Risco , Ultrassonografia , Reino Unido
6.
Nat Commun ; 11(1): 2797, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32493999

RESUMO

Fat distribution is an independent cardiometabolic risk factor. However, its molecular and cellular underpinnings remain obscure. Here we demonstrate that two independent GWAS signals at RSPO3, which are associated with increased body mass index-adjusted waist-to-hip ratio, act to specifically increase RSPO3 expression in subcutaneous adipocytes. These variants are also associated with reduced lower-body fat, enlarged gluteal adipocytes and insulin resistance. Based on human cellular studies RSPO3 may limit gluteofemoral adipose tissue (AT) expansion by suppressing adipogenesis and increasing gluteal adipocyte susceptibility to apoptosis. RSPO3 may also promote upper-body fat distribution by stimulating abdominal adipose progenitor (AP) proliferation. The distinct biological responses elicited by RSPO3 in abdominal versus gluteal APs in vitro are associated with differential changes in WNT signalling. Zebrafish carrying a nonsense rspo3 mutation display altered fat distribution. Our study identifies RSPO3 as an important determinant of peripheral AT storage capacity.


Assuntos
Adipócitos/citologia , Adipócitos/metabolismo , Distribuição da Gordura Corporal , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Trombospondinas/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Adipócitos/efeitos dos fármacos , Tecido Adiposo/metabolismo , Adiposidade/genética , Adulto , Alelos , Animais , Biomarcadores/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Tamanho Celular/efeitos dos fármacos , Doxiciclina/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Polimorfismo de Nucleotídeo Único/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Caracteres Sexuais , Células-Tronco/metabolismo , Trombospondinas/genética , Relação Cintura-Quadril , Via de Sinalização Wnt/efeitos dos fármacos , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
7.
J Bone Miner Res ; 35(7): 1224-1235, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32163637

RESUMO

Several epidemiological studies have reported a relationship between statin treatment and increased bone mineral density (BMD) and reduced fracture risk, but the mechanism underlying the purported relationship is unclear. We used Mendelian randomization (MR) to assess whether this relationship is explained by a specific effect in response to statin use or by a general effect of lipid lowering. We utilized 400 single-nucleotide polymorphisms (SNPs) robustly associated with plasma lipid levels as exposure. The outcome results were obtained from a heel estimated BMD (eBMD) genomewide association study (GWAS) from the UK Biobank and dual-energy X-ray absorptiometry (DXA) BMD at four body sites and fracture GWAS from the GEFOS consortium. We performed univariate and multivariable MR analyses of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride levels on BMD and fracture. Univariate MR analyses suggested a causal effect of LDL-C on eBMD (ß = -0.06; standard deviation change in eBMD per standard deviation change in LDL-C, 95% confidence interval [CI] = -0.08 to -0.04; p = 4 × 10-6 ), total body BMD (ß = -0.05, 95% CI = -0.08 to -0.01, p = 6 × 10-3 ) and potentially on lumbar spine BMD. Multivariable MR suggested that the effects of LDL-C on eBMD and total body BMD were independent of HDL-C and triglycerides. Sensitivity MR analyses suggested that the LDL-C results were robust to pleiotropy. MR analyses of LDL-C restricted to SNPs in the HMGCR region showed similar effects on eBMD (ß = -0.083; -0.132 to -0.034; p = .001) to those excluding these SNPs (ß = -0.063; -0.090 to -0.036; p = 8 × 10-6 ). Bidirectional MR analyses provided some evidence for a causal effect of eBMD on plasma LDL-C levels. Our results suggest that effects of statins on eBMD and total body BMD are at least partly due to their LDL-C lowering effect. Further studies are required to examine the potential role of modifying plasma lipid levels in treating osteoporosis. © 2020 American Society for Bone and Mineral Research.

8.
J Bone Miner Res ; 35(1): 92-105, 2020 01.
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.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31824424

RESUMO

Epidemiological studies have identified many risk factors for osteoporosis, however it is unclear whether these observational associations reflect true causal effects, or the effects of latent confounding or reverse causality. Mendelian randomization (MR) enables causal relationships to be evaluated, by examining the relationship between genetic susceptibility to the risk factor in question, and the disease outcome of interest. This has been facilitated by the development of two-sample MR analysis, where the exposure and outcome are measured in different studies, and by exploiting summary result statistics from large well-powered genome-wide association studies that are available for thousands of traits. Though MR has several inherent limitations, the field is rapidly evolving and at least 14 methodological extensions have been developed to overcome these. The present paper aims to discuss some of the limitations in the MR analytical framework, and how this method has been applied to the osteoporosis field, helping to reinforce conclusions about causality, and discovering potential new regulatory pathways, exemplified by our recent MR study of sclerostin.

11.
J Bone Miner Res ; 34(7): 1306-1313, 2019 07.
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.


Assuntos
Densidade Óssea/fisiologia , Ácido Cítrico/sangue , Osso Cortical/fisiologia , Programas de Rastreamento , Metabolômica , Adolescente , Colágeno Tipo I/sangue , Feminino , Humanos , Masculino , Peptídeos/sangue , Puberdade/fisiologia , Análise de Regressão , Tomografia Computadorizada por Raios X
12.
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
13.
Am J Hum Genet ; 103(5): 691-706, 2018 11 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.


Assuntos
Loci Gênicos/genética , Inflamação/genética , Redes e Vias Metabólicas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Transtorno Bipolar/genética , Transtorno Bipolar/metabolismo , Índice de Massa Corporal , Proteína C-Reativa/genética , Criança , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Inflamação/metabolismo , Fígado/metabolismo , Fígado/patologia , Masculino , Análise da Randomização Mendeliana/métodos , Pessoa de Meia-Idade , Esquizofrenia/genética , Esquizofrenia/metabolismo , Adulto Jovem
14.
Bone ; 114: 62-71, 2018 09.
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.


Assuntos
Densidade Óssea/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Vértebras Lombares/diagnóstico por imagem , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Proteínas da Matriz Extracelular/genética , Feminino , Humanos , Vértebras Lombares/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade
15.
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.


Assuntos
Dedos/anatomia & histologia , Estudo de Associação Genômica Ampla , Testosterona/metabolismo , Adulto , Androgênios/metabolismo , Biomarcadores , Feminino , Dedos/crescimento & desenvolvimento , Variação Genética , Humanos , Masculino , Gravidez , Estudos Retrospectivos , Caracteres Sexuais , Testosterona/genética
16.
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.


Assuntos
Densidade Óssea/genética , Estudo de Associação Genômica Ampla , Adolescente , Fatores Etários , Animais , Criança , Pré-Escolar , Loci Gênicos , Humanos , Lactente , Recém-Nascido , Camundongos Knockout , Polimorfismo de Nucleotídeo Único/genética , Característica Quantitativa Herdável , Análise de Regressão
17.
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
18.
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
19.
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
20.
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
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