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1.
Hum Mol Genet ; 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31504550

RESUMO

Although hundreds of GWAS-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity, and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of thirty studies consisting of up to 13,005 cases (≥95th percentile of BMI achieved 2-18 years old) and 15,599 controls (consistently <50th percentile of BMI) of European, African, North/South American and East Asian ancestry. Suggestive loci were taken forward for replication in a sample of 1,888 cases and 4,689 controls from seven cohorts of European and North/South American ancestry. In addition to observing eighteen previously implicated BMI or obesity loci, for both early and late onset, we uncovered one completely novel locus in this trans-ancestral analysis (nearest gene: METTL15). The variant was nominally associated in only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than ten SNPs (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci.

2.
Am J Hum Genet ; 105(1): 89-107, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31204013

RESUMO

Deciphering the impact of genetic variation on gene regulation is fundamental to understanding common, complex human diseases. Although histone modifications are important markers of gene regulatory elements of the genome, any specific histone modification has not been assayed in more than a few individuals in the human liver. As a result, the effects of genetic variation on histone modification states in the liver are poorly understood. Here, we generate the most comprehensive genome-wide dataset of two epigenetic marks, H3K4me3 and H3K27ac, and annotate thousands of putative regulatory elements in the human liver. We integrate these findings with genome-wide gene expression data collected from the same human liver tissues and high-resolution promoter-focused chromatin interaction maps collected from human liver-derived HepG2 cells. We demonstrate widespread functional consequences of natural genetic variation on putative regulatory element activity and gene expression levels. Leveraging these extensive datasets, we fine-map a total of 74 GWAS loci that have been associated with at least one complex phenotype. Our results reveal a repertoire of genes and regulatory mechanisms governing complex disease development and further the basic understanding of genetic and epigenetic regulation of gene expression in the human liver tissue.

3.
Nat Commun ; 10(1): 1260, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30890710

RESUMO

Osteoporosis is a devastating disease with an essential genetic component. GWAS have discovered genetic signals robustly associated with bone mineral density (BMD), but not the precise localization of effector genes. Here, we carry out physical and direct variant to gene mapping in human mesenchymal progenitor cell-derived osteoblasts employing a massively parallel, high resolution Capture C based method in order to simultaneously characterize the genome-wide interactions of all human promoters. By intersecting our Capture C and ATAC-seq data, we observe consistent contacts between candidate causal variants and putative target gene promoters in open chromatin for ~ 17% of the 273 BMD loci investigated. Knockdown of two novel implicated genes, ING3 at 'CPED1-WNT16' and EPDR1 at 'STARD3NL', inhibits osteoblastogenesis, while promoting adipogenesis. This approach therefore aids target discovery in osteoporosis, here on the example of two relevant genes involved in the fate determination of mesenchymal progenitors, and can be applied to other common genetic diseases.


Assuntos
Densidade Óssea/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Osteoporose/genética , Regiões Promotoras Genéticas/genética , Adipogenia/genética , Adulto , Diferenciação Celular/genética , Mapeamento Cromossômico , Feminino , Técnicas de Silenciamento de Genes , Loci Gênicos/genética , Células Hep G2 , Proteínas de Homeodomínio/genética , Humanos , Masculino , Proteínas de Membrana/genética , Células-Tronco Mesenquimais , Proteínas de Neoplasias/genética , Osteoblastos/fisiologia , Osteogênese/genética , Polimorfismo de Nucleotídeo Único , Cultura Primária de Células , Proteínas Proto-Oncogênicas/genética , RNA Interferente Pequeno/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Wnt/genética , Adulto Jovem
4.
Bone ; 121: 221-226, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30711642

RESUMO

Over the past two decades, a low frequency variant (rs1800012) within the first intron of the type I collagen alpha 1 (COLIA1) gene has been implicated in lower areal BMD (aBMD) and increased risk of osteoporotic fracture. This association is particularly strong in postmenopausal women, in whom net bone loss arises in the context of high bone turnover. High bone turnover also accompanies childhood linear growth; however, the role of rs1800012 in this stage of net bone accretion is less well understood. Thus, we assessed the association between rs1800012 and aBMD and bone mineral content (BMC) Z-scores for the 1/3 distal radius, lumbar spine, total hip, and femoral neck total body less head in the Bone Mineral Density in Childhood Study, a mixed-longitudinal cohort of children and adolescents (total n = 804 girls and 771 boys; n = 19 girls and 22 boys with the TT genotype). Mixed effects modeling, stratified by sex, was used to test for associations between rs1800012 and aBMD or BMC Z-scores and for pubertal stage interactions. Separately, SITAR growth modeling of aBMD and BMC in subjects with longitudinal data reduced the complex longitudinal bone accrual curves into three parameters representing a-size, b-timing, and c-velocity. We tested for differences in these three parameters by rs1800012 genotype using t-tests. Girls with the TT genotype had significantly lower aBMD and BMC Z-scores prior to puberty completion (e.g. spine aBMD-Z P-interaction = 1.0 × 10-6), but this association was attenuated post-puberty. SITAR models revealed that TT girls began pubertal bone accrual later (b-timing; e.g. total hip BMC, P = 0.03). BMC and aBMD Z-scores also increased across puberty in TT homozygous boys. Our data, along with previous findings in post-menopausal women, suggest that rs1800012 principally affects female bone density during periods of high turnover. Insights into the genetics of bone gain and loss may be masked during the relatively quiescent state in mid-adulthood, and discovery efforts should focus on early and late life.

5.
J Clin Endocrinol Metab ; 104(7): 2961-2970, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30811542

RESUMO

CONTEXT: Mutations in melanocortin receptor (MC4R) are the most common cause of monogenic obesity in children of European ancestry, but little is known about their prevalence in children from the minority populations in the United States. OBJECTIVE: This study aims to identify the prevalence of MC4R mutations in children with severe early-onset obesity of African American or Latino ancestry. DESIGN AND SETTING: Participants were recruited from the weight management clinics at two hospitals and from the institutional biobank at a third hospital. Sequencing of the MC4R gene was performed by whole exome or Sanger sequencing. Functional testing was performed to establish the surface expression of the receptor and cAMP response to its cognate ligand α-melanocyte-stimulating hormone. PARTICIPANTS: Three hundred twelve children (1 to 18 years old, 50% girls) with body mass index (BMI) >120% of 95th percentile of Centers for Disease Control and Prevention 2000 growth charts at an age <6 years, with no known pathological cause of obesity, were enrolled. RESULTS: Eight rare MC4R mutations (2.6%) were identified in this study [R7S, F202L (n = 2), M215I, G252D, V253I, I269N, and F284I], three of which were not previously reported (G252D, F284I, and R7S). The pathogenicity of selected variants was confirmed by prior literature reports or functional testing. There was no significant difference in the BMI or height trajectories of children with or without MC4R mutations in this cohort. CONCLUSIONS: Although the prevalence of MC4R mutations in this cohort was similar to that reported for obese children of European ancestry, some of the variants were novel.

6.
Diabetes Care ; 41(11): 2396-2403, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30254083

RESUMO

OBJECTIVE: Latent autoimmune diabetes in adults (LADA) shares clinical features with both type 1 and type 2 diabetes; however, there is ongoing debate regarding the precise definition of LADA. Understanding its genetic basis is one potential strategy to gain insight into appropriate classification of this diabetes subtype. RESEARCH DESIGN AND METHODS: We performed the first genome-wide association study of LADA in case subjects of European ancestry versus population control subjects (n = 2,634 vs. 5,947) and compared against both case subjects with type 1 diabetes (n = 2,454 vs. 968) and type 2 diabetes (n = 2,779 vs. 10,396). RESULTS: The leading genetic signals were principally shared with type 1 diabetes, although we observed positive genetic correlations genome-wide with both type 1 and type 2 diabetes. Additionally, we observed a novel independent signal at the known type 1 diabetes locus harboring PFKFB3, encoding a regulator of glycolysis and insulin signaling in type 2 diabetes and inflammation and autophagy in autoimmune disease, as well as an attenuation of key type 1-associated HLA haplotype frequencies in LADA, suggesting that these are factors that distinguish childhood-onset type 1 diabetes from adult autoimmune diabetes. CONCLUSIONS: Our results support the need for further investigations of the genetic factors that distinguish forms of autoimmune diabetes as well as more precise classification strategies.

7.
Hum Genet ; 137(5): 413-425, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29797095

RESUMO

Although Genome Wide Association Studies (GWAS) have led to many valuable insights into the genetic bases of common diseases over the past decade, the issue of missing heritability has surfaced, as the discovered main effect genetic variants found to date do not account for much of a trait's predicted genetic component. We present a workflow, integrating epigenomics and topologically associating domain data, aimed at discovering trait-associated SNP pairs from GWAS where neither SNP achieved independent genome-wide significance. Each analyzed SNP pair consists of one SNP in a putative active enhancer and another SNP in a putative physically interacting gene promoter in a trait-relevant tissue. As a proof-of-principle case study, we used this approach to identify focused collections of SNP pairs that we analyzed in three independent Type 2 diabetes (T2D) GWAS. This approach led us to discover 35 significant SNP pairs, encompassing both novel signals and signals for which we have found orthogonal support from other sources. Nine of these pairs are consistent with eQTL results, two are consistent with our own capture C experiments, and seven involve signals supported by recent T2D literature.

8.
Med Sci Sports Exerc ; 50(5): 977-986, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29465475

RESUMO

PURPOSE: This study aimed to determine if replacing time spent in high- and low-impact physical activity (PA) predicts changes in pediatric bone mineral density (BMD) and content (BMC). METHODS: We analyzed data from the longitudinal Bone Mineral Density in Childhood Study (N = 2337 with up to seven visits). The participants were age 5-19 yr at baseline, 51.2% were female, and 80.6% were nonblack. Spine, total hip, and femoral neck areal BMD and total body less head (TBLH) BMC Z-scores were calculated. Hours per day spent in high- and low-impact PA were self-reported. Standard covariate-adjusted (partition model) and time allocation-sensitive isotemporal substitution modeling frameworks were applied to linear mixed models. Statistical interactions with sex, self-reported ancestry, age, and bone fragility genetic scores (percentage of areal BMD-lowering alleles carried) were tested. RESULTS: In standard models, high-impact PA was positively associated with bone Z-score at all four skeletal sites (e.g., TBLH-BMC Z-score: beta = 0.05, P = 2.0 × 10), whereas low-impact PA was not associated with any of the bone Z-scores. In isotemporal substitution models, replacing 1 h·d of low- for high-impact PA was associated with higher bone Z-scores (e.g., TBLH-BMC Z-score: beta = 0.06, P = 2.9 × 10). Conversely, replacing 1 h·d of high- for low-impact PA was associated with lower bone Z-scores (e.g., TBLH-BMC Z-score: beta = -0.06, P = 2.9 × 10). The substitution associations were similar for each sex and ancestry group, and for those with higher and lower genetic scores for bone fragility (P-interactions > 0.05), but increased in strength among the older adolescents (P-age interactions < 0.05). CONCLUSIONS: Time-sensitive models suggest that replacing low-impact PA for high-impact PA would be beneficial for the growing skeleton in the majority of children.

9.
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.

10.
J Clin Endocrinol Metab ; 103(4): 1380-1392, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29325163

RESUMO

Context: Vitamin D inadequacy is common in the adult population of the United States. Although the genetic determinants underlying vitamin D inadequacy have been studied in people of European ancestry, less is known about populations with Hispanic or African ancestry. Objective: The Trans-Ethnic Evaluation of Vitamin D (TRANSCEN-D) genomewide association study (GWAS) consortium was assembled to replicate genetic associations with 25-hydroxyvitamin D [25(OH)D] concentrations from the Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits (SUNLIGHT) meta-analyses of European ancestry and to identify genetic variants related to vitamin D concentrations in African and Hispanic ancestries. Design: Ancestry-specific (Hispanic and African) and transethnic (Hispanic, African, and European) meta-analyses were performed with Meta-Analysis Helper software (METAL). Patients or Other Participants: In total, 8541 African American and 3485 Hispanic American (from North America) participants from 12 cohorts and 16,124 European participants from SUNLIGHT were included in the study. Main Outcome Measures: Blood concentrations of 25(OH)D were measured for all participants. Results: Ancestry-specific analyses in African and Hispanic Americans replicated single nucleotide polymorphisms (SNPs) in GC (2 and 4 SNPs, respectively). An SNP (rs79666294) near the KIF4B gene was identified in the African American cohort. Transethnic evaluation replicated GC and DHCR7 region SNPs. Additionally, the transethnic analyses revealed SNPs rs719700 and rs1410656 near the ANO6/ARID2 and HTR2A genes, respectively. Conclusions: Ancestry-specific and transethnic GWASs of 25(OH)D confirmed findings in GC and DHCR7 for African and Hispanic American samples and revealed findings near KIF4B, ANO6/ARID2, and HTR2A. The biological mechanisms that link these regions with 25(OH)D metabolism warrant further investigation.


Assuntos
Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/etnologia , Vitamina D/análogos & derivados , Adolescente , Adulto , Afro-Americanos/genética , Idoso , Índice de Massa Corporal , Criança , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Hispano-Americanos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estados Unidos/epidemiologia , Vitamina D/sangue , Vitamina D/genética , Deficiência de Vitamina D/genética , Adulto Jovem
11.
J Bone Miner Res ; 33(3): 430-436, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29068475

RESUMO

Later puberty associates with lower areal bone mineral density (aBMD), and both are risk factors for osteoporosis. However, the association between puberty timing-associated genetic variants and aBMD during development, and the causal relationship between puberty timing and aBMD, remain uncharacterized. We constructed sex-specific polygenic risk scores (GRS) consisting of 333 genetic variants associated with later puberty in European-descent children in the Bone Mineral Density in Childhood Study (BMDCS), consisting of a longitudinal cohort with up to seven assessments (n = 933) and a cross-sectional cohort (n = 486). These GRS were tested for associations with age- and sex-specific aBMD Z-scores at the lumbar spine (LS), femoral neck (FN), total hip, and distal radius, accounting for clinical covariates using sex-stratified linear mixed models. The causal relationship between puberty timing and aBMD was tested in the BMDCS and in publicly available adult data (GEFOS consortium) using two-sample Mendelian randomization (MR). The puberty-delaying GRS was associated with later puberty and lower LS-aBMD in the BMDCS in both sexes (combined beta ± SE = -0.078 ± 0.024; p = 0.0010). In the MR framework, the puberty-delaying genetic instrument also supported a causal association with lower LS-aBMD and FN-aBMD in adults of both sexes. Our results suggest that pubertal timing is causal for diminished aBMD in a skeletal site- and sex-specific manner that tracks throughout life, potentially impacting later risk for osteoporosis, which should be tested in future studies. © 2017 American Society for Bone and Mineral Research.

12.
J Bone Miner Res ; 33(5): 812-821, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29240982

RESUMO

Osteoporosis is a complex disease with developmental origins. It is therefore important to understand the genetic contribution to pediatric areal bone mineral density (aBMD). Individual skeletal site phenotyping has been primarily used to identify pediatric aBMD loci. However, this approach is limited because there is a degree of aBMD discordance across skeletal sites. We therefore applied a novel multidimensional phenotyping approach to further understand the genetic regulation of pediatric aBMD. Our sample comprised a prospective, longitudinal cohort of 1293 children of European ancestry (52% female; up to seven annual measurements). Principal components analysis was applied to dual-energy X-ray absorptiometry-derived aBMD Z-scores for total hip, femoral neck, spine, and distal radius to generate multidimensional aBMD phenotypes (ie, principal component scores). We tested the association between a genetic score (percentage of bone lowering alleles at 63 loci) and each principal component. We also performed a genomewide association study (GWAS) using the multiethnic baseline data (n = 1885) to identify novel loci associated with these principal components. The first component (PC1) reflected a concordant phenotypic model of the skeleton (eg, higher loading score = higher BMD across all sites). In contrast, PC2 was discordant for distal radius versus spine and hip aBMD, and PC3 was discordant for spine versus distal radius and hip aBMD. The genetic score was associated with PC1 (beta = -0.05, p = 3.9 × 10-10 ), but was not associated with discordant PC2 or PC3. Our GWAS discovered variation near CPED1 that associated with PC2 (rs67991850, p = 2.5 × 10-11 ) and near RAB11FIP5 (rs58649746, p = 4.8 × 10-9 ) that associated with PC3. In conclusion, an established bone fragility genetic summary score was associated with a concordant skeletal phenotype, but not discordant skeletal phenotypes. Novel associations were observed for the discordant multidimensional skeletal phenotypes that provide new biological insights into the developing skeleton. © 2017 American Society for Bone and Mineral Research.

13.
Pac Symp Biocomput ; 23: 548-558, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29218913

RESUMO

We utilized evidence for enhancer-promoter interactions from functional genomics data in order to build biological filters to narrow down the search space for two-way Single Nucleotide Polymorphism (SNP) interactions in Type 2 Diabetes (T2D) Genome Wide Association Studies (GWAS). This has led us to the identification of a reproducible statistically significant SNP pair associated with T2D. As more functional genomics data are being generated that can help identify potentially interacting enhancer-promoter pairs in larger collection of tissues/cells, this approach has implications for investigation of epistasis from GWAS in general.


Assuntos
Diabetes Mellitus Tipo 2/genética , Epistasia Genética , Biologia Computacional/métodos , Bases de Dados Genéticas/estatística & dados numéricos , Elementos Facilitadores Genéticos , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Genômica/estatística & dados numéricos , Humanos , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas
14.
Am J Hum Genet ; 101(5): 643-663, 2017 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-29056226

RESUMO

Neurodegenerative diseases pose an extraordinary threat to the world's aging population, yet no disease-modifying therapies are available. Although genome-wide association studies (GWASs) have identified hundreds of risk loci for neurodegeneration, the mechanisms by which these loci influence disease risk are largely unknown. Here, we investigated the association between common genetic variants at the 7p21 locus and risk of the neurodegenerative disease frontotemporal lobar degeneration. We showed that variants associated with disease risk correlate with increased expression of the 7p21 gene TMEM106B and no other genes; co-localization analyses implicated a common causal variant underlying both association with disease and association with TMEM106B expression in lymphoblastoid cell lines and human brain. Furthermore, increases in the amount of TMEM106B resulted in increases in abnormal lysosomal phenotypes and cell toxicity in both immortalized cell lines and neurons. We then combined fine-mapping, bioinformatics, and bench-based approaches to functionally characterize all candidate causal variants at this locus. This approach identified a noncoding variant, rs1990620, that differentially recruits CTCF in lymphoblastoid cell lines and human brain to influence CTCF-mediated long-range chromatin-looping interactions between multiple cis-regulatory elements, including the TMEM106B promoter. Our findings thus provide an in-depth analysis of the 7p21 locus linked by GWASs to frontotemporal lobar degeneration, nominating a causal variant and causal mechanism for allele-specific expression and disease association at this locus. Finally, we show that genetic variants associated with risk of neurodegenerative diseases beyond frontotemporal lobar degeneration are enriched in CTCF-binding sites found in brain-relevant tissues, implicating CTCF-mediated gene regulation in risk of neurodegeneration more generally.


Assuntos
Demência/genética , Regulação da Expressão Gênica/genética , Expressão Gênica/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único/genética , Alelos , Encéfalo/patologia , Fator de Ligação a CCCTC , Linhagem Celular Tumoral , Cromatina , Degeneração Lobar Frontotemporal/genética , Estudo de Associação Genômica Ampla , Genótipo , Células HeLa , Humanos , Neurônios/patologia , Fenótipo , Regiões Promotoras Genéticas/genética , Proteínas Repressoras/genética , Risco
15.
JAMA Pediatr ; 171(9): e171769, 2017 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-28672287

RESUMO

Importance: Prevention of osteoporosis in adulthood begins with optimizing bone health in early life. The longitudinal association between growth and bone accretion during childhood is not fully understood. Objectives: To assess the acquisition of whole-body (WB) and skeletal site-specific bone mineral content (BMC) relative to linear growth in a healthy, diverse, longitudinal cohort of children, adolescents, and young adults and to test for differences related to sex and African American race. Design, Setting, and Participants: This investigation was a mixed longitudinal study with annual assessments for up to 7 years at 5 US clinical centers. Participants were healthy children, adolescents, and young adults. The study dates were July 2002 through March 2010. The dates of the analysis were June through December 2016. Main Outcomes and Measures: Anthropometrics, BMC, and body composition via dual-energy x-ray absorptiometry. The superimposition by translation and rotation (SITAR) analysis method was used to define the mean trajectories for height, WB lean soft tissue, appendicular lean soft tissue, and WB and skeletal site-specific BMC acquisition and to measure the age and magnitude of peak velocity for each parameter. The SITAR modeling was performed separately by sex and self-reported race. Results: Among 2014 healthy children, adolescents, and young adults (1022 [50.7%] female and 479 [23.8%] African American) aged 5 to 19 years at study entry, the mean age of peak height velocity was 13.1 years (95% CI, 13.0-13.2 years) in African American boys vs 13.4 years (95% CI, 13.3-13.4 years) in non-African American boys (difference, -0.3 years; 95% CI, -0.4 to -0.1 years) and 11.0 years (95% CI, 10.8-11.1 years) in African American girls vs 11.6 years (95% CI, 11.5-11.6 years) in non-African American girls (difference, -0.6 years; 95% CI, -0.7 to -0.5 years). Age of peak acquisition of WB BMC was 14.0 years (95% CI, 13.8-14.1 years) in African American boys vs 14.0 years (95% CI, 13.9-14.1 years) in non-African American boys (difference, -0.0 years; 95% CI, -0.2 to 0.2 years) and 12.1 years (95% CI, 12.0-12.3 years) in African American girls vs 12.4 years (95% CI, 12.3-12.5 years) in non-African American girls (difference, -0.3 years; 95% CI, -0.4 to -0.1 years). At age 7 years, children had acquired 69.5% to 74.5% of maximal observed height but only 29.6% to 38.1% of maximal observed WB BMC. Adolescents gained 32.7% to 35.8% of maximal observed WB BMC during the 2 years before and 2 years after peak height velocity. Another 6.9% to 10.7% of maximal observed WB BMC occurred after linear growth had ceased. In the group at highest risk for fracture, non-African American boys, peak fracture incidence occurred approximately 1 year before peak height velocity. Conclusions and Relevance: In this longitudinal study, height gains substantially outpaced gains in BMC during childhood, which could contribute to fracture risk. A significant proportion of bone is accrued after adult height is achieved. Therefore, late adolescence represents a potentially underrecognized window of opportunity to optimize bone mass.


Assuntos
Composição Corporal/fisiologia , Densidade Óssea/fisiologia , Desenvolvimento Infantil/fisiologia , Absorciometria de Fóton , Adolescente , Criança , Feminino , Humanos , Estudos Longitudinais , Masculino , Estados Unidos , Adulto Jovem
16.
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
17.
PLoS Genet ; 13(4): e1006719, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28430825

RESUMO

Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained ≤ 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations.


Assuntos
Adiposidade/genética , Obesidade/genética , Serina Endopeptidases/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Grupo com Ancestrais do Continente Africano/genética , Antropometria , Índice de Massa Corporal , Mapeamento Cromossômico , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Masculino , Obesidade/patologia , Polimorfismo de Nucleotídeo Único , Relação Cintura-Quadril
18.
BMC Med ; 15(1): 88, 2017 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-28438156

RESUMO

BACKGROUND: In adulthood, autoimmune diabetes can present as non-insulin-requiring diabetes, termed as 'latent autoimmune diabetes in adults' (LADA). In this study, we investigated established type 1 diabetes (T1D) and type 2 diabetes (T2D) genetic loci in a large cohort of LADA cases to assess where LADA is situated relative to these two well-characterized, classic forms of diabetes. METHODS: We tested the association of T1D and T2D GWAS-implicated loci in 978 LADA cases and 1057 non-diabetic controls of European ancestry using a linear mixed model. We then compared the associations of T1D and T2D loci between LADA and T1D and T2D cases, respectively. We quantified the difference in genetic risk between each given disease at each locus, and also calculated genetic risk scores to quantify how genetic liability to T1D and T2D distinguished LADA cases from controls. RESULTS: Overall, our results showed that LADA is genetically more similar to T1D, with the exception of an association at the T2D HNF1A locus. Several T1D loci were associated with LADA, including the major histocompatibility complex region, as well as at PTPN22, SH2B3, and INS. Contrary to previous studies, the key T2D risk allele at TCF7L2 (rs7903146-T) had a significantly lower frequency in LADA cases, suggesting that this locus does not play a role in LADA etiology. When constrained on antibody status, the similarity between LADA and T1D became more apparent; however, the HNF1A and TCF7L2 observations persisted. CONCLUSION: LADA is genetically closer to T1D than T2D, although the genetic load of T1D risk alleles is less than childhood-onset T1D, particularly at the major histocompatibility complex region, potentially accounting for the later disease onset. Our results show that the genetic spectrum of T1D extends into adult-onset diabetes, where it can clinically masquerade as T2D. Furthermore, T2D genetic risk plays a small role in LADA, with a degree of evidence for the HNF1A locus, highlighting the potential for genetic risk scores to contribute towards defining diabetes subtypes.


Assuntos
Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/genética , Adulto , Idoso , Alelos , Humanos , Pessoa de Meia-Idade , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética
19.
J Bone Miner Res ; 32(6): 1274-1281, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28181694

RESUMO

Failure to achieve optimal bone mineral accretion during childhood and adolescence results in subsequent suboptimal peak bone mass, contributing to osteoporosis risk later in life. To identify novel genetic factors that influence pediatric bone mass at discrete skeletal sites, we performed a sex-stratified genomewide association study of areal bone mineral density (BMD) measured by dual-energy X-ray absorptiometry at the 1/3 distal radius, spine, total hip, and femoral neck in a cohort of 933 healthy European American children. We took forward signals with p < 5 × 10-5 and minor allele frequency (MAF) >5% into an independent cohort of 486 European American children in search of replication. In doing so, we identified five loci that achieved genome wide significance in the combined cohorts (nearest genes: CPED1, IZUMO3, RBFOX1, SPBT, and TBPL2), of which the last four were novel and two were sex-specific (SPTB in females and IZUMO3 in males), with all of them yielding associations that were particularly strong at a specific skeletal site. Annotation of potential regulatory function, expression quantitative trait loci (eQTL) effects and pathway analyses identified several potential target genes at these associated loci. This study highlights the importance of sex-stratified analyses at discrete skeletal sites during the critical period of bone accrual, and identifies novel loci for further functional follow-up to pinpoint key genes and better understand the regulation of bone development in children. © 2017 American Society for Bone and Mineral Research.


Assuntos
Densidade Óssea/genética , Osso e Ossos/fisiologia , Estudo de Associação Genômica Ampla , Imunoglobulinas/genética , Proteínas de Membrana/genética , Locos de Características Quantitativas/genética , Caracteres Sexuais , Espectrina/genética , Adolescente , Criança , Feminino , Humanos , Masculino , Anotação de Sequência Molecular , Adulto Jovem
20.
J Bone Miner Res ; 32(1): 115-124, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27419386

RESUMO

More rapid skeletal maturation in African-American (AA) children is recognized and generally attributed to an increased prevalence of obesity. The objective of the present study was to evaluate the effects of population ancestry on relative skeletal maturation in healthy, non-obese children and adolescents, accounting for body composition and sexual maturation. To do this, we leveraged a multiethnic, mixed-longitudinal study with annual assessments for up to 7 years (The Bone Mineral Density in Childhood Study and its ancillary cohort) conducted at five US clinical centers. Participants included 1592 children, skeletally immature (45% females, 19% AA) who were aged 5 to 17 years at study entry. The primary outcome measure was relative skeletal maturation as assessed by hand-wrist radiograph. Additional covariates measured included anthropometrics, body composition by dual-energy X-ray absorptiometry (DXA), and Tanner stage of sexual maturation. Using mixed effects longitudinal models, without covariates, advancement in relative skeletal maturation was noted in self-reported AA girls (∼0.33 years, p < 0.001) and boys (∼0.43 years, p < 0.001). Boys and girls of all ancestry groups showed independent positive associations of height, lean mass, fat mass, and puberty with relative skeletal maturation. The effect of ancestry was attenuated but persistent after accounting for covariates: for girls, 0.19 years (ancestry by self-report, p = 0.02) or 0.29 years (ancestry by admixture, p = 0.004); and for boys, 0.20 years (ancestry by self-report, p = 0.004), or 0.29 years (ancestry by admixture, p = 0.004). In summary, we conclude that advancement in relative skeletal maturation was associated with AA ancestry in healthy, non-obese children, independent of growth, body composition, and puberty. Further research into the mechanisms underlying this observation may provide insights into the regulation of skeletal maturation. © 2016 American Society for Bone and Mineral Research.


Assuntos
Desenvolvimento Ósseo , Grupos de Populações Continentais , Obesidade/epidemiologia , Adolescente , Determinação da Idade pelo Esqueleto , Distribuição por Idade , Composição Corporal , Estatura , Índice de Massa Corporal , Criança , Pré-Escolar , Feminino , Genética Populacional , Humanos , Masculino , Análise de Regressão , Maturidade Sexual , Adulto Jovem
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