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2.
PLoS Genet ; 16(10): e1009141, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33095761

RESUMO

The UK Biobank is a very large, prospective population-based cohort study across the United Kingdom. It provides unprecedented opportunities for researchers to investigate the relationship between genotypic information and phenotypes of interest. Multiple regression methods, compared with genome-wide association studies (GWAS), have already been showed to greatly improve the prediction performance for a variety of phenotypes. In the high-dimensional settings, the lasso, since its first proposal in statistics, has been proved to be an effective method for simultaneous variable selection and estimation. However, the large-scale and ultrahigh dimension seen in the UK Biobank pose new challenges for applying the lasso method, as many existing algorithms and their implementations are not scalable to large applications. In this paper, we propose a computational framework called batch screening iterative lasso (BASIL) that can take advantage of any existing lasso solver and easily build a scalable solution for very large data, including those that are larger than the memory size. We introduce snpnet, an R package that implements the proposed algorithm on top of glmnet and optimizes for single nucleotide polymorphism (SNP) datasets. It currently supports ℓ1-penalized linear model, logistic regression, Cox model, and also extends to the elastic net with ℓ1/ℓ2 penalty. We demonstrate results on the UK Biobank dataset, where we achieve competitive predictive performance for all four phenotypes considered (height, body mass index, asthma, high cholesterol) using only a small fraction of the variants compared with other established polygenic risk score methods.


Assuntos
Asma/epidemiologia , Bancos de Espécimes Biológicos , Genética Populacional , Estudo de Associação Genômica Ampla , Algoritmos , Asma/sangue , Asma/genética , Estatura/genética , Índice de Massa Corporal , Colesterol/sangue , Estudos de Coortes , Genótipo , Humanos , Modelos Logísticos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Modelos de Riscos Proporcionais , Reino Unido/epidemiologia
3.
PLoS Med ; 17(10): e1003288, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33031386

RESUMO

BACKGROUND: Observational studies have identified height as a strong risk factor for atrial fibrillation, but this finding may be limited by residual confounding. We aimed to examine genetic variation in height within the Mendelian randomization (MR) framework to determine whether height has a causal effect on risk of atrial fibrillation. METHODS AND FINDINGS: In summary-level analyses, MR was performed using summary statistics from genome-wide association studies of height (GIANT/UK Biobank; 693,529 individuals) and atrial fibrillation (AFGen; 65,446 cases and 522,744 controls), finding that each 1-SD increase in genetically predicted height increased the odds of atrial fibrillation (odds ratio [OR] 1.34; 95% CI 1.29 to 1.40; p = 5 × 10-42). This result remained consistent in sensitivity analyses with MR methods that make different assumptions about the presence of pleiotropy, and when accounting for the effects of traditional cardiovascular risk factors on atrial fibrillation. Individual-level phenome-wide association studies of height and a height genetic risk score were performed among 6,567 European-ancestry participants of the Penn Medicine Biobank (median age at enrollment 63 years, interquartile range 55-72; 38% female; recruitment 2008-2015), confirming prior observational associations between height and atrial fibrillation. Individual-level MR confirmed that each 1-SD increase in height increased the odds of atrial fibrillation, including adjustment for clinical and echocardiographic confounders (OR 1.89; 95% CI 1.50 to 2.40; p = 0.007). The main limitations of this study include potential bias from pleiotropic effects of genetic variants, and lack of generalizability of individual-level findings to non-European populations. CONCLUSIONS: In this study, we observed evidence that height is likely a positive causal risk factor for atrial fibrillation. Further study is needed to determine whether risk prediction tools including height or anthropometric risk factors can be used to improve screening and primary prevention of atrial fibrillation, and whether biological pathways involved in height may offer new targets for treatment of atrial fibrillation.


Assuntos
Fibrilação Atrial/genética , Estatura/genética , Adulto , Idoso , Causalidade , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Previsões , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Análise da Randomização Mendeliana/métodos , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
4.
PLoS Genet ; 16(9): e1008780, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32925905

RESUMO

Genome-Wide Association Studies (GWAS) in large human cohorts have identified thousands of loci associated with complex traits and diseases. For identifying the genes and gene-associated variants that underlie complex traits in livestock, especially where sample sizes are limiting, it may help to integrate the results of GWAS for equivalent traits in humans as prior information. In this study, we sought to investigate the usefulness of results from a GWAS on human height as prior information for identifying the genes and gene-associated variants that affect stature in cattle, using GWAS summary data on samples sizes of 700,000 and 58,265 for humans and cattle, respectively. Using Fisher's exact test, we observed a significant proportion of cattle stature-associated genes (30/77) that are also associated with human height (odds ratio = 5.1, p = 3.1e-10). Result of randomized sampling tests showed that cattle orthologs of human height-associated genes, hereafter referred to as candidate genes (C-genes), were more enriched for cattle stature GWAS signals than random samples of genes in the cattle genome (p = 0.01). Randomly sampled SNPs within the C-genes also tend to explain more genetic variance for cattle stature (up to 13.2%) than randomly sampled SNPs within random cattle genes (p = 0.09). The most significant SNPs from a cattle GWAS for stature within the C-genes did not explain more genetic variance for cattle stature than the most significant SNPs within random cattle genes (p = 0.87). Altogether, our findings support previous studies that suggest a similarity in the genetic regulation of height across mammalian species. However, with the availability of a powerful GWAS for stature that combined data from 8 cattle breeds, prior information from human-height GWAS does not seem to provide any additional benefit with respect to the identification of genes and gene-associated variants that affect stature in cattle.


Assuntos
Estatura/genética , Bovinos/genética , Estudo de Associação Genômica Ampla/métodos , Animais , Cruzamento/métodos , Bases de Dados Genéticas , Variação Genética/genética , Humanos , Gado/genética , Herança Multifatorial/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética
5.
Proc Natl Acad Sci U S A ; 117(35): 21364-21372, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32817564

RESUMO

A person's genome typically contains millions of variants which represent the differences between this personal genome and the reference human genome. The interpretation of these variants, i.e., the assessment of their potential impact on a person's phenotype, is currently of great interest in human genetics and medicine. We have developed a prioritization tool called OpenCausal which takes as inputs 1) a personal genome and 2) a reference context-specific TF expression profile and returns a list of noncoding variants prioritized according to their impact on chromatin accessibility for any given genomic region of interest. We applied OpenCausal to 6,430 samples across 18 tissues derived from the GTEx project and found that the variants prioritized by OpenCausal are highly enriched for eQTLs and caQTLs. We further propose a strategy to integrate the predicted open scores with genome-wide association studies (GWAS) data to prioritize putative causal variants and regulatory elements for a given risk locus (i.e., fine-mapping analysis). As an initial example, we applied this method to a GWAS dataset of human height and found that the prioritized putative variants and elements are correlated with the phenotype (i.e., heights of individuals) better than others.


Assuntos
Técnicas Genéticas , Variação Genética , Genoma Humano , Modelos Genéticos , Elementos Reguladores de Transcrição , Estatura/genética , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Locos de Características Quantitativas , Software , Fatores de Transcrição/metabolismo
6.
Nature ; 582(7811): 234-239, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32499652

RESUMO

On average, Peruvian individuals are among the shortest in the world1. Here we show that Native American ancestry is associated with reduced height in an ethnically diverse group of Peruvian individuals, and identify a population-specific, missense variant in the FBN1 gene (E1297G) that is significantly associated with lower height. Each copy of the minor allele (frequency of 4.7%) reduces height by 2.2 cm (4.4 cm in homozygous individuals). To our knowledge, this is the largest effect size known for a common height-associated variant. FBN1 encodes the extracellular matrix protein fibrillin 1, which is a major structural component of microfibrils. We observed less densely packed fibrillin-1-rich microfibrils with irregular edges in the skin of individuals who were homozygous for G1297 compared with individuals who were homozygous for E1297. Moreover, we show that the E1297G locus is under positive selection in non-African populations, and that the E1297 variant shows subtle evidence of positive selection specifically within the Peruvian population. This variant is also significantly more frequent in coastal Peruvian populations than in populations from the Andes or the Amazon, which suggests that short stature might be the result of adaptation to factors that are associated with the coastal environment in Peru.


Assuntos
Estatura/genética , Fibrilina-1/genética , Mutação de Sentido Incorreto , Seleção Genética , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Hereditariedade , Humanos , Índios Sul-Americanos/genética , Masculino , Microfibrilas/química , Microfibrilas/genética , Peru
7.
Am J Hum Genet ; 107(1): 60-71, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32533944

RESUMO

Adult height is one of the earliest putative examples of polygenic adaptation in humans. However, this conclusion was recently challenged because residual uncorrected stratification from large-scale consortium studies was considered responsible for the previously noted genetic difference. It thus remains an open question whether height loci exhibit signals of polygenic adaptation in any human population. We re-examined this question, focusing on one of the shortest European populations, the Sardinians, in addition to mainland European populations. We utilized height-associated loci from the Biobank Japan (BBJ) dataset to further alleviate concerns of biased ascertainment of GWAS loci and showed that the Sardinians remain significantly shorter than expected under neutrality (∼0.22 standard deviation shorter than Utah residents with ancestry from northern and western Europe [CEU] on the basis of polygenic height scores, p = 3.89 × 10-4). We also found the trajectory of polygenic height scores between the Sardinian and the British populations diverged over at least the last 10,000 years (p = 0.0082), consistent with a signature of polygenic adaptation driven primarily by the Sardinian population. Although the polygenic score-based analysis showed a much subtler signature in mainland European populations, we found a clear and robust adaptive signature in the UK population by using a haplotype-based statistic, the trait singleton density score (tSDS), driven by the height-increasing alleles (p = 9.1 × 10-4). In summary, by ascertaining height loci in a distant East Asian population, we further supported the evidence of polygenic adaptation at height-associated loci among the Sardinians. In mainland Europeans, the adaptive signature was detected in haplotype-based analysis but not in polygenic score-based analysis.


Assuntos
Adaptação Fisiológica/genética , Estatura/genética , Herança Multifatorial/genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Bancos de Espécimes Biológicos , Grupo com Ancestrais do Continente Europeu/genética , Genética Populacional/métodos , Genoma Humano/genética , Estudo de Associação Genômica Ampla/métodos , Haplótipos/genética , Humanos , Itália , Japão , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Seleção Genética/genética
8.
Hum Genet ; 139(11): 1471-1483, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32583022

RESUMO

Human growth is a complex trait determined by genetic factors in combination with external stimuli, including environment, nutrition and hormonal status. In the past, several genome-wide association studies (GWAS) have collectively identified hundreds of genetic variants having a putative effect on determining adult height in different worldwide populations. Theoretically, a valuable approach to better understand the mechanisms of complex traits as adult height is to study a population exhibiting extreme stature phenotypes, such as African Baka Pygmies. After phenotypic characterization, we sequenced the whole exomes of a cohort of Baka Pygmies and their non-Pygmies Bantu neighbors to highlight genetic variants associated with the reduced stature. Whole exome data analysis revealed 29 single nucleotide polymorphisms (SNPs) significantly associated with the reduced height in the Baka group. Among these variants, we focused on SNP rs7629425, located in the 5'-UTR of the Hyaluronidase-2 (HYAL2) gene. The frequency of the alternative allele was significantly increased compared to African and non-African populations. In vitro luciferase assay showed significant differences in transcription modulation by rs7629425 C/T alleles. In conclusion, our results suggested that the HYAL2 gene variants may play a role in the etiology of short stature in Baka Pygmies population.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Moléculas de Adesão Celular/genética , Proteínas Ligadas por GPI/genética , Transtornos do Crescimento/genética , Hialuronoglucosaminidase/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Alelos , Estatura/genética , Exoma/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino
10.
Eur J Endocrinol ; 183(2): C9-C10, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32413843

RESUMO

Short stature is one of the most common causes for referrals to pediatric endocrinologists. However, in a majority of the children, no underlying cause can be identified and the child instead receives the unhelpful diagnosis of idiopathic short stature (ISS), often after extensive work-up and testing. Recent advances in genetic methodology have allowed for the identification of a number of different monogenic conditions within the large cohort of ISS children. Isolated short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans (MIM#165800) due to heterozygous aggrecan gene mutations exemplifies how this progress is changing the way we assess, counsel and treat children with non-endocrine growth disorders.


Assuntos
Agrecanas/genética , Estatura/genética , Nanismo/genética , Transtornos do Crescimento/genética , Adolescente , Criança , Pré-Escolar , Humanos , Lactente , Mutação/genética
11.
PLoS One ; 15(4): e0230555, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32275720

RESUMO

This study uses a Mendelian randomization approach to resolve the difficulties of identifying the causal relationship between height and earnings by using a unique sample of 3,427 respondents from mainland China with sociodemographic information linked to individual genotyping data. Exploiting genetic variations to create instrumental variables for observed height, we find that while OLS regressions yield that an additional centimeter in height is associated with a 10-13% increase in one's annual earnings, IV estimates reveal only an insubstantial causal effect of height. Further analyses suggest that the observed height premium is likely to pick up the impacts of several cognitive/noncognitive skills on earnings confounded in previous studies, such as mental health, risk preference, and personality factors. Our study is the first empirical study that employs genetic IVs in developing countries, and our results contribute to the recent debate on the mechanism of height premium.


Assuntos
Estatura/genética , Renda , China , Feminino , Humanos , Masculino , Análise da Randomização Mendeliana/métodos
12.
J Clin Endocrinol Metab ; 105(3)2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31990356

RESUMO

CONTEXT: The C-type natriuretic peptide receptor encoded by the NPR2 gene is a paracrine regulator of the growth plate; heterozygous NPR2 variants cause short stature with possible presence of different signs of bone dysplasia. To date, the effect of growth hormone (GH) treatment has been described in a few individuals with NPR2 gene variants with inconsistent results. OBJECTIVES: To identify NPR2 gene variants among children with familial short stature (FSS) and to describe their phenotype, including GH treatment response. DESIGN, SETTINGS AND PATIENTS: Out of 747 patients with short stature treated with GH in a single center, 87 with FSS met the inclusion criteria (pretreatment height ≤ -2 standard deviation in both the patient and the shorter parent, unknown genetic etiology). Next-generation sequencing methods were performed to search for NPR2 gene variants. The results were evaluated using the American College of Medical Genetics and Genomics guidelines. The GH treatment response (growth velocity improvement and height standard deviation score development over the first 5 years of treatment) was evaluated. RESULTS: In 5/87 children (5.7%), a (likely) pathogenic variant in the NPR2 gene was identified (p.Ile558Thr [in 2], p.Arg205*, p.Arg557His, p.Ser603Thr). Two children had disproportionate short-limbed short stature, 1 a dysplastic 5th finger phalanx. The growth velocity in the first year of GH treatment accelerated by 3.6 to 4.2 cm/year; the height improved by 1.2 to 1.8 SD over 5 years of treatment. CONCLUSIONS: NPR2 gene variants cause FSS in a significant proportion of children. Their GH treatment response is promising. Studies including final height data are necessary to assess the long-term efficacy of this therapy.


Assuntos
Estatura/genética , Nanismo/tratamento farmacológico , Nanismo/genética , Hormônio do Crescimento Humano/administração & dosagem , Polimorfismo de Nucleotídeo Único , Receptores do Fator Natriurético Atrial/genética , Adolescente , Adulto , Biomarcadores/análise , Estatura/efeitos dos fármacos , Criança , Pré-Escolar , Estudos de Coortes , Nanismo/patologia , Feminino , Seguimentos , Humanos , Lactente , Masculino , Fenótipo , Prognóstico , Adulto Jovem
13.
Anim Genet ; 51(2): 336-340, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31960458

RESUMO

Sheep, an important source of meat, dairy products and wool, play an essential part in the global agricultural economy. Body weight and body conformation are key traits in the sheep industry; however, their underlying genetic mechanisms are poorly understood. In this study, a GWAS was implemented to identify promising genes possibly linked to birth weight (BW) and body conformation traits in neonatal sheep, using a high-throughput chip (630 K). After quality control, 277 individuals and 518 203 variants were analyzed using gemma software in a mixed linear model. A total of 48 genome-wide suggestive SNPs were obtained, of which four were associated with BW, four with withers height (WH), 11 with body length (BL) and 29 with chest girth (CG). In total, 39 genes associated with BW and body conformation traits were identified by aligning to the sheep genome (Ovis aries_v4.0), and most of them were involved in the cell cycle and body development. Promising candidate genes found included the following: FOS like 2 or AP-1 transcription factor subunit (FOSL2) for BW; potassium voltage-gated channel subfamily D member 2 (KCND2) for WH; transmembrane protein 117 (TMEM117), transforming growth factor beta induced (TGFBI), and leukocyte cell-derived chemotaxin 2 (LECT2) for BL; and trafficking kinesin protein 1 (TRAK1) and LOC101102529 for CG. These results provide cues for similar studies aiming at uncovering the genetic mechanisms underlying body development, and marker-assisted selection programs focusing on BW and body conformation traits in sheep.


Assuntos
Animais Recém-Nascidos/genética , Tamanho Corporal/genética , Peso Corporal/genética , Estudo de Associação Genômica Ampla/veterinária , Polimorfismo de Nucleotídeo Único , Carneiro Doméstico/fisiologia , Animais , Peso ao Nascer/genética , Estatura/genética , Humanos , Modelos Lineares , Modelos Genéticos , Carneiro Doméstico/genética
14.
Eur J Med Genet ; 63(1): 103614, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30654153

RESUMO

In everyday practice, a pediatric endocrinologist will face a variety of different endocrine issues (such as short or tall stature, dysthyroidism, abnormal pubertal timing or impaired glucose metabolism), which relevantly contribute to the global care of a number of syndromic conditions. On the other hand, the presence of endocrine features may assist in the diagnostic process, leading to final diagnosis of a syndromic disorder. The intention of this review is to provide a referenced overview of different genetic syndromes characterized by endocrine features, and to present a possible classification, based on whether the endocrinopathy or the syndrome is typically recognized first. Thus, the first part of the manuscript deals with the most common syndromes associated with endocrine dysfunctions, while the second part describes the conditions by which a syndrome is most frequently diagnosed after an endocrine finding. The aim is to provide a practical overview of the assessment of syndromic patients, so that they can be recognized and managed in an integrated, multidisciplinary fashion.


Assuntos
Doenças do Sistema Endócrino/genética , Transtornos do Crescimento/genética , Hormônio do Crescimento Humano/genética , Estatura/genética , Criança , Doenças do Sistema Endócrino/metabolismo , Doenças do Sistema Endócrino/patologia , Endocrinologistas , Transtornos do Crescimento/epidemiologia , Transtornos do Crescimento/patologia , Hormônio do Crescimento Humano/metabolismo , Humanos , Pediatria/tendências
15.
Eur J Endocrinol ; 182(2): 139-147, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31751304

RESUMO

Context: Patients with tall stature often remain undiagnosed after clinical investigation and few studies have genetically assessed this group, most of them without a systematic approach. Objective: To assess prospectively a group of individuals with tall stature, with and without syndromic features, and to establish a molecular diagnosis for their growth disorder. Design: Screening by karyotype (n = 42), chromosome microarray analyses (CMA) (n = 16), MS-MLPA (n = 2) targeted panel (n = 12) and whole-exome sequencing (n = 31). Patients and methods: We selected 42 patients with tall stature after exclusion of pathologies in GH/IGF1 axis and divided them into syndromic (n = 30) and non-syndromic (n = 12) subgroups. Main outcome measures: Frequencies of pathogenic findings. Results: We identified two patients with chromosomal abnormalities including SHOX trisomy by karyotype, one 9q22.3 microdeletion syndrome by CMA, two cases of Beckwith-Wiedemann syndrome by targeted MS-MLPA analysis and nine cases with heterozygous pathogenic or likely pathogenic genetic variants by multigene analysis techniques (FBN1 = 3, NSD1 = 2, NFIX = 1, SUZ12 = 1, CHD8 = 1, MC4R = 1). Three of 20 patients analyzed by WES had their diagnosis established. Only one non-syndromic patient had a definitive diagnosis. The sequential genetic assessment diagnosed 14 out of 42 (33.3%) tall patients. Conclusion: A systematic molecular approach of patients with tall stature was able to identify the etiology in 13 out of 30 (43.3%) syndromic and 1 out of 12 (8.3%) non-syndromic patients, contributing to the genetic counseling and avoiding unfavorable outcomes in the syndromic subgroup.


Assuntos
Gigantismo/genética , Transtornos do Crescimento/genética , Adolescente , Adulto , Estatura/genética , Criança , Pré-Escolar , Variações do Número de Cópias de DNA/genética , Heterozigoto , Humanos , Cariótipo , Cariotipagem , Pessoa de Meia-Idade , Estudos Prospectivos , Proteína de Homoeobox de Baixa Estatura/genética , Sequenciamento Completo do Exoma/métodos , Adulto Jovem
16.
Ir J Med Sci ; 189(1): 365-372, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31230227

RESUMO

BACKGROUND: Estimating human stature is a major concern to formulate a biological profile which provides effective data for forensic identification. This research was aimed to generate a formula for estimating stature from human foot anthropometry. METHODS: This study was conducted in selected 150 male and 150 female subjects within the range of 18 to 60 years randomly. From each subject, stature and seven-foot measurements were taken by applying the standard technique. Stature was estimated from foot measurements by using linear and multiple regression equations. RESULTS: The result showed that each foot measurement was significantly (p < 0.001) and positively correlated with stature. Bilateral difference among male and female was not significant (p < 0.05). Multiple regression models showed better accuracy in estimating stature than linear regression models. CONCLUSION: In conclusion, it can be said that human stature can be successfully estimated by using foot measurements which can be applied in forensic investigation.


Assuntos
Antropometria/métodos , Estatura/genética , Pé/anatomia & histologia , Adolescente , Adulto , Bangladesh , Grupos Étnicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
17.
J Bone Miner Metab ; 38(1): 117-125, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31471646

RESUMO

Pathogenic mutations in the melanocortin-4 receptor (MC4R) are associated with obesity, increased linear growth, and higher bone mass in children, and rodent studies have indicated an effect of the MC4R on bone turnover. Furthermore, GLP-1 receptor agonists (GLP-1 RAs) may influence bone metabolism. However, these associations have not been assessed in adults with pathogenic MC4R mutations. Thus, we wished to assess the impact of the MC4R on bone mass and metabolism. Secondly, we wished to investigate the impact of the GLP-1 RA liraglutide on bone mass in adults with pathogenic MC4R mutations. 17 patients with obesity-causing MC4R mutations (BMI: 35.5 ± 7.6) and 35 matched control participants with common obesity (BMI: 34.3 ± 7.1) underwent a DEXA scan for assessment of bone mineral density (BMD), bone mineral apparent density [BMAD = (BMD/√(bone area)], and bone turnover markers (BTMs). Individuals with a BMI above 28 (14 MC4R mutation carriers and 28 matched control participants) underwent 16 weeks treatment with liraglutide 3.0 mg. The MC4R group had higher BMD [mean difference: 0.065 g/m2 (- 0.008 to 0.138), p = 0.03], but BMAD and BTMS were not different compared to the control group. In response to liraglutide, BMAD increased in the control group, compared to no change in the MC4R group [mean group difference: 0.0007 (0.0001-0.001), p = 0.04]. In conclusion, BMD is increased in MC4R causal obesity compared to common obesity, but when corrected for body size (BMAD), bone mass was not increased, and no evidence of an influence of the MC4R on bone metabolism in adults was found. Liraglutide treatment did not change bone metabolism in MC4R causal obesity, but increased bone mass as measured by BMAD in common obesity.


Assuntos
Estatura/genética , Osso e Ossos/patologia , Mutação/genética , Receptor Tipo 4 de Melanocortina/genética , Absorciometria de Fóton , Adulto , Composição Corporal/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Liraglutida/farmacologia , Masculino , Tamanho do Órgão/efeitos dos fármacos
18.
Anim Genet ; 51(1): 87-90, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31643102

RESUMO

Stature is an important quantitative trait for cattle performance, which influences herd productivity. Previous studies have reported that an SNP (AC_000171.1:g.25015640G>T, rs109815800) in Pleomorphic adenoma gene 1 (PLAG1) on chromosome 14 (CHR14) is associated with bovine stature. To validate whether rs109815800 is associated with the body height of Chinese cattle, we carried out an association analysis using 558 adult cattle samples from seven populations. Then, 1038 samples from 38 Chinese cattle breeds were used to show the geographical distribution of this variant in China. The results showed that the Q allele (G allele) increased the height of cattle. Furthermore, the frequencies of Q allele in Chinese native breeds tend to decrease from northern China to southern China, and the frequency of Q allele in two Chinese beef cattle breeds is much higher than that in another 36 Chinese local cattle breeds. Our data suggest that the prevalence of the Q allele is correlated with latitude in China.


Assuntos
Estatura/genética , Bovinos/genética , Proteínas de Ligação a DNA/genética , Polimorfismo de Nucleotídeo Único , Alelos , Animais , Cruzamento , China , Frequência do Gene , Estudos de Associação Genética/veterinária , Humanos
19.
Mol Biol Evol ; 37(2): 429-441, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31639821

RESUMO

Genomic imprinting leads to mono-allelic expression of genes based on parent of origin. Therian mammals and angiosperms evolved this mechanism in nutritive tissues, the placenta, and endosperm, where maternal and paternal genomes are in conflict with respect to resource allocation. We used RNA-seq to analyze allelic bias in the expression of 91 known imprinted genes in term human placentas from a prospective cohort study in Mali. A large fraction of the imprinted exons (39%) deviated from mono-allelic expression. Loss of imprinting (LOI) occurred in genes with either maternal or paternal expression bias, albeit more frequently in the former. We characterized LOI using binomial generalized linear mixed models. Variation in LOI was predominantly at the gene as opposed to the exon level, consistent with a single promoter driving the expression of most exons in a gene. Some genes were less prone to LOI than others, particularly lncRNA genes were rarely expressed from the repressed allele. Further, some individuals had more LOI than others and, within a person, the expression bias of maternally and paternally imprinted genes was correlated. We hypothesize that trans-acting maternal effect genes mediate correlated LOI and provide the mother with an additional lever to control fetal growth by extending her influence to LOI of the paternally imprinted genes. Limited evidence exists to support associations between LOI and offspring phenotypes. We show that birth length and placental weight were associated with allelic bias, making this the first comprehensive report of an association between LOI and a birth phenotype.


Assuntos
Peso ao Nascer/genética , Estatura/genética , Perfilação da Expressão Gênica/métodos , Impressão Genômica , Placenta/química , Adolescente , Feminino , Humanos , Recém-Nascido , Modelos Lineares , Mali , Herança Materna , Gravidez , Regiões Promotoras Genéticas , Estudos Prospectivos , Análise de Sequência de RNA , Adulto Jovem
20.
Am J Med Genet A ; 182(1): 169-175, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31782896

RESUMO

Prader-Willi syndrome (PWS) affects 1/15,000-1/30,000 live births and is characterized by lack of expression of paternally inherited genes on 15q11.2-15q13 caused by paternal deletions, maternal uniparental disomy (UPD), or imprinting defects. Affected individuals have distinct physical features, and growth hormone (GH) deficiency occurs in some individuals with PWS. The aim of this study is to test the hypotheses that (a) individuals with deletions and UPD have different physical and dysmorphic features, (b) individuals treated with GH have different physical and dysmorphic features than those not treated, and (c) GH treatment effects are different for individuals with UPD in comparison to those with deletions. Study participants included 30 individuals with deletions or UPD, who did or did not have GH treatment. Participants' molecular abnormalities were determined by molecular and cytogenetic analysis. Clinical data were obtained by a single dysmorphologist. Individuals with deletions were found to be heavier (p = .001), taller (p = .031), with smaller head circumferences (p = .042) and were more likely to have fair skin and hair than their family members (p = .031, .049, respectively) compared to UPD patients. Females with deletions more commonly had hypoplastic labia minora (p = .009) and clitoris (.030) in comparison to those with UPD. Individuals who received GH in both deletion and UPD groups were taller (p = .004), had larger hands (p = .011) and feet (p = .006) and a trend for a larger head circumference (p = .103). Interestingly, the GH-treated group also had a lower rate of strabismus (esotropia [p = .017] and exotropia [p = .039]). This study showed statistically significant correlations between phenotype and molecular subtypes and also between phenotype and GH treatment.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 15/genética , Hormônio do Crescimento/genética , Síndrome de Prader-Willi/genética , Adolescente , Estatura/genética , Criança , Pré-Escolar , Análise Citogenética/métodos , Exotropia/genética , Exotropia/patologia , Feminino , Impressão Genômica/efeitos dos fármacos , Hormônio do Crescimento/administração & dosagem , Humanos , Masculino , Fenótipo , Síndrome de Prader-Willi/classificação , Síndrome de Prader-Willi/tratamento farmacológico , Síndrome de Prader-Willi/patologia , Dissomia Uniparental/genética , Dissomia Uniparental/patologia
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