In the clinical routine of pediatricians, height is the most reliable indicator for assessing growth. However, there are situations where it is not possible to measure this parameter directly, making ...the estimation of height or length a useful alternative. The main goal of this study is to identify which segmental measure, including upper arm length (UAL), tibial length (TL), and knee-heel length (KHL), provides the stature estimate that most closely approximates directly measured height in the study participants.
Analytical cross-sectional study of the anthropometric and segmental measures of 248 participants, aged 0 to 14 years old, using Stevenson's and Kihara's equations to estimate indirectly measured height.
The segmental measure that provided a measurement that deviated the least from the actual height was the KHL, followed by TL, both calculated using Stevenson's equations.
The use of segmental measures to infer a child's stature is valuable in clinical practice, particularly in bedridden and incapacitated patients. Based on the present findings, the KHL and TL segments yielded more accurate results than the UAL
Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions ...requires huge sample sizes
. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel
) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.
Gonadotropin-releasing hormone analogs revolutionized the treatment of central precocious puberty. However, questions remain regarding their optimal use in central precocious puberty and other ...conditions. The Lawson Wilkins Pediatric Endocrine Society and the European Society for Pediatric Endocrinology convened a consensus conference to review the clinical use of gonadotropin-releasing hormone analogs in children and adolescents.
When selecting the 30 participants, consideration was given to equal representation from North America (United States and Canada) and Europe, an equal male/female ratio, and a balanced spectrum of professional seniority and expertise.
Preference was given to articles written in English with long-term outcome data. The US Public Health grading system was used to grade evidence and rate the strength of conclusions. When evidence was insufficient, conclusions were based on expert opinion.
Participants were put into working groups with assigned topics and specific questions. Written materials were prepared and distributed before the conference, revised on the basis of input during the meeting, and presented to the full assembly for final review. If consensus could not be reached, conclusions were based on majority vote. All participants approved the final statement.
The efficacy of gonadotropin-releasing hormone analogs in increasing adult height is undisputed only in early-onset (girls <6 years old) central precocious puberty. Other key areas, such as the psychosocial effects of central precocious puberty and their alteration by gonadotropin-releasing hormone analogs, need additional study. Few controlled prospective studies have been performed with gonadotropin-releasing hormone analogs in children, and many conclusions rely in part on collective expert opinion. The conference did not endorse commonly voiced concerns regarding the use of gonadotropin-releasing hormone analogs, such as promotion of weight gain or long-term diminution of bone mineral density. Use of gonadotropin-releasing hormone analogs for conditions other than central precocious puberty requires additional investigation and cannot be suggested routinely.
Human height is a representative phenotype to elucidate genetic architecture. However, the majority of large studies have been performed in European population. To investigate the rare and ...low-frequency variants associated with height, we construct a reference panel (N = 3,541) for genotype imputation by integrating the whole-genome sequence data from 1,037 Japanese with that of the 1000 Genomes Project, and perform a genome-wide association study in 191,787 Japanese. We report 573 height-associated variants, including 22 rare and 42 low-frequency variants. These 64 variants explain 1.7% of the phenotypic variance. Furthermore, a gene-based analysis identifies two genes with multiple height-increasing rare and low-frequency nonsynonymous variants (SLC27A3 and CYP26B1; P
< 2.5 × 10
). Our analysis shows a general tendency of the effect sizes of rare variants towards increasing height, which is contrary to findings among Europeans, suggesting that height-associated rare variants are under different selection pressure in Japanese and European populations.
Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated ...coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
To investigate the effect of age at growth hormone (GH) treatment start on near adult height (NAH) in children with isolated GH deficiency (GHD).
NordiNet® International Outcome Study (IOS) ...(Nbib960128), a non-interventional, multicentre study, evaluates the long-term effectiveness and safety of Norditropin® (somatropin) (Novo Nordisk A/S) in the real-life clinical setting.
Patients (
= 172) treated to NAH (height at ≥18 years, or height velocity <2 cm/year at ≥16 (boys) or ≥15 (girls) years) were grouped by age (years) at treatment start (early (girls, <8; boys, <9), intermediate (girls, 8-10; boys, 9-11) or late (girls, >10; boys, >11)) and GHD severity (<3 ng/mL or 3 to ≤10 ng/mL). Multiple regression analysis was used to evaluate the effect of age at treatment start (as a categorical and continuous variable) on NAH standard deviation score (SDS).
Age at treatment start had a marked effect on NAH SDS; NAH SDS achieved by patients starting treatment early (
= 40 (boys, 70.0%); least squares mean (standard error) -0.76 (0.14)) exceeded that achieved by those starting later (intermediate,
= 42 (boys, 57.1%); -1.14 (0.15); late,
= 90 (boys, 68.9%); -1.21 (0.10)). Multiple regression analysis showed a significant association between NAH SDS and age at treatment start (
< 0.0242), baseline height SDS (HSDS) (
< 0.0001), target HSDS (
< 0.0001), and GHD severity (
= 0.0012). Most (78.5%) patients achieved a normal NAH irrespective of age at treatment start.
Early initiation of GH treatment in children with isolated GHD improves their chance of achieving their genetic height potential.
Developing untethered millirobots that can adapt to harsh environments with high locomotion efficiency is of interest for emerging applications in various industrial and biomedical settings. Despite ...recent success in exploiting soft materials to impart sophisticated functions which are not available in conventional rigid robotics, it remains challenging to achieve superior performances in both wet and dry conditions. Inspired by the flexible, soft, and elastic leg/foot structures of many living organisms, here we report an untethered soft millirobot decorated with multiple tapered soft feet architecture. Such robot design yields superior adaptivity to various harsh environments with ultrafast locomotion speed (>40 limb length/s), ultra-strong carrying capacity (>100 own weight), and excellent obstacle-crossing ability (stand up 90° and across obstacle >10 body height). Our work represents an important advance in the emerging area of bio-inspired robotics and will find a wide spectrum of applications.
Methods to detect polygenic adaptation have recently been shown to be sensitive to uncorrected stratification in GWAS, thereby casting doubts on whether polygenic adaptation is prevalent among ...humans. Consistent with a signal of adaptation at human height loci, the mean F
among African, East Asian, and European populations was shown to be significantly higher at height-associated SNPs than that at non-associated SNPs. This conclusion was reached, however, using height-associated SNPs ascertained from a GWAS design impacted by residual confounding due to uncorrected stratification. Specifically, we show here that the estimated effect sizes are significantly correlated with population structure across continents, potentially explaining the elevated differentiation previously reported. We alleviated these concerns of confounding by ascertaining height-associated SNPs from two biobank GWAS (UK Biobank, UKB, and Biobank Japan, BBJ), where measures to control for confounding in GWAS are more effective. Consistent with a global signature of polygenic adaptation, we found that compared to non-associated SNPs, frequencies of height-associated SNPs are indeed significantly more differentiated among continental populations from both the 1000 Genomes Project (p = 0.0012 for UKB and p = 0.0265 for BBJ), and the Human Genome Diversity Project (p = 0.0225 for UKB and p = 0.0032 for BBJ). However, we found no significant difference among continental populations in polygenic height scores. Through simulations, we found that polygenic score-based statistics could lose power in detecting polygenic adaptation in presence of independent converging selections, thereby potentially explaining the inconsistent results based on F
and polygenic scores.
Many human proteins contain domains that vary in size or copy number because of variable numbers of tandem repeats (VNTRs) in protein-coding exons. However, the relationships of VNTRs to most ...phenotypes are unknown because of difficulties in measuring such repetitive elements. We developed methods to estimate VNTR lengths from whole-exome sequencing data and impute VNTR alleles into single-nucleotide polymorphism haplotypes. Analyzing 118 protein-altering VNTRs in 415,280 UK Biobank participants for association with 786 phenotypes identified some of the strongest associations of common variants with human phenotypes, including height, hair morphology, and biomarkers of health. Accounting for large-effect VNTRs further enabled fine-mapping of associations to many more protein-coding mutations in the same genes. These results point to cryptic effects of highly polymorphic common structural variants that have eluded molecular analyses to date.
The nature and underlying mechanisms of an inverse association between adult height and the risk of coronary artery disease (CAD) are unclear.
We used a genetic approach to investigate the ...association between height and CAD, using 180 height-associated genetic variants. We tested the association between a change in genetically determined height of 1 SD (6.5 cm) with the risk of CAD in 65,066 cases and 128,383 controls. Using individual-level genotype data from 18,249 persons, we also examined the risk of CAD associated with the presence of various numbers of height-associated alleles. To identify putative mechanisms, we analyzed whether genetically determined height was associated with known cardiovascular risk factors and performed a pathway analysis of the height-associated genes.
We observed a relative increase of 13.5% (95% confidence interval CI, 5.4 to 22.1; P<0.001) in the risk of CAD per 1-SD decrease in genetically determined height. There was a graded relationship between the presence of an increased number of height-raising variants and a reduced risk of CAD (odds ratio for height quartile 4 versus quartile 1, 0.74; 95% CI, 0.68 to 0.84; P<0.001). Of the 12 risk factors that we studied, we observed significant associations only with levels of low-density lipoprotein cholesterol and triglycerides (accounting for approximately 30% of the association). We identified several overlapping pathways involving genes associated with both development and atherosclerosis.
There is a primary association between a genetically determined shorter height and an increased risk of CAD, a link that is partly explained by the association between shorter height and an adverse lipid profile. Shared biologic processes that determine achieved height and the development of atherosclerosis may explain some of the association. (Funded by the British Heart Foundation and others.).
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