scholarly journals Genes with Specificity for Expression in the Round Cell Layer of the Growth Plate are Enriched in GWAS of Human Height

2021 ◽  
Author(s):  
Nora E. Renthal ◽  
Priyanka Nakka ◽  
John M. Baronas ◽  
Henry M. Kronenberg ◽  
Joel N. Hirschhorn
Keyword(s):  
Growth Plate ◽  
Cell Layer ◽  
Skeletal Growth ◽  
Gwas Data ◽  
Growth Disorders ◽  
Genome Wide Association Studies ◽  
Round Cell ◽  
P Values ◽  
Gene Set ◽  
Human Height

ABSTRACTHuman adult height reflects the outcome of childhood skeletal growth. Growth plate (epiphyseal) chondrocytes are key determinants of height. As epiphyseal chondrocytes mature and proliferate, they pass through three developmental stages, which are organized into three distinct layers in the growth plate: 1) resting (round), 2) proliferative (flat), and 3) hypertrophic. Recent genome-wide association studies (GWAS) of human height identified numerous associated loci, which are enriched for genes expressed in growth plate chondrocytes. However, it remains unclear which specific genes expressed in which layers of the growth plate regulate skeletal growth and human height.To connect the genetics of height and growth plate biology, we analyzed GWAS data through the lens of gene expression in the three dissected layers of murine newborn tibial growth plate. For each gene, we derived a specificity score for each growth plate layer and regressed these scores against gene-level p-values from recent height GWAS data. We found that specificity for expression in the round cell layer, which contains chondrocytes early in maturation, is significantly associated with height GWAS p-values (p=8.5×10−9); this association remains after conditioning on specificity for the other cell layers. The association also remains after conditioning on membership in an “OMIM gene set” (genes known to cause monogenic skeletal growth disorders, p<9.7×10−6). We replicated the association in RNA-seq data from maturing chondrocytes sampled at early and late time points during differentiation in vitro: we found that expression early in differentiation is significantly associated with p-values from height GWAS (p=6.1×10−10) and that this association remains after conditioning on expression at 10 days in culture and on the OMIM gene set (p<0.006). These findings newly implicate genes highlighted by GWAS of height and specifically expressed in the round cell layer as being potentially important regulators of skeletal biology.

scholarly journals Specificity for the Epiphyseal Round Cell Layer is Significantly Associated With Height GWAS​

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A685-A685
Author(s):  
Nora Edwards Renthal ◽  
Priyanka Nakka ◽  
John Baronas ◽  
Henry M Kronenberg ◽  
Joel N Hirschhorn
Keyword(s):  
Gene Expression ◽  
Growth Plate ◽  
Cell Layer ◽  
Skeletal Growth ◽  
The Other ◽  
Skeletal Biology ◽  
Growth Disorders ◽  
Round Cell ◽  
P Values ◽  
Gene Level

Abstract Human height is a model polygenic trait with thousands of height-related SNPs identified in GWAS to date. An important determinant of height is the proliferation and hypertrophy of growth plate chondrocytes during childhood long bone elongation. Connecting the expression of specific genes that affect skeletal biology to associated variants in GWAS remains a difficult challenge. To connect the genetics of height and growth plate gene expression, we studied the relationship between gene expression in the murine growth plate and common-variant associations from GWAS of height. To obtain gene expression data from the growth plate, we dissected three layers of murine tibial growth plates, extracted RNA from each layer, and measured expression using the Affymetrix GeneChip 430 3.0. For each gene, we derived a specificity score for each growth plate layer, and SNP-level p-values from a published GWAS of height (N~700000) were combined into gene-level p-values using MAGMA. We then used MAGMA to test for association between specificity of expression for each growth plate layer and the GWAS gene level p-values for height. We found that specificity for the round cell layer is significantly associated with height GWAS p-values (p = 8.5x10-9). This association remains when we condition on each of the other cell layers and on membership in a set of genes from OMIM that cause skeletal growth disorders (3.3x10-8 &lt; p &lt; 4.1x10-6). We replicated this result in a RNA-seq dataset of maturing chondrocytes sampled at three time points during development in vitro (days 3, 5, and 10): we found that z-scores for expression in the earliest two days of development are significantly associated with gene-level p-values from height GWAS (pDay3 = 1.2x10-21 and pDay5 = 2.0x10-20) and that this association remains after conditioning on the other timepoints and on the OMIM gene set (3.1x10-20 &lt; pDay3 &lt; 8.3x10-5; 3.7x10-19 &lt; pDay5 &lt; 0.002). We then performed pathway analysis of genes that are both highly specific to the round layer and highly significant in GWAS using Enrichr. Together, our results suggest that genes expressed in early chondrocyte development (the round cell layer) are particularly relevant to the contribution of growth plate-expressed genes to height. This conclusion both sheds light on the regulation of human skeletal growth and also helps prioritize relevant genes implicated from the height GWAS in skeletal biology.

MICROCHEMICAL ANALYSIS OF HUMAN TIBIAL GROWTH CARTILAGE IN VARIOUS FORMS OF DWARFISM

1972 ◽  
Vol 69 (4) ◽  
pp. 659-688 ◽  
Author(s):  
V. Stanescu ◽  
R. Stanescu ◽  
J. A. Szirmai
Keyword(s):  
Growth Plate ◽  
Chondroitin Sulphate ◽  
Epiphyseal Plate ◽  
Molecular Characteristics ◽  
Growth Disorders ◽  
Normal Children ◽  
Collagen Concentration ◽  
Vitamin D Resistant Rickets ◽  
Pooled Samples ◽  
Tibial Epiphyseal

ABSTRACT Microchemical determinations of glycosaminoglycans and collagen were preformed in isolated histological zones from sections of tibial epiphyseal plate biopsies obtained from children with growth disorders (pituitary dwarfism, congenital myxoedema, Turner's syndrome, Noonan's syndrome, mucopolysaccharidosis type VI, vitamin D resistant rickets and achondroplasia). Alternate sections were used for histochemical localization of glycosaminoglycans and proteins. The values were compared with those found in comparable zones of the growth plate from normal children of the same age. The chondroitin sulphate concentration (% of defatted dry wt.) in the normal epiphyseal plate increased from the resting zone towards the proliferating/hypertrophic zone; collagen exhibited a reverse trend. In some of the pathological biopsies the concentration of chondroitin sulphate was slightly decreased whereas that of collagen was slightly increased. A marked increase in the collagen concentration was found in achondroplasia. The solubility profiles of the cetylpyridinium complexes of the chondroitin sulphate fraction showed three main peaks with slight but characteristic differences in the various zones of the normal cartilage plate. Significant shifts in the proportion of these peaks were observed in several pathological biopsies, indicating possible deviations from the normal molecular characteristics of the chondroitin sulphate. Analysis of the main chondroitin sulphate fraction, obtained from pooled samples of normal tibial growth plate after fractionation on the macroscale, indicated that all three peaks contained both chondroitin-4 sulphate and chondroitin-6 sulphate and that they probably differed in their molecular weight.

scholarly journals A practical approach to adjusting for population stratification in genome-wide association studies: principal components and propensity scores (PCAPS)

2018 ◽  
Vol 17 (6) ◽  
Author(s):  
Huaqing Zhao ◽  
Nandita Mitra ◽  
Peter A. Kanetsky ◽  
Katherine L. Nathanson ◽  
Timothy R. Rebbeck
Keyword(s):  
Principal Components ◽  
Population Stratification ◽  
Propensity Scores ◽  
Association Studies ◽  
Germ Cell Tumors ◽  
Gwas Data ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Testicular Germ Cell ◽  
Genome Wide

Abstract Genome-wide association studies (GWAS) are susceptible to bias due to population stratification (PS). The most widely used method to correct bias due to PS is principal components (PCs) analysis (PCA), but there is no objective method to guide which PCs to include as covariates. Often, the ten PCs with the highest eigenvalues are included to adjust for PS. This selection is arbitrary, and patterns of local linkage disequilibrium may affect PCA corrections. To address these limitations, we estimate genomic propensity scores based on all statistically significant PCs selected by the Tracy-Widom (TW) statistic. We compare a principal components and propensity scores (PCAPS) approach to PCA and EMMAX using simulated GWAS data under no, moderate, and severe PS. PCAPS reduced spurious genetic associations regardless of the degree of PS, resulting in odds ratio (OR) estimates closer to the true OR. We illustrate our PCAPS method using GWAS data from a study of testicular germ cell tumors. PCAPS provided a more conservative adjustment than PCA. Advantages of the PCAPS approach include reduction of bias compared to PCA, consistent selection of propensity scores to adjust for PS, the potential ability to handle outliers, and ease of implementation using existing software packages.

scholarly journals RECENT RESEARCH ON THE GROWTH PLATE: Recent insights into the regulation of the growth plate

2014 ◽  
Vol 53 (1) ◽  
pp. T1-T9 ◽  
Author(s):  
Julian C Lui ◽  
Ola Nilsson ◽  
Jeffrey Baron
Keyword(s):  
Growth Plate ◽  
Bone Morphogenetic Proteins ◽  
Bone Growth ◽  
Association Studies ◽  
Expression Patterns ◽  
Human Growth ◽  
Cytokine Signaling ◽  
Genome Wide Association Studies ◽  
Paracrine Factors ◽  
Large Numbers

For most bones, elongation is driven primarily by chondrogenesis at the growth plates. This process results from chondrocyte proliferation, hypertrophy, and extracellular matrix secretion, and it is carefully orchestrated by complex networks of local paracrine factors and modulated by endocrine factors. We review here recent advances in the understanding of growth plate physiology. These advances include new approaches to study expression patterns of large numbers of genes in the growth plate, using microdissection followed by microarray. This approach has been combined with genome-wide association studies to provide insights into the regulation of the human growth plate. We also review recent studies elucidating the roles of bone morphogenetic proteins, fibroblast growth factors, C-type natriuretic peptide, and suppressor of cytokine signaling in the local regulation of growth plate chondrogenesis and longitudinal bone growth.

Distinct Genetic Profiles in Postpartum Depression With Different Trajectory of Illness

2020 ◽  
Author(s):  
Nagahide Takahashi ◽  
Hanae Tainaka ◽  
Tomoko Nishimura ◽  
Taeko Harada ◽  
Akemi Okumura ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Postpartum Depression ◽  
Risk Score ◽  
Association Studies ◽  
Depression Scale ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Gene Set Enrichment ◽  
Polygenic Risk ◽  
Gene Set

Abstract BackgroundPostpartum depression (PPD) is a common and highly heritabledisorder in the postnatal period of new mothers. The development of PPD is shown to affectneurodevelopment in children and recent evidence suggests thatthe trajectory of PPDisalso associated with children’s neurodevelopment and mental conditions. Thus, early identification and intervention for individuals at high risk of PPD are urgently needed.Additionally, it is not clear whether genetic factors affect thetrajectory of PPD. Therefore, using a polygenic risk score (PRS) approach, we investigated if PRS for depression (Depression-PRS) and bipolar disorder (Bipolar-PRS) are associated with the development and clinical course of PPD.Methods Usingrecent large genome-wide association studies(GWAS) of depression and bipolar disorder as discovery cohorts, we calculatedDepression-PRS and Bipolar-PRS in each individual. Then, we investigated the possible association between Depression-PRS and Bipolar-PRS with the development andtrajectory of PPD insubjects from the Hamamatsu Birth Cohort for mothers and children (n = 136). Depressive symptoms were assessed using the Edinburgh Postpartum Depression Scale. Gene-set enrichment analyses were used to identify pathways underlying these conditions. ResultsDepression-PRS was significantly higher in subjects with PPD than in those without PPD(t = -3.283, P = 0.002)and logistic analysis showed that Depression-PRS significantly increases therisk of developing PPD(OR [SE] = 2.274 [0.585], P = 0.002). Furthermore, Depression-PRS was positively associated with continuity of PPD (β [SE]=1.621 [0.672]; P = 0.032).Gene-set enrichment analyses revealed that pathways such as“response to hormone”(β[SE] -2.285[1.002], P < 0.001) and “epigenetic regulation”(β[SE] 2.831 [1.317], P < 0.001) were involved in the continuity of PPD. ConclusionThese preliminary findings indicate that the genetic component plays an important role not only in the development but also inthe continuity of PPD. A polygenic risk score approach could be useful to identify subjects at risk for PPD, especially for persistent PPD,who needcareful monitoring and intervention after delivery.

scholarly journals Valproic Acid Impacts the Growth of Growth Plate Chondrocytes

2020 ◽  
Vol 17 (10) ◽  
pp. 3675
Author(s):  
Hueng-Chuen Fan ◽  
Shih-Yu Wang ◽  
Yi-Jen Peng ◽  
Herng-Sheng Lee
Keyword(s):  
Valproic Acid ◽  
Short Stature ◽  
Growth Plate ◽  
Caspase 3 ◽  
Skeletal Growth ◽  
Growth Plate Chondrocytes ◽  
Protein Levels ◽  
Rat Growth ◽  
Cox 2 ◽  
Bone Abnormalities

A range of bone abnormalities including short stature have been reported to be associated with the use of antiepileptic drugs (AEDs) in children. Exactly how AEDs impact skeletal growth, however, is not clear. In the present study, rat growth plate chondrocytes were cultured to study the effects of AEDs, including valproic acid (VPA), oxcarbazepine (OXA), levetiracetam (LEV), lamotrigine (LTG), and topiramate (TPM) on the skeletal growth. VPA markedly reduced the number of chondrocytes by apoptosiswhile other AEDs had no effect. The apoptosis associated noncleaved and cleaved caspase 3, and caspases were increased by exposure to VPA, which up-regulated cyclooxygenase 2 (COX-2) mRNA and protein levels likely through histone acetylation. The COX-2 inhibitor NS-398 attenuated the effects of VPA up-regulating COX-2 expression and decreased VPA-induced caspase 3 expression. The use of VPA in children should be closely monitored or replaced, where appropriate, by AEDs which do not apparently affect the growth plate chondrocytes.

scholarly journals Integration of GWAS Summary Statistics and Gene Expression Reveals Target Cell Types Underlying Kidney Function Traits

2020 ◽  
Vol 31 (10) ◽  
pp. 2326-2340 ◽  
Author(s):  
Yong Li ◽  
Stefan Haug ◽  
Pascal Schlosser ◽  
Alexander Teumer ◽  
Adrienne Tin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Kidney Function ◽  
Cell Types ◽  
Gene Set Enrichment Analysis ◽  
Genome Wide Association Studies ◽  
Summary Statistics ◽  
Rna Seq ◽  
Cell Type ◽  
Gene Set Enrichment ◽  
Gene Set

BackgroundGenetic variants identified in genome-wide association studies (GWAS) are often not specific enough to reveal complex underlying physiology. By integrating RNA-seq data and GWAS summary statistics, novel computational methods allow unbiased identification of trait-relevant tissues and cell types.MethodsThe CKDGen consortium provided GWAS summary data for eGFR, urinary albumin-creatinine ratio (UACR), BUN, and serum urate. Genotype-Tissue Expression Project (GTEx) RNA-seq data were used to construct the top 10% specifically expressed genes for each of 53 tissues followed by linkage disequilibrium (LD) score–based enrichment testing for each trait. Similar procedures were performed for five kidney single-cell RNA-seq datasets from humans and mice and for a microdissected tubule RNA-seq dataset from rat. Gene set enrichment analyses were also conducted for genes implicated in Mendelian kidney diseases.ResultsAcross 53 tissues, genes in kidney function–associated GWAS loci were enriched in kidney (P=9.1E-8 for eGFR; P=1.2E-5 for urate) and liver (P=6.8·10-5 for eGFR). In the kidney, proximal tubule was enriched in humans (P=8.5E-5 for eGFR; P=7.8E-6 for urate) and mice (P=0.0003 for eGFR; P=0.0002 for urate) and confirmed as the primary cell type in microdissected tubules and organoids. Gene set enrichment analysis supported this and showed enrichment of genes implicated in monogenic glomerular diseases in podocytes. A systematic approach generated a comprehensive list of GWAS genes prioritized by cell type–specific expression.ConclusionsIntegration of GWAS statistics of kidney function traits and gene expression data identified relevant tissues and cell types, as a basis for further mechanistic studies to understand GWAS loci.

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