Genes with specificity for expression in the round cell layer of the growth plate are enriched in genomewide association study (GWAS) of human height

Abstract

Human 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: (i) resting (round), (ii) proliferative (flat), and (iii) hypertrophic. Recent genomewide association studies (GWASs) 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 “Online Mendelian Inheritance in Man (OMIM) gene set” (genes known to cause monogenic skeletal growth disorders, p < 9.7 × 10−6). We replicated the association in RNA‐sequencing (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 GWASs (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 GWASs of height and specifically expressed in the round cell layer as being potentially important regulators of skeletal biology. © 2021 American Society for Bone and Mineral Research (ASBMR).

The genetic architecture of the human skeletal form

“…To connect the genetics of skeletal proportions and growth plate biology, we looked for enrichment of genes associated with our skeletal proportion GWAS in gene expression data in three dissected layers of murine newborn tibial growth plate following an analysis described in Renthal et al ( 109 ). Specifically, we were interested to see if we could identify which layers of the growth plate (i.e., the resting (round), proliferative (flat) or hypertrophic layer) would associate with increased limb length.…”

Genetic regulation of body size and morphology in children: a twin study of 22 anthropometric traits

“…There is evidence from a GWA study that the genetic variants associated with body fat distribution are related to lipid metabolism and adipose tissue regulation in particular [35]. On the other hand, the expression of genes associated with height have been found to be enriched in growth plate chondrocytes [36]. It is interesting to note that there are genetic correlations between height and anthropometric traits not related to the ossification of bones, such as skinfold thicknesses, which is also consistent with a previous family study [17].…”

Nutrient-regulated dynamics of chondroprogenitors in the postnatal murine growth plate

“…4,5 A genome-wide association study of human height revealed that the specificity of gene expression in the resting chondrocytes in newborn mice is significantly associated with height GWAS p values, stressing the important role of these cell populations in determining human skeletal growth. 6 Malnutrition is considered a leading cause of growth retardation in children. 7,8 When transient nutritional impairment is resolved, the long bone growth rate often accelerates beyond the normal rate; this phenomenon is termed catch-up growth.…”