Genetic pathways explain why some people grow tall and others stay short

Genetic pathways explain why some people grow tall and others stay short

From dwarf sentinel to overgrown, scientists are unraveling the complex genetic blueprint that determines how tall - or short - we grow.

A review article published in the journalNature Reviews GeneticsProvides an in-depth overview of rare and common genetic factors that contribute to human height.

background

Human height is a polygenic trait determined by the combined effect of multiple genes, each contributing to the overall phenotype. Like other polygenic traits such as skin color, height can also be influenced by environmental factors such as diet, childhood health status and overall lifestyle.

The same gene can play “good cop, bad cop”—while FGFR3 functional variants cause achondroplasia, reduced FGFR3 activity has been linked to CatSHL syndrome, which is characterized by abnormally long limbs and tall stature.

Recent evidence from twin studies shows that genetic makeup contributes up to 90% of an individual's size, although genome-wide association studies (GWAS) common variants suggest ~80% of heritability is explained. In monogenic diseases caused by mutations in a single gene, height can be severely affected by single gene variants, often causing severe changes in stature compared to population averages.

Any induction or reduction in human height compared to population average has been associated with altered risk of cancer and cardiometabolic diseases. It has been found that people who are taller than the population average have an increased risk of cancer. Shorter people have an increased risk of coronary heart disease and diabetes.

These observations highlight the importance of deciphering the genetic architecture of human height for understanding its clinical relevance. This review article aimed to summarize the genetic contributors to human height from both monogenic and polygenic studies.

Monogenic states related to human height

Growth alteration is characterized as a clinical feature in several monogenic disorders. Such a growth change is usually caused by pathogenic variants in genes associated with the regulation of longitudinal growth.

Their size may depend on an obscure DNA repair protein - variants in ATR, best known for fixing replication errors, cause Seckel syndrome by impairing prenatal growth through centrosome dysfunction.

The syndromic diseases (which have additional clinical features beyond height) that cause short stature (medically termed dwarfism when adult height is <147 cm) include skeletal dysplasia, which is characterized by abnormalities in the formation, growth or maintenance of the human skeleton. Most genetic variants associated with skeletal dysplasia exert their primary effects by downregulating the proliferation or hypertrophy of growth plates (physis) chondrocytes (cells responsible for cartilage formation).

For example, a recurrent functional variant in the FGFR3 gene (P.gly380ARG) causes achondroplasia, the most common skeletal dysplasia. Variants in genes that represent common components of the growth hormone signaling pathway (e.g. Growth hormone activates the growth hormone receptor, which in turn leads to synthesis of insulin-like growth factors (IGFs) and accessory proteins. At the growth plate, IGFs serve as endocrine factors for the activation of pro-proliferation pathways.

Pathogenic variants in several signaling pathways related to skeletal growth plate homeostasis, including the transforming growth factor-β (TGFβ) bone morphometric protein (BMP) pathway, atrial natriuretic peptide receptor 2 (NPR2) pathway, and muthyroid hormone (PTH1R) pathway, were identified as major hormone (PTH1R) pathways. Disturbances.

Primordial dwarfism is a group of genetic disorders characterized by severe growth arrest that begins before birth and continues throughout life. Loss-of-function variants in genes such as PCNT (encoding pericentrin), CEP152 and ORC1 disrupt centrosome function or DNA replication, resulting in a subtype known as microcephalic osteodysplastic primordial Zwarkus dwarf-dwarf-dwarf-dwarf.

Genetic causes of tall stature

Overgrowth is not always easy - in Sotos syndrome, NSD1 mutations not only increase height - they trigger advanced bone age and different facial features through dysregulated H3K36 methylation.

Regarding the genetic causes of tall stature and overgrowth, existing evidence highlights the role of extracellular matrix proteins and related signaling molecules in growth homeostasis. Marfan syndrome, caused by FBN1 mutations, is characterized by tall stature, joint neglect, and cardiovascular complications. Fibrillin-1 deficiency due to mutations in the FBN1 gene can lead to impaired perichondrium (a connective tissue that covers cartilage), which in turn can lead to bone lengthening.

Simpson-Golabi-Behmel syndrome is an X-burning overgrowth disorder characterized by tall stature. Loss-of-function variants in the GPC3 and GPC4 genes, encoding glypican 3 and glypican 4 proteins, respectively, have been identified as causative factors. Glypican 3 and Glypican 4 bind to the plasma membrane and regulate Wnt, BMP and FGF signaling pathways associated with bone growth.

Polygenic contributors to human height

Human height is a highly heritable trait, and GWAS has identified 12,111 common variants, mostly in populations in European ancestry, explaining ~50% of heritability. Rare variant burden tests, as analyzed in the UK biobank-linked Genebassbrowser, have identified 78 genes (including 18 monogenic skeletal growth genes) in which aggregate loss-of-function variants significantly associate with height. Most of the remaining heritability can be explained by polygenic rare variants or other inherited factors, with only a small amount of heritability accounted for by very rare monogenic variants.

Recent whole-genome sequencing studies have identified rare non-coding variants in several loci that affect height. Whole-exome low-frequency variant genotype microarray studies have identified rare missense or loss-of-function variants associated with altitude, including several genes underlying monogenic disorders (e.g., Acan, IHH, PTH1R, COL2A1).

Height regulation paths and bidirectional effects

Why do some families have “fine” bones? – Subtle Acan variants produce “hidden” skeletal dysplasia in which a short stature appears isolated but arises from impaired cartilage template formation.

Several pathways were identified to have associations with increased and decreased levels depending on the altered functions of the proteins involved. For example, DNMT3A loss-of-function variants cause Tatton-Brown-Rahman overgrowth syndrome, while gain-of-function variants in the same gene lead to microcephalic dwarfism. Epigenetic regulators such as Polycomb repressive complex 2 (PRC2) subunits (EED, Suz12, EZH2) and the histone methyltransferase NSD1 also influence stature bidirectionally. PRC2-mediated H3K27 trimethylation suppresses chondrocyte proliferation, while NSD1 haploinsufficiency in SOTOS syndrome disrupts H3K36 methylation, leading to growth plate dysregulation and surveillance through altered Wnt/β-catenin and TGF-β signaling.

Activation of the FGFR3-MAPK-STAT signaling pathway has been found to inhibit chondrocyte proliferation and extracellular matrix synthesis in the growth plate, resulting in reduced endochondral bone growth. Conversely, binding of C-type natriuretic peptide to its receptor NPR2 leads to inhibition of the MAPK signaling pathway. The interplay between FGFR3, CNP and NPR2 pathways has been found to increase or decrease the activity of the MAPK signaling pathway, thus affecting chondrocyte proliferation or differentiation.

Therapeutic implications

The review highlights emerging therapies such as vosoritide (a CNP analogue), which restores growth plate function in achondroplasia by counteracting overactive FGFR3 signaling.

Diploma

This review provides a detailed genetic architecture of human height and shows that genes involved in both monogenic and polygenic studies converge on common developmental or cellular pathways. The authors emphasize the need for increasing diversity in genetic studies that include indigenous populations according to fair/careful principles, identify cumulative variants, and improve equity in genomic research.

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