From dwarfism to overgrowth, scientists unravel the complex genetic blueprint that determines how tall—or short—we become.
Review: The genetic basis of human height. Image Credit: XiXinXing / Shutterstock
A review article published in the journal Nature Reviews Genetics provides an in-depth overview of rare and common genetic factors that contribute to human height.
Background
Human height is a polygenic trait governed 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 nutrition, childhood health status, and overall lifestyle.
Recent evidence from twin studies reveals that genetic makeup contributes up to 90% to an individual’s height, though genome-wide association studies (GWAS) suggest common variants explain ~80% of heritability. In monogenic disorders caused by mutations in a single gene, height can be severely affected by single-gene variants, often causing severe alterations in stature relative to population averages.
Any induction or reduction in human height compared to population averages has been linked to an altered risk of cancer and cardiometabolic diseases. People who are taller than the population average have been found to have an increased risk of cancer; whereas, 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 in understanding its clinical relevance. This review article aimed to summarize the genetic contributors to human height implicated by both monogenic and polygenic studies.
Monogenic Conditions Associated With Human Height
Growth alteration is characterized as a clinical feature in multiple monogenic disorders. Such growth alteration is commonly caused by pathogenic variants in genes associated with the regulation of longitudinal growth.
Syndromic conditions (involving additional clinical features beyond differences in height) that cause short stature (medically termed dwarfism when adult height is <147 cm) include skeletal dysplasia, which is characterized by abnormalities of formation, growth, or maintenance of the human skeleton. Most of the genetic variants associated with skeletal dysplasia exert their primary effects by downregulating the proliferation or hypertrophy of growth plate (physis) chondrocytes (cells responsible for cartilage formation).
For example, a recurrent gain-of-function variant in the FGFR3 gene (p.Gly380Arg) causes achondroplasia, the most common skeletal dysplasia. Variants in genes encoding common components of the growth hormone signaling pathway (e.g., GHR mutations in Laron syndrome) have been identified as contributors to monogenic short stature. Growth hormone activates 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 to activate pro-proliferation pathways.
Pathogenic variants in several signaling pathways related to skeletal growth plate homeostasis, including transforming growth factor-β (TGFβ)-bone morphometric protein (BMP) pathway, atrial natriuretic peptide receptor 2 (NPR2) pathway, and parathyroid hormone (PTH1R) pathway, have been identified as major contributors to the short stature in skeletal disorders.
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, leading to a subtype known as microcephalic osteodysplastic primordial dwarfism.
Genetic Causes of Tall Stature
Regarding genetic causes of tall stature and overgrowth, existing evidence highlights the roles of extracellular matrix proteins and related signaling molecules in growth homeostasis. Marfan syndrome, caused by FBN1 mutations, is characterized by tall stature, joint laxity, and cardiovascular complications. Fibrillin 1 deficiency due to mutations in the FBN1 gene can lead to impaired formation of perichondrium (a connective tissue covering cartilage), which in turn can result in bone lengthening.
Simpson–Golabi–Behmel syndrome is an X-linked 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 the Wnt, BMP, and FGF signaling pathways associated with bone growth.
Polygenic Contributors to Human Height
Human height is a highly heritable trait, and GWAS have identified 12,111 common variants, primarily in European-ancestry populations, that explain ~50% of heritability. Rare variant burden tests, such as those analyzed in the UK Biobank–linked Genebass browser, have identified 78 genes (including 18 monogenic skeletal growth genes) where aggregated loss-of-function variants significantly associate with height. The majority 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 multiple loci that influence height. Microarray studies designed to genotype low-frequency variants across the exome have identified rare missense or loss-of-function variants associated with height, including several genes underlying monogenic disorders (e.g., ACAN, IHH, PTH1R, COL2A1).
Height Regulatory Pathways and Bidirectional Effects
Several pathways have been identified to have associations with both increased and decreased height, depending on the altered functions of the affected proteins. For instance, 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 bidirectionally influence stature. PRC2-mediated H3K27 trimethylation suppresses chondrocyte proliferation, while NSD1 haploinsufficiency in Sotos syndrome disrupts H3K36 methylation, leading to growth plate dysregulation and overgrowth through altered Wnt/β-catenin and TGF-β signaling.
The activation of FGFR3–MAPK–STAT signaling pathway has been found to inhibit chondrocyte proliferation and extracellular matrix synthesis in the growth plate, leading to reduced endochondral bone growth. Conversely, the binding of C-type natriuretic peptide (CNP) 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 activity of the MAPK pathway, and thus, influence chondrocyte proliferation or differentiation.
Therapeutic Implications
The review highlights emerging therapies, such as vosoritide (a CNP analog), which restores growth plate function in achondroplasia by counteracting overactive FGFR3 signaling.
Conclusion
This review article provides a detailed genetic architecture of human height and depicts that genes implicated by both monogenic and polygenic studies converge on common developmental or cellular pathways. The authors emphasize the need for increasing diversity in genetic studies, incorporating Indigenous populations under FAIR/CARE principles, to identify ancestry-specific variants and improve equity in genomic research.