Height is largely influenced by genetics, with recent studies suggesting that up to 90% of an individual’s height is determined by their genetic makeup. Polygenic traits, like height and skin color, are governed by the interaction of numerous genetic variants. These traits can also be shaped by environmental factors. Height alterations, whether shorter or taller than the average, have been associated with increased risks of conditions such as cancer and cardiometabolic diseases.
In the context of human height, growth is regulated by a variety of genetic pathways, and both rare and common variants contribute to variations in stature.
Monogenic Conditions Associated with Human Height
Some genetic disorders, known as monogenic conditions, result in significant changes in height. These are caused by mutations in single genes that affect the regulation of growth, such as FGFR3 mutations, which lead to achondroplasia (dwarfism). Other genetic disorders that affect growth include Laron syndrome (caused by mutations in the GHR gene) and Seckel syndrome (due to mutations in ATR, which is involved in DNA repair).
Genetic Causes of Tall Stature
On the other end of the spectrum, certain genetic conditions lead to tall stature. Marfan syndrome, caused by mutations in the FBN1 gene, results in a tall, slender physique. Similarly, Simpson–Golabi–Behmel syndrome, associated with mutations in GPC3 and GPC4, also results in tall stature. These overgrowth disorders are caused by mutations that influence bone growth and development.
Polygenic Contributors to Human Height
While monogenic mutations can lead to severe alterations in height, the majority of human height variation is governed by polygenic factors. Genome-wide association studies (GWAS) have identified thousands of genetic variants that contribute to human height, explaining a significant portion of its heritability. The remaining heritability is likely explained by rare variants or other inherited factors that are not fully understood.
Height Regulatory Pathways and Bidirectional Effects
Some genetic variants have bidirectional effects on height. For example, mutations in the DNMT3A gene can either lead to overgrowth (Tatton-Brown–Rahman syndrome) or dwarfism, depending on whether the mutation is a gain or loss of function. Similarly, proteins involved in epigenetic regulation, such as those in the polycomb repressive complex 2 (PRC2), can influence stature in either direction, depending on how they affect cellular processes like chondrocyte proliferation.
Therapeutic Implications
The review also touches on therapeutic strategies for addressing height-related disorders. One promising therapy is vosoritide, a CNP analog that has shown potential in treating achondroplasia by counteracting the overactive FGFR3 signaling pathway that inhibits bone growth.
Conclusion
In conclusion, the review emphasizes the complexity of the genetic architecture behind human height. It highlights that both monogenic and polygenic factors converge on common developmental pathways that regulate growth. The authors call for more inclusive genetic studies, especially focusing on underrepresented populations, to identify ancestry-specific variants and improve the equity of genomic research.
This article sheds light on the fascinating genetic and molecular mechanisms that determine why some individuals grow tall while others remain short, linking these findings to both clinical and therapeutic implications for genetic height-related conditions.
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