Ivan Kairatov, a renowned Biopharma expert, has an impressive background in tech and innovation within the industry, as well as extensive experience in research and development. His insights into genetic factors influencing human height offer a compelling look into the intricate blueprint that governs why some people grow tall while others remain shorter. In this interview, Jan Kaiserle invites Ivan to dive deep into the key themes of genetic contributions to human height, discussing monogenic disorders, polygenic factors, rare variants, signaling pathways, and emerging therapies.
Can you explain the key findings from your review article published in Nature Reviews Genetics?
The review article provides a comprehensive overview of the genetic factors that contribute to human height, including both rare and common variants. It emphasizes the importance of understanding how multiple genes interact to influence height, and highlights the impact of genetic and environmental factors on this polygenic trait. Key findings include the identification of numerous genetic variants associated with height, the role of monogenic disorders, and the potential therapeutic implications of this research.
How significant is the genetic contribution to human height according to twin studies and genome-wide association studies (GWAS)?
Twin studies indicate that genetic makeup contributes up to 90% to an individual’s height. GWAS further supports this by suggesting that common variants explain around 80% of heritability. This underscores the profound influence of genetics on height, although environmental factors also play a crucial role.
What role do monogenic disorders play in influencing human height?
Monogenic disorders, caused by mutations in a single gene, can significantly affect human height. These disorders often result in severe deviations from average stature, either leading to short stature or tall stature depending on the specific genetic mutation involved. Understanding these conditions helps in identifying the key genes involved in height regulation.
Could you provide examples of specific genes or variants associated with short stature in monogenic conditions?
Examples include the FGFR3 gene, where a recurrent gain-of-function variant (p.Gly380Arg) leads to achondroplasia, the most common form of dwarfism. Similarly, mutations in the GHR gene cause Laron syndrome, characterized by growth hormone insensitivity and short stature.
How do FGFR3 variants contribute to conditions like achondroplasia and CATSHL syndrome?
FGFR3 variants can act as “good cop, bad cop” depending on their gain or loss of function. Gain-of-function variants are linked to achondroplasia, causing inhibited chondrocyte proliferation and reduced endochondral bone growth. Conversely, reduced FGFR3 activity is associated with CATSHL syndrome, resulting in unusually long limbs and tall stature.
What are some of the genetic syndromes that lead to short stature, and what are the mechanisms behind these conditions?
Syndromes like skeletal dysplasia and primordial dwarfism lead to short stature due to abnormalities in the formation, growth, or maintenance of the human skeleton. These conditions often involve pathogenic variants in genes that regulate longitudinal growth and disrupt growth plate homeostasis.
How do signaling pathways like the growth hormone pathway and TGFβ-BMP pathway influence height?
The growth hormone pathway involves growth hormone activating its receptor, leading to the synthesis of insulin-like growth factors (IGFs) that promote growth plate chondrocyte proliferation. The TGFβ-BMP pathway similarly influences bone growth, with disruptions in these pathways leading to altered height.
What is primordial dwarfism and which genes are commonly involved in its underlying genetic causes?
Primordial dwarfism is characterized by severe growth arrest that starts before birth and continues throughout life. Loss-of-function variants in genes such as PCNT, CEP152, and ORC1 disrupt centrosome function or DNA replication, causing this subtype of dwarfism.
Can you tell us about the genetic factors contributing to tall stature and overgrowth?
Genetic factors such as mutations in the FBN1 gene cause Marfan syndrome, characterized by tall stature and joint laxity. Loss-of-function variants in GPC3 and GPC4 genes lead to Simpson-Golabi-Behmel syndrome, associating with tall stature through disruption of bone growth signaling pathways.
How do mutations in extracellular matrix proteins and signaling molecules lead to conditions such as Marfan syndrome?
Mutations in extracellular matrix proteins like fibrillin 1, encoded by the FBN1 gene, impair perichondrium formation, which lengthens bones and leads to Marfan syndrome. These mutations disrupt growth homeostasis and often result in tall stature with associated complications.
What are the roles of glypican 3 and glypican 4 in bone growth, and how do they contribute to Simpson-Golabi-Behmel syndrome?
Glypican 3 and glypican 4 regulate signaling pathways such as Wnt, BMP, and FGF that are crucial for bone growth. Loss-of-function variants in these genes result in Simpson-Golabi-Behmel syndrome, an overgrowth disorder characterized by tall stature.
How do polygenic factors influence human height, and how many common variants have been identified by GWAS?
Human height is highly heritable, with GWAS identifying 12,111 common variants that explain roughly 50% of heritability. These polygenic factors contribute collectively to height, with numerous genes involved in regulating growth.
Are there specific rare or low-frequency genetic variants that significantly impact height?
Yes, rare and low-frequency genetic variants, such as those identified in the UK Biobank, significantly impact height. These variants often involve loss-of-function mutations in genes that play a role in skeletal growth and development.
What are some of the genetic pathways that have bidirectional effects on human height?
Genetic pathways, such as those involving DNMT3A and epigenetic regulators like PRC2 subunits, can have bidirectional effects on height. For example, DNMT3A loss-of-function variants cause overgrowth, while gain-of-function variants result in dwarfism.
How do epigenetic regulators like PRC2 subunits and NSD1 influence stature, and what are their associated syndromes?
PRC2 subunits like EED, SUZ12, and EZH2, and the histone methyltransferase NSD1, influence stature through epigenetic modifications. PRC2-mediated H3K27 trimethylation suppresses chondrocyte proliferation, while NSD1 haploinsufficiency disrupts H3K36 methylation, leading to overgrowth in Sotos syndrome.
Can you explain the interplay between FGFR3, CNP, and NPR2 pathways in regulating chondrocyte proliferation and endochondral bone growth?
FGFR3, CNP, and NPR2 pathways collectively regulate chondrocyte proliferation. FGFR3 inhibits chondrocyte proliferation, while CNP binding to its receptor NPR2 counteracts this inhibition. This interplay modulates the activity of the MAPK pathway, impacting bone growth.
Are there any emerging therapies for height disorders based on the genetic understanding of these conditions?
Emerging therapies, such as vosoritide, a CNP analog, offer potential treatments for height disorders like achondroplasia. Vosoritide restores growth plate function by counteracting overactive FGFR3 signaling, demonstrating the therapeutic potential of targeting specific genetic pathways.
What potential treatment does vosoritide offer for achondroplasia?
Vosoritide offers a treatment for achondroplasia by mimicking CNP and inhibiting overactive FGFR3 signaling. This restores growth plate function, promoting normal bone growth and addressing the underlying genetic cause of the condition.
Why is increasing diversity in genetic studies important, and how can incorporating Indigenous populations advance genomic research?
Increasing diversity in genetic studies is crucial to identify ancestry-specific variants and improve equity in genomic research. Incorporating Indigenous populations under the principles of FAIR and CARE ensures that diverse genetic backgrounds are represented, advancing our understanding of human height.
What message do you hope readers take away from the review about the genetic architecture of human height?
I hope readers understand the complexity of genetic contributions to human height, appreciate the interplay of monogenic and polygenic factors, and recognize the importance of increasing diversity in genetic studies to provide a more comprehensive and equitable understanding of height regulation.
