Rare and low-frequency coding variants alter human adult height.

Area of Science:

• Human Genetics
• Molecular Biology
• Biochemistry

Background:

• Human height is a complex polygenic trait influenced by numerous common genetic variants.
• Previous genome-wide association studies (GWAS) have identified around 700 common variants associated with height.

Purpose of the Study:

• To identify rare and low-frequency genetic variants with substantial effects on human height.
• To investigate the functional mechanisms and biological pathways underlying height variation.

Main Methods:

• Genome-wide association studies (GWAS) were conducted on a large scale to identify height-associated variants.
• Functional follow-up studies, including in vitro experiments, were performed to elucidate the impact of specific variants.

Main Results:

• Eighty-three height-associated coding variants with minor allele frequencies between 0.1-4.8% were identified.
• Several variants, notably in STC2, demonstrated large effects on height (1-2 cm per allele) by influencing insulin-like growth factor bioavailability.
• These variants overlap with genes implicated in monogenic growth disorders, highlighting novel genes (e.g., ADAMTS3, IL11RA, NOX4) and pathways (e.g., proteoglycan synthesis).

Conclusions:

• Large sample sizes enable the discovery of rare and low-frequency variants with moderate-to-large effects on polygenic traits like height.
• These variants provide insights into the genetic architecture of human growth and identify new biological targets for growth-related research.