Rare and low-frequency coding variants were associated with human adult height, demonstrating effects of up to 2 centimeters per allele.
Observational
Rare and low-frequency coding variants can have moderate-to-large effects on polygenic human phenotypes such as adult height.
Effect estimate: up to 2 centimetres per allele
Abstract Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1–4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1–2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
Marouli et al. (2017) conducted an observational in Human adult height. Rare and low-frequency coding variants was evaluated on Adult height (up to 2 centimetres per allele). Rare and low-frequency coding variants were associated with human adult height, demonstrating effects of up to 2 centimeters per allele.