Rare protein-coding variation and the genetic architecture of height in >1.4 million individuals

The study analyzed rare genetic variants affecting human height in 826,066 individuals in the discovery phase and validated results in an additional 624,567 individuals. Researchers identified 207 genes associated with height, of which 98 percent were confirmed in the replication group. The rarest and most deleterious variants (singleton variants with frequency lower than 0.0001 percent) were associated with 17 genes that had large effects on height - ranging from -17 cm (ACAN gene) to +11 cm (FBN1 gene) per allele. These effects were 52 times larger than the average impact of common height-associated variants. Some genes such as TET1, DTL, and IGF2BP2 had effects comparable to known Mendelian height genes but without documented growth syndromes. The study demonstrated that height is an underappreciated clinical feature of Mendelian disorders.