Height matters-from monogenic disorders to normal variation

Height is a classic polygenic quantitative trait with a high level of heritability. As it is a simple and stable parameter to measure, height is a model for both common, complex disorders and monogenic, Mendelian disease. In this Review, we examine height from the perspective of monogenic and complex genetics and discuss the lessons learned so far. We explore several examples of rare sequence variants with large effects on height and compare these variants to the common variants identified in genome-wide association studies that have small effects on height. We discuss how copy number changes or genetic interactions might contribute to the unidentified aspects of the heritability of height. We also ask whether information derived from genome-wide association studies on specific loci in the vicinity of genes can be used for further research in clinical paediatric endocrinology. Furthermore, we address key challenges that remain for gene discovery and for the transition of moving from genomic localization to mechanistic insights, with an emphasis on using next-generation sequencing to identify causative variants of people at the extremes of height distribution.