Journal Article

Height matters—from monogenic disorders to normal variation

Rappold, Gudrun A., Durand, Claudia

2013

Overview

In this Review, the authors discuss the genetics of height, including examples of rare sequence variants that can result in large effects on height and common variants with small effects on height. The key challenges in discovering further genes associated with height and the transition from gene discovery to mechanistic insights are also outlined. 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. Key Points Height is a classic polygenic trait and a very good model for both common, complex disorders and monogenic, Mendelian disease Extremes in height are often caused by monogenic mutations in one of the genes critical for control of growth The role of four prominent genes implicated in growth control illustrates the diversity of the different pathways involved; progress on therapeutic options depends on the underlying gene defect and mechanism Variations within the normal range of height are associated with common variants that have been uncovered by genome-wide association studies (GWAS); a discrepancy still exists between heritability and the identified loci Comparison of common variants detected by GWAS and genes with a role in monogenic short stature shows some overlap; GWAS might pinpoint further genes that cause monogenic short stature Next-generation sequencing will probably replace GWAS and thus yield insight into the genetic pathways involved in monogenic and complex disorders

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208 / 631/443/163 / 692/699/2743/1530 / Body Height - genetics / Child development / Diagnosis / Disease / Endocrinology / Fibrillins / Genes / Genetic aspects / Genetic disorders / Genetic Variation - genetics / Genetics / Genome-Wide Association Study / Genomes / Growth - genetics / Growth hormones / Height / Homeodomain Proteins - genetics / Human Growth Hormone - genetics / Humans / Medicine / Medicine & Public Health / Microfilament Proteins - genetics / Multifactorial Inheritance / Mutation / Pituitary gland / Quantitative Trait Loci / Quantitative Trait, Heritable / Receptor, Fibroblast Growth Factor, Type 3 - genetics / review-article / Short Stature Homeobox Protein / Stature