King's College London

Research portal

The Genetic Architecture of High Bone Mass

Research output: Contribution to journalReview article

Celia L. Gregson, Emma L. Duncan

Original languageEnglish
Article number595653
JournalFrontiers in Endocrinology
Published29 Oct 2020

King's Authors


The phenotypic trait of high bone mass (HBM) is an excellent example of the nexus between common and rare disease genetics. HBM may arise from carriage of many ‘high bone mineral density [BMD]’-associated alleles, and certainly the genetic architecture of individuals with HBM is enriched with high BMD variants identified through genome-wide association studies of BMD. HBM may also arise as a monogenic skeletal disorder, due to abnormalities in bone formation, bone resorption, and/or bone turnover. Individuals with monogenic disorders of HBM usually, though not invariably, have other skeletal abnormalities (such as mandible enlargement) and thus are best regarded as having a skeletal dysplasia rather than just isolated high BMD. A binary etiological division of HBM into polygenic vs. monogenic, however, would be excessively simplistic: the phenotype of individuals carrying rare variants of large effect can still be modified by their common variant polygenic background, and by the environment. HBM disorders—whether predominantly polygenic or monogenic in origin—are not only interesting clinically and genetically: they provide insights into bone processes that can be exploited therapeutically, with benefits both for individuals with these rare bone disorders and importantly for the many people affected by the commonest bone disease worldwide—i.e., osteoporosis. In this review we detail the genetic architecture of HBM; we provide a conceptual framework for considering HBM in the clinical context; and we discuss monogenic and polygenic causes of HBM with particular emphasis on anabolic causes of HBM.

View graph of relations

© 2020 King's College London | Strand | London WC2R 2LS | England | United Kingdom | Tel +44 (0)20 7836 5454