Abstract
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.
Highlights
Most people are first introduced to genetics through the gardening career of Gregor Mendel and his observations regarding various features of the pea plant
Initial attempts at reconciliation proposed that continuously distributed phenotypes might still be determined by a single locus but with a ‘blending’ of each parent’s characteristics rather than a pure dominant/recessive model of inheritance; but this question was resolved by the demonstration that continuously distributed traits arise from the effect of multiple genetic loci, each of which individually exhibits Mendelian inheritance [3], which combine, both additively and interactively, and within a given environment, to produce the final phenotype
We first used a screening threshold T or Z-score ≥+4 at any lumbar/hip site to identify those with extreme high bone mineral density (BMD), in whom we investigated the potential underlying causes for a high BMD, trying to identify within this heterogeneous population with high BMD, a sub-group with unexplained generalized high bone mass (HBM) [34]
Summary
Most people are first introduced to genetics through the gardening career of Gregor Mendel and his observations regarding various features of the pea plant (flower color, pod shape, etc.). The World Health Organization (WHO) estimates that monogenic disease affect 1% of the worldwide population [7]; and there are many skeletal dysplasias that display classic Mendelian inheritance, with either high (e.g. osteopetroses) or low (e.g. osteogenesis imperfecta) bone mineral density (BMD) [8]. Loss-of-function SOST mutations cause sclerosteosis, generally thought the more severe of the two disorders; in contrast, a 52-kb intronic deletion downstream of SOST, thought to disrupt post-transcriptional sclerostin processing, results in the milder phenotype of van Buchem’s disease [110, 111] In both disorders, reduced osteocytic production of sclerostin permits activation of osteoblastic Wnt signaling, leading to enhanced bone formation, increased bone strength, and resistance to fracture [110, 112] (Table 2). Clinical Features other than HBM (reported in at least one person in the kindred)
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