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How rare bone diseases have informed our knowledge of complex diseases.

ABSTRACT: Rare bone diseases, generally defined as monogenic traits with either autosomal recessive or dominant patterns of inheritance, have provided a rich database of genes and associated pathways over the past 2-3 decades. The molecular genetic dissection of these bone diseases has yielded some major surprises in terms of the causal genes and/or involved pathways. The discovery of genes/pathways involved in diseases such as osteopetrosis, osteosclerosis, osteogenesis imperfecta and many other rare bone diseases have all accelerated our understanding of complex traits. Importantly these discoveries have provided either direct validation for a specific gene embedded in a group of genes within an interval identified through a complex trait genome-wide association study (GWAS) or based upon the pathway associated with a monogenic trait gene, provided a means to prioritize a large number of genes for functional validation studies. In some instances GWAS studies have yielded candidate genes that fall within linkage intervals associated with monogenic traits and resulted in the identification of causal mutations in those rare diseases. Driving all of this discovery is a complement of technologies such as genome sequencing, bioinformatics and advanced statistical analysis methods that have accelerated genetic dissection and greatly reduced the cost. Thus, rare bone disorders in partnership with GWAS have brought us to the brink of a new era of personalized genomic medicine in which the prevention and management of complex diseases will be driven by the molecular understanding of each individuals contributing genetic risks for disease.

SUBMITTER: Johnson ML

PROVIDER: S-EPMC5030722 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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How rare bone diseases have informed our knowledge of complex diseases.

Johnson Mark L ML

BoneKEy reports 20160921

Rare bone diseases, generally defined as monogenic traits with either autosomal recessive or dominant patterns of inheritance, have provided a rich database of genes and associated pathways over the past 2-3 decades. The molecular genetic dissection of these bone diseases has yielded some major surprises in terms of the causal genes and/or involved pathways. The discovery of genes/pathways involved in diseases such as osteopetrosis, osteosclerosis, osteogenesis imperfecta and many other rare bon ...[more]

PMID: 27688878

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Project description:Identifying drivers of complex traits from the noisy signals of genetic variation obtained from high-throughput genome sequencing technologies is a central challenge faced by human geneticists today. We hypothesize that the variants involved in complex diseases are likely to exhibit non-neutral evolutionary signatures. Uncovering the evolutionary history of all variants is therefore of intrinsic interest for complex disease research. However, doing so necessitates the simultaneous elucidation of the targets of natural selection and population-specific demographic history.Here we characterize the action of natural selection operating across complex disease categories, and use population genetic simulations to evaluate the expected patterns of genetic variation in large samples. We focus on populations that have experienced historical bottlenecks followed by explosive growth (consistent with many human populations), and describe the differences between evolutionarily deleterious mutations and those that are neutral.Genes associated with several complex disease categories exhibit stronger signatures of purifying selection than non-disease genes. In addition, loci identified through genome-wide association studies of complex traits also exhibit signatures consistent with being in regions recurrently targeted by purifying selection. Through simulations, we show that population bottlenecks and rapid growth enable deleterious rare variants to persist at low frequencies just as long as neutral variants, but low-frequency and common variants tend to be much younger than neutral variants. This has resulted in a large proportion of modern-day rare alleles that have a deleterious effect on function and that potentially contribute to disease susceptibility.The key question for sequencing-based association studies of complex traits is how to distinguish between deleterious and benign genetic variation. We used population genetic simulations to uncover patterns of genetic variation that distinguish these two categories, especially derived allele age, thereby providing inroads into novel methods for characterizing rare genetic variation driving complex diseases.

Project description:Osteocytes are the most abundant (~95%) cells in bone with the longest half-life (~25 years) in humans. In the past osteocytes have been regarded as vestigial cells in bone, since they are buried inside the tough bone matrix. However, during the last 30 years it has become clear that osteocytes are as important as bone forming osteoblasts and bone resorbing osteoclasts in maintaining bone homeostasis. The osteocyte cell body and dendritic processes reside in bone in a complex lacuno-canalicular system, which allows the direct networking of osteocytes to their neighboring osteocytes, osteoblasts, osteoclasts, bone marrow, blood vessels, and nerves. Mechanosensing of osteocytes translates the applied mechanical force on bone to cellular signaling and regulation of bone adaptation. The osteocyte lacuno-canalicular system is highly efficient in transferring external mechanical force on bone to the osteocyte cell body and dendritic processes via displacement of fluid in the lacuno-canalicular space. Osteocyte mechanotransduction regulates the formation and function of the osteoblasts and osteoclasts to maintain bone homeostasis. Osteocytes produce a variety of proteins and signaling molecules such as sclerostin, cathepsin K, Wnts, DKK1, DMP1, IGF1, and RANKL/OPG to regulate osteoblast and osteoclast activity. Various genetic abnormality-associated rare bone diseases are related to disrupted osteocyte functions, including sclerosteosis, van Buchem disease, hypophosphatemic rickets, and WNT1 and plastin3 mutation-related disorders. Meticulous studies during the last 15 years on disrupted osteocyte function in rare bone diseases guided for the development of various novel therapeutic agents to treat bone diseases. Studies on genetic, molecular, and cellular mechanisms of sclerosteosis and van Buchem disease revealed a role for sclerostin in bone homeostasis, which led to the development of the sclerostin antibody to treat osteoporosis and other bone degenerative diseases. The mechanism of many other rare bone diseases and the role of the osteocyte in the development of such conditions still needs to be investigated. In this review, we mainly discuss the knowledge obtained during the last 30 years on the role of the osteocyte in rare bone diseases. We speculate about future research directions to develop novel therapeutic drugs targeting osteocyte functions to treat both common and rare bone diseases.

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How rare bone diseases have informed our knowledge of complex diseases.

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How rare bone diseases have informed our knowledge of complex diseases.

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