Research Reveals Novel Genetic Influences On Osteoporosis

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By IMPC

Published 19th March 2019

Recent research, published in nature genetics, identifies novel genetic influences on osteoporosis, with the potential to empower future research on osteoporosis and potentially lead to new drug targets.

Osteoporosis is a condition that develops slowly over several years and leads to increased bone fragility. Fragile bones are more prone to fracture, with hip, wrist and spine bones being particularly vulnerable to breakage. Whilst there are many factors that affect the chances of an individual developing osteoporosis such as low body weight, certain medical conditions and age, the disease is highly heritable – you are much more likely to develop osteoporosis if your family has a history of the condition. By assessing the genetic determinants of bone mineral density (BMD), the most clinically relevant factor for diagnosis, the researchers were able to create an atlas of genetic influences on osteoporosis.

GWAS identifies gene loci linked to bone mineral density and fracture risk

Using UK Biobank data, the researchers carried out a genome-wide association study (GWAS), with the aim of identifying the common genetic variants associated with estimated bone mineral density (eBMD). The study found 518 genome-wide significant loci, with 301 of these being novel. Additionally, they undertook a GWAS aimed at identifying genetic loci linked with fracture risk. The results revealed 13 loci associated with risk of fracture. As might be expected, genetic variation associated with risk of fracture was also found to be associated with BMD i.e. alleles associated with low eBMD increased fracture risk.

Causal genes linked to genetic loci

Genetic associations in humans, however, rarely result in improved clinical care, usually due to a lack of identification of causal genes at the associated loci. With this in mind, the researchers tested the DNA locations associated with BMD and fracture risk, to see which features of the DNA linked to genes that are known to influence bone biology in humans. This resulted in a set of ‘Target Genes’ that are known to have an effect on bone density and strength in humans – prioritising genes at associated loci for functional testing.

Using mouse models for in-depth analysis

The study initially used mouse models to successfully test the validity of the identified Target Genes, with outlier phenotypes more frequent in mice with disruptions to 126 Target Genes compared with 526 unselected knockout lines. The in vivo and in vitro data produced thus far in the study converged to identify DAAM2 as a highly credible and novel osteoporosis gene.

After discovering that inducing a double strand break in the DAAM2 gene severely impairs mineralization in human bone cells, the researchers used mice obtained from the Wellcome Trust/Sanger Institute (generated as part of the IMPC, using ES cells) for in-depth characterisation of DAAM2. Mice with both versions of their DAAM2 gene disrupted (Daam2tm1a/tm1a) exhibited reduced vertebral bone mineral content accompanied by a small reduction in femur length.  Perhaps most significantly, the mutant mice also had markedly reduced bone strength. The increased cortical porosity observed in both male and female Daam2tm1a/tm1a mutants, along with the abnormal bone composition and structure exhibited, allowed the researchers to conclude that this decreased bone strength in Daam2tm1a/tm1a mice was not simply a result of abnormal bone turnover. If DAAM2 proves to be a viable drug target – it could result in a complementary therapeutic strategy for the prevention and treatment of osteoporosis.

The goal of the IMPC is to knock out and phenotype all 20,000 or so genes in the mouse genome, potentially providing major insights into unexplored areas of the mammalian genome. To order IMPC mice, click on the shopping cart on the top part of the gene page of interest or scroll down to “Order Mouse and ES Cells”.

IMPC Data

Details on more phenotype associations for DAAM2 can be found on the IMPC Daam2 gene page. Various phenotype association data can be found such as that shown below.


Research Paper: An atlas of genetic influences on osteoporosis in humans and mice

Scientists from the University of Cambridge have identified a potential therapeutic target in the devastating genetic disease Hutchinson-Gilford Progeria Syndrome (HGPS), which is characterised by premature ageing. The research utilises IMPC resources through the use of mouse phenotypic data.

The paper is published in Nature Communications, with preclinical data showing that chemical inhibition or genetic deregulation of the enzyme N-acetyltransferase 10 (NAT10) leads to significant health and lifespan gains in a mouse model of HGPS.

HGPS is a rare condition: patients have an average life expectancy of around 15 years, suffering a variety of symptoms including short stature, low body weight, hair loss, skin thickening, problems with fat storage, osteoporosis, and cardiovascular disease, typically dying of a heart attack.

The disease arises from specific mutations in the gene for the protein Lamin A, which lead to production of a shorter, dysfunctional protein that accumulates in cells, specifically in the membranes surrounding the nucleus. This causes disorganisation of chromatin (the ‘packaging’ around DNA), deregulated transcription, accumulation of DNA damage and defective cell proliferation.

By screening candidate molecules for an effect on nuclear membranes in human HGPS patient-derived cells in vitro, the authors have previously identified a small molecule called remodelin as an effective ameliorative agent. They then identified which component of the cells was being affected by remodelin: an enzyme with a variety of cell functions, called NAT10.

Their aim in the new study was to take these findings into a mouse model with the same genetic defect as HGPS patients, to see whether inhibiting NAT10 – either chemically by administration of remodelin or genetically by engineering reduced production of NAT10 – could ameliorate the disease. The results show that these approaches indeed significantly improved the health of the diseased mice, increased their lifespan, and reduced the effects of the HGPS mutation across a variety of measures in body tissues and at the cellular level.

The research was led by Dr Gabriel Balmus from the Wellcome Trust/ Cancer Research UK Gurdon Institute and Dr Delphine Larrieu from the Cambridge Institute for Medical Research, University of Cambridge; and Dr David Adams from the Wellcome Sanger Institute.

 

Senior author Professor Steve Jackson commented: “We’re very excited by the possibility that drugs targeting NAT10 may, in future, be tested on people suffering from HGPS. I like to describe this approach as a ‘re-balancing towards the healthy state’.

“We first studied the cell biology to understand how the disease affects cells, and then used those findings to identify ways to re-balance the defect at the whole-organism level. Our findings in mice suggest a therapeutic approach to HGPS and other premature ageing diseases.”

 

Research article: https://www.nature.com/articles/s41467-018-03770-3.pdf

Nat10 gene on the IMPC website: http://www.mousephenotype.org/data/genes/MGI:2138939

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By IMPC

Published 3rd July 2018

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