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Bone Mineral Density GWAS Leads to New Loci With Potential Role in Osteoporosis

NEW YORK (GenomeWeb) – An international team led by investigators in Australia, the UK, and Canada has identified genetic variants with apparent ties to bone mineral density (BMD) — a collection that is expected to guide future functional studies of both BMD and osteoporosis.

Through a genome-wide association study involving nearly 142,500 participants in the UK Biobank resource, the researchers uncovered BMD-associated variants at 203 genetic loci, including more than 150 sites in the genome that had not been linked to the trait in the past. After a series of follow-up analyses using gene expression profiles for human bone forming cells and experiments in knockout mice and cell models, for example, they found a role for the GPC6 gene in BMD and flagged 100 genes for additional scrutiny.

"[O]ur findings shed light on the pathophysiological mechanisms that underlie changes in BMD and fracture risk in humans," the authors wrote in Nature Genetics, noting that "proteins identified and prioritized by these studies identify signaling pathways that represent new drug targets for the prevention and treatment of osteoporosis — a major health care priority."

The researchers reasoned that a more complete understanding of BMD genetics could also provide better insights into osteoporosis, since low BMD has been linked to risk of that age-related condition. To expand on the set of established BMD-associated variants, they performed array-based genotyping on 142,487 UK Biobank participants who had had one or both heel bones measured by quantitative ultrasound at baseline.

A subset of the individuals had heel measurements taken at additional time points, and just shy of 14,500 participants reported having a bone fracture over the previous five years.

Based on BMD estimates made from the bone measurements, together with variant patterns at some 17.2 million SNPs, the team identified 307 suspicious SNPs at 203 loci, including some relatively rare variants. A dozen of the BMD-associated SNPs also coincided with fracture risk in the UK Biobank participants.

The researchers subsequently considered patterns for loci with known ties to BMD alongside results from past GWAS. And with a series of bioinformatic analyses, functional genomic experiments, and phenotyping, they went on to explore possible mechanisms for the 153 new BMD-linked loci, using human and mouse osteoblast expression data and knockout mice.

One gene, in particular, caught the team's attention in these follow-up experiments: the glypican signaling protein-coding gene GPC6, which appears to contribute to several bone formation- and mineralization-related processes.

The study significantly boosts the number of loci linked to BMD in humans, which together explain an estimated 12 percent of the trait's variance, the authors noted. Moreover, they wrote, the work "prioritized genes for future study and provided functional evidence that GPC6 has a role in determining BMD and the pathophysiology of osteoporosis."