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Icelandic GWAS Reveals Variants Linked to Bone Mineral Density, Osteoporotic Fracture Risk

NEW YORK (GenomeWeb) – In a study appearing online today in Nature Communications, researchers from Decode Genetics and elsewhere described new genetic variants that appear to coincide with both bone mineral density (BMD) in the spine and risk of osteoporotic fractures.

Through a genome-wide association study involving some 20,100 Icelandic individuals with established BMD measurements, the team verified associations for variants in known BMD genes. The results also uncovered a new BMD-related gene, PTCH1, as well as a previously undescribed variant in a gene with prior ties to BMD called RSPO3 — results confirmed in nearly 10,100 more individuals with European or East Asian ancestry.

The non-coding PTCH1 and RSPO3 variants showed ties to not only diminished BMD in the spine, but also to osteoporotic fracture risk, the researchers reported, perhaps as a consequence of expression changes detected in the genes when such variants are present.

Indeed, the study's authors noted that non-coding variants at the PTCH1 and RSPO3 loci appear to alter gene expression in ways that are expected to affect the Hedgehog and the Wnt signaling pathways, respectively.

Because BMD can help to predict the risk of osteoporotic fractures, the researchers explained, they reasoned that they might be able to add to the tally of genetic factors related to the risk of osteoporosis and related bone breaks by assessing a large number of individuals with known BMDs.

They noted that past GWAS and meta-analyses have unearthed some 56 BMD-linked loci, including more than a dozen signals that also coincide with osteoporotic fracture risk, though it is believed that still more BMD-related variants remain undiscovered.

For their new analysis, the researchers scrutinized patterns at tens of millions of variants in the genomes of more than 20,100 Icelanders with hip and/or spine BMD measurements using array-based genotyping, as well as SNP and indel patterns imputed with the help of more than 2,600 previously sequenced Icelandic genomes.

Along with associations between BMD and many variants identified in the past, the team saw a suspicious signal in and around the chromosome 9 gene PTCH1, which codes for a receptor that interacts with three hedgehog signaling protein morphogens.

After replicating the association in 10,091 individuals from Denmark, Australia, Korea, and Hong Kong, the researchers turned their attention to the rs28377268 SNP, a variant previously associated with height that falls in a PTCH1 intron and appears to overlap with a regulatory histone mark.

In an analysis of 10,389 cases and 264,522 controls from Iceland, Denmark, Australia, Korea, and China, the researchers saw a corresponding association between osteoporotic fracture risk and the same PTCH1variant.

Similarly, the team found a new BMD-related variant in a previously described BMD locus on chromosome 6 that landed at a site upstream of RSPO3's transcriptional start site and was previously implicated in high-density lipoprotein cholesterol and triglyceride levels.

The presence of this variant — which showed ties to BMD and osteoporotic fracture risk— appeared to dial up expression of the RSPO3 gene in adipose tissue, the researchers noted.

Still other new associations turned up in loci containing the AXIN1, SOST, and EN1 genes, albeit for alleles found at lower frequency than the rs28377268 variant in PTCH1.