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Icelandic DNA Sequences Lead to Rare Osteoarthritis Risk Variants

NEW YORK (GenomeWeb) – A study based in Iceland has identified rare genetic variants contributing to osteoarthritis risk, including a mutation shared across multiple populations and another that appears specific to individuals in Iceland.

The researchers tapped into whole-genome sequence data for almost 8,500 Icelandic individuals, using these sequences to flesh out variant patterns in 4,657 Icelanders who had had total hip replacements to treat their osteoarthritis. As they reported in Nature Genetics today, comparisons with hundreds of thousands of population controls led to rare changes in the COMP and CHADL genes that were over-represented in individuals with hip osteoarthritis.

The team saw signs that missense mutations in COMP and frameshift mutations in CHADL were linked to earlier hip replacement times. That was particularly true for individuals with one mutant and one normal version of the gene, who had surgery more than a decade earlier than usual, on average.

"Both [COMP and CHADL] variants confer substantial risk of [total hip replacement]," co-corresponding authors Kari Stefansson and Unnur Thorsteinsdottir, from Decode Genetics/Amgen, and their co-authors wrote. They further noted that the odds ratios associated with these mutations "are substantially higher than those for the previously reported common osteoarthritis risk variants."

In an effort to unearth osteoarthritis-associated variants with effect sizes stronger than those found in past genome-wide association studies, the researchers considered patterns at some 31.6 million variants in 4,657 Icelanders with a history of total hip replacement and in more than 207,500 control individuals from the Icelandic population.

The team settled on the variants to profile using whole-genome sequences from almost 8,500 Icelanders, sequenced with Illumina GAIIx or HiSeq 2000 instruments, coupled with imputation information from 150,656 genotyped individuals. Study participants with or without total hip replacement had been genotyped directly or had genotyped relatives.

From these data, the researchers saw significant ties between total hip replacement and two rare variants: a missense change in COMP — a chromosome 19 gene previously implicated in skeletal dysplasia conditions — and a frameshift mutation in the chromosome 22 gene CHADL.

Based on data for another 5,109 cases and more than 222,400 controls, they found that the COMP mutation coincided with osteoarthritis cases, even in individuals who did not undergo hip replacement.

That mutation appeared to be specific to the Icelandic population, the authors noted, while genotyping data for 10 populations suggest that frameshift changes to CHADL "is widespread in populations of European and Middle Eastern descent and is found at lower frequency in East Asians, suggesting that the mutation occurred a long time ago."