AI Article Synopsis
- A genome-wide association study was conducted on total hip replacements among 4,657 Icelandic patients and 207,514 controls, revealing two significant genetic variants linked to osteoarthritis.
- The first variant is a rare missense mutation in the COMP gene, while the second is a frameshift mutation in the CHADL gene, which is inherited recessively.
- Individuals carrying these mutations underwent hip replacement surgeries significantly earlier, with average differences of 13.5 years for the COMP mutation and 4.9 years for the CHADL mutation.
Article Abstract
We performed a genome-wide association study of total hip replacements, based on variants identified through whole-genome sequencing, which included 4,657 Icelandic patients and 207,514 population controls. We discovered two rare signals that strongly associate with osteoarthritis total hip replacement: a missense variant, c.1141G>C (p.Asp369His), in the COMP gene (allelic frequency = 0.026%, P = 4.0 × 10, odds ratio (OR) = 16.7) and a frameshift mutation, rs532464664 (p.Val330Glyfs*106), in the CHADL gene that associates through a recessive mode of inheritance (homozygote frequency = 0.15%, P = 4.5 × 10, OR = 7.71). On average, c.1141G>C heterozygotes and individuals homozygous for rs532464664 had their hip replacement operation 13.5 years and 4.9 years earlier than others (P = 0.0020 and P = 0.0026), respectively. We show that the full-length CHADL transcript is expressed in cartilage. Furthermore, the premature stop codon introduced by the CHADL frameshift mutation results in nonsense-mediated decay of the mutant transcripts.
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| http://dx.doi.org/10.1038/ng.3816 | DOI Listing |
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