Whole-genome sequencing identifies rare genotypes in COMP and CHADL associated with high risk of hip osteoarthritis.
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Norddahl, Gudmundur L
Agustsdottir, Arna B
Reynard, Louise N
Halldorsson, Gisli H
Johannsdottir, Hrefna S
Almdahl, Ina S
Koh, Jung Min
Tang, Nelson L S
Daneshpour, Maryam S
Mayordomo, Jose I
Braund, Peter S
Samani, Nilesh J
Kiemeney, Lambertus A
Lohmander, L Stefan
Andreassen, Ole A
MetadataShow full item record
CitationWhole-genome sequencing identifies rare genotypes in COMP and CHADL associated with high risk of hip osteoarthritis. 2017, 49 (5):801-805 Nat. Genet.
AbstractWe 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(-12), 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(-18), 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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