期刊
NATURE GENETICS
卷 49, 期 5, 页码 801-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3816
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资金
- Arthritis Research UK [20771] Funding Source: Medline
- Medical Research Council [G0900753, MR/K006312/1, G0901461, G0600237, MR/K002279/1, G0100594] Funding Source: Medline
- Versus Arthritis [20771, 20679] Funding Source: Medline
- MRC [G0100594, MR/K006312/1, G0600237, G0900753, G0901461, MR/K002279/1] Funding Source: UKRI
- Medical Research Council [G0600237, MR/K002279/1, G0901461, G0100594, G0900753, MR/K006312/1] Funding Source: researchfish
- Versus Arthritis [20771, 20679] Funding Source: researchfish
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 x 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 x 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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