Severe osteoarthritis of the hand associates with markers within the ALDH1A2 gene and with very rare variants at 1p31

Osteoarthritis is the most common form of arthritis and a major cause of pain and dis-ability in the elderly. Genome-wide association studies (GWAS) and meta-analyses efforts have yielded several significant loci for osteoarthritis of the hip and osteoarthritis of the knee 1-7 . With the aim of discovering sequence variants that confer risk of osteoarthritis of the hand, we carried out a genome wide association study in subjects with severe hand osteoarthritis, using variants identified through a whole genome sequencing effort of 2,230 Icelanders. We found two significant loci in the Icelandic discovery set; at 15q22 (freq. 50.7%, OR 1.51, P = 3.99 × 10 -10 ) in the ALDH1A2 gene, and at 1p31 (freq. 0.02%, OR 50.6, P = 9.8 × 10 -10 ). The rare variant at 1p31 segregates with osteoarthritis in one dense family, and is present in other populations. The markers within the ALDH1A2 gene were confirmed in replication sets from the Netherlands and the United Kingdom, yielding an overall association of OR = 1.46 and P = 1.1× 10 -11 (rs3204689).

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