Meta-analysis of Icelandic and UK data sets identifies missense variants in SMO, IL11, COL11A1 and 13 more new loci associated with osteoarthritis

Osteoarthritis has a highly negative impact on quality of life because of the associated pain and loss of joint function. Here we describe the largest meta-analysis so far of osteoarthritis of the hip and the knee in samples from Iceland and the UK Biobank (including 17,151 hip osteoarthritis patien...

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Published in:	Nature genetics Vol. 50; no. 12; pp. 1681 - 1687
Main Authors:	Styrkarsdottir, Unnur, Lund, Sigrun H., Thorleifsson, Gudmar, Zink, Florian, Stefansson, Olafur A., Sigurdsson, Jon K., Juliusson, Kristinn, Bjarnadottir, Kristbjörg, Sigurbjornsdottir, Sara, Jonsson, Stefan, Norland, Kristjan, Stefansdottir, Lilja, Sigurdsson, Asgeir, Sveinbjornsson, Gardar, Oddsson, Asmundur, Bjornsdottir, Gyda, Gudmundsson, Reynir L., Halldorsson, Gisli H., Rafnar, Thorunn, Jonsdottir, Ingileif, Steingrimsson, Eirikur, Norddahl, Gudmundur L., Masson, Gisli, Sulem, Patrick, Jonsson, Helgi, Ingvarsson, Thorvaldur, Gudbjartsson, Daniel F., Thorsteinsdottir, Unnur, Stefansson, Kari
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01.12.2018 Nature Publishing Group
Subjects:	45/23 45/43 631/208/1516 631/208/205/2138 631/208/457 692/699/1670 692/699/67 Adult Aged Agriculture Analysis Animal Genetics and Genomics Arthritis Biocompatibility Biomedical and Life Sciences Biomedicine Cancer Research Case-Control Studies Collagen Type XI - genetics Consortia Datasets Datasets as Topic - statistics & numerical data Deoxyribonucleic acid Disease DNA Female Gene expression Gene Frequency Gene Function Genes Genetic aspects Genetic Loci Genetic Predisposition to Disease Genetic variation Genetics Genome-Wide Association Study Genomes Genotype Haplotypes Health aspects Hip Human Genetics Humans Iceland - epidemiology Influence Interleukin 1 Interleukin 11 Interleukin-11 - genetics Knee Letter Loci Male Meta-analysis Middle Aged Mutation Mutation, Missense Osteoarthritis Osteoarthritis - epidemiology Osteoarthritis - genetics Pain Patients Polymorphism, Single Nucleotide Quality of life Risk factors Smoothened Receptor - genetics United Kingdom - epidemiology United Kingdom Iceland United Kingdom > UK
ISSN:	1061-4036, 1546-1718, 1546-1718
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Summary:	Osteoarthritis has a highly negative impact on quality of life because of the associated pain and loss of joint function. Here we describe the largest meta-analysis so far of osteoarthritis of the hip and the knee in samples from Iceland and the UK Biobank (including 17,151 hip osteoarthritis patients, 23,877 knee osteoarthritis patients, and more than 562,000 controls). We found 23 independent associations at 22 loci in the additive meta-analyses, of which 16 of the loci were novel: 12 for hip and 4 for knee osteoarthritis. Two associations are between rare or low-frequency missense variants and hip osteoarthritis, affecting the genes SMO (rs143083812, frequency 0.11%, odds ratio (OR) = 2.8, P = 7.9 × 10 −12 , p.Arg173Cys) and IL11 (rs4252548, frequency 2.08%, OR = 1.30, P = 2.1 × 10 −11 , p.Arg112His). A common missense variant in the COL11A1 gene also associates with hip osteoarthritis (rs3753841, frequency 61%, P = 5.2 × 10 –10 , OR = 1.08, p.Pro1284Leu). In addition, using a recessive model, we confirm an association between hip osteoarthritis and a variant of CHADL 1 (rs117018441, P = 1.8 × 10 −25 , OR = 5.9). Furthermore, we observe a complex relationship between height and risk of osteoarthritis. Genome-wide association meta-analysis of data sets from Iceland and the UK identifies 16 new risk loci for osteoarthritis, including missense variants in SMO , IL11 , and COL11A1 .
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 content type line 14 ObjectType-Feature-3 ObjectType-Evidence Based Healthcare-1 ObjectType-Feature-2 ObjectType-Correspondence-1 content type line 23 ObjectType-Article-3
ISSN:	1061-4036 1546-1718 1546-1718
DOI:	10.1038/s41588-018-0247-0