Review J Med Genet: first published as 10.1136/jmedgenet-2013-101754 on 18 July 2013. Downloaded from Advances in osteoarthritis genetics Kalliope Panoutsopoulou, Eleftheria Zeggini Department of Human ABSTRACT the rise. In the USA alone 27 million adults had Genetics, Wellcome Trust Osteoarthritis (OA), the most common form of arthritis, clinical evidence of OA in 2005, a rise of nearly Sanger Institute, 67 Cambridgeshire, UK is a highly debilitating disease of the joints and can lead 30% from the estimate of 21 million in 1995. to severe pain and disability. There is no cure for OA. With longer life expectancies and the obesity pan- Correspondence to Current treatments often fail to alleviate its symptoms demic—with age and obesity/overweight being well Dr Eleftheria Zeggini and leading to an increased demand for joint replacement established risk factors for disease development and Dr Kalliope Panoutsopoulou, surgery. Previous epidemiological and genetic research progression—the prevalence of OA is expected to Wellcome Trust Sanger Institute, Hinxton, The Morgan has established that OA is a multifactorial disease with increase continuously and sharply. Building, Wellcome Trust both environmental and genetic components. Over the Although the aetiology of OA is not fully under- Genome Campus, Hinxton, past 6 years, a candidate gene study and several stood it has been well established that the disease is Cambridgeshire, genome-wide association scans (GWAS) in populations caused by complex interplay between environmen- CB10 1HH, UK; [email protected] and of Asian and European descent have collectively tal and genetic factors. Age is the strongest risk [email protected] established 15 loci associated with knee or hip OA that factor for all types of OA whereas obesity appears have been replicated with genome-wide significance, to confer the greatest risk in knee OA, particularly Received 16 April 2013 shedding some light on the aetiogenesis of the disease. among women. Epidemiological research also sug- Revised 19 June 2013 All OA associated variants to date are common in gests that occupational physical workload, high Accepted 22 June 2013 Published Online First frequency and appear to confer moderate to small effect sporting activity, joint injuries and being female 18 July 2013 sizes. Some of the associated variants are found within may increase the risk of developing OA at particu- or near genes with clear roles in OA pathogenesis, lar joints (reviewed in Altman,2 and Bierma- whereas others point to unsuspected, less characterised Zeinstra and Koes8). pathways. These studies have also provided further evidence in support of the existence of ethnic, sex, and GENETIC STUDIES IN OA fi joint speci c effects in OA and have highlighted the The pre-genome-wide association scans era importance of expanded and more homogeneous fi Twin pair, sibling risk and segregation studies con- phenotype de nitions in genetic studies of OA. ducted in Europe and the USA have demonstrated a substantial genetic component for OA that is transmitted in a non-Mendelian manner, which is INTRODUCTION typical of multifactorial diseases. Heritability esti- Osteoarthritis (OA) is a set of disorders of the mus- mates range between 40–65%, with precise esti- culoskeletal system characterised by degradation mates varying depending on gender, affected joint, http://jmg.bmj.com/ and loss of articular cartilage in synovial joints and severity of the disease, but overall appear most commonly of the knee, hip, hand, foot, and stronger for hand and hip OA than for knee spine. OA development appears to be a result of a OA.910Familial aggregation studies in the UK have complex set of interactions between mechanical, estimated that the sibling recurrence risk (λs)— biological, biochemical, and molecular factors that which indicates the disease risk of a sibling to an destabilise the normal coupling of degradation and individual with OA compared to the disease preva- synthesis of articular cartilage chondrocytes and lence in the general population—is ∼5.10 The on September 29, 2021 by guest. Protected copyright. extracellular matrix, and subchondral bone. notion that OA is simply a wear-and-tear disease of Although OA invariably involves articular cartilage, old age was largely superseded and these epidemio- it affects all tissues of the joint; loss of articular car- logical studies provided a firm foundation for con- tilage is accompanied by subchondral bone remod- siderable genetic research aimed at identifying elling with sclerosis and in many instances cysts, genetic loci responsible for OA susceptibility. osteophyte formation at joint margins, ligamentous To date five genome-wide linkage scans per- contractures and relaxation, muscle atrophy and formed on individuals collected in the UK, Finland, spasms, and at clinical stages of the disease inflam- Iceland, and the USA have been published for OA mation of the synovial membrane.12 but had limited success.10 Gene centric association The health and socioeconomic burden posed by studies, commonly known as candidate gene OA is substantial. The main symptom of OA is pain studies, have been extensively applied in popula- and loss of physical function leading to impaired tions of European and Asian ancestry to survey var- mobility and impaired quality of life.3 Current regi- iants across genes believed to be implicated in OA mens for OA management are multimodal in based on prior biological knowledge. The majority Open Access nature—that is, a combination of pharmacologic of reported associations, however, have been either Scan to access more 2 free content and non-pharmacologic treatments. However, false positives—due to small sample sizes, lack of these are often ineffective in targeting the main replication and lack of stringency in the reporting disease symptom leading to an increased demand of significant results based on observed p values— To cite: Panoutsopoulou K, for total joint replacement (TJR).4 OA is the most or have yielded only suggestive evidence for associ- Zeggini E. J Med Genet prevalent form of arthritis affecting over 40% of ation; that is, replication in at least one other study – 2013;50:715 724. people over the age of 70,5 and its incidence is on but not meeting genome-wide significance defined Panoutsopoulou K, et al. J Med Genet 2013;50:715–724. doi:10.1136/jmedgenet-2013-101754 715 Review J Med Genet: first published as 10.1136/jmedgenet-2013-101754 on 18 July 2013. Downloaded from − as p<5×10 8 (for examples, see Valdes and Spector10). A fine mapping and functional studies are required to identify the notable exception of the success of the candidate gene sequen- causal variants and precise genes involved in OA pathogenesis. cing approach in OA is the robust and reproducible association of rs143383 in the growth differentiation factor 5 (GDF5) GENETIC ARCHITECTURE OF OA – gene,11 13 discussed in more detail below. In line with other common complex disorders the genetic archi- tecture of OA appears to be highly polygenic with multiple var- The genome-wide association scans era iants across the full allele frequency spectrum contributing In the last decade, the Human Genome and International modest and small effects. The theory of a polygenic inheritance HapMap Projects have revolutionised the field of common model for OA was first tested by the arcOGEN Consortium in a complex disease genetics by providing an extensive catalogue of GWAS of 3177 cases and 4984 population based controls from genome sequence variation and linkage disequilibrium (LD) pat- the UK.23 Using analytical approaches previously applied to test terns between common variants. This has enabled the selection the polygenic inheritance of schizophrenia and bipolar dis- of tag single nucleotide polymorphisms (tag SNPs)—a set of order,24 a set of independent associated SNPs was derived from informative, non-redundant markers capturing the majority of a subset of the data (90% of arcOGEN samples); this score common variations across the genome—which led to the devel- allele set was then used to evaluate the proportion of case– opment of high throughput genotyping platforms in which hun- control status accounted for in the remaining samples (10% of dreds of thousands of SNPs can be concurrently examined for arcOGEN samples). These analyses revealed a substantial association with disease. In recent years, this hypothesis-free genetic component to OA comprising multiple contributing var- approach of interrogating common variation in a genome-wide iants with small effect sizes. manner dominated the field of human genetics and led to the identification of numerous novel associations with several OA ESTABLISHED LOCI common complex diseases and traits.14 OA was relatively late to GDF5 enter the genome-wide association scans (GWAS) era but the In the only candidate gene study that yielded a strong reprodu- returns were substantial; two novel associations from studies in cible association with OA thus far, Miyamoto et al,11 searched individuals of Asian origin,15 16 and 12 novel associations from for sequence variations in the exons and flanking regions of the – scans performed in individuals of European ancestry,17 22 were GDF5 gene and identified the rs143383 polymorphism—aTto detected with genome-wide significance bringing the total of C transition located in the 50 untranslated region (50UTR) of the established OA loci to 15 (table 1). This review considers all gene—to be significantly associated with hip OA. Combined evi- associations with OA