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Osteoarthritis affects over 300 million people worldwide. Here, we conduct a genome-wide association study meta-analysis across 826,690 individuals (177,517 with osteoarthritis) and identify 100 independently associated risk variants across 11 osteoarthritis phenotypes, 52 of which have not been associated with the disease before. We report thumb and spine osteoarthritis risk variants and identify differences in genetic effects between weight-bearing and non-weight-bearing joints. We identify sex-specific and early age-at-onset osteoarthritis risk loci. We integrate functional genomics data from primary patient tissues (including articular cartilage, subchondral bone, and osteophytic cartilage) and identify high-confidence effector genes. We provide evidence for genetic correlation with phenotypes related to pain, the main disease symptom, and identify likely causal genes linked to neuronal processes. Our results provide insights into key molecular players in disease processes and highlight attractive drug targets to accelerate translation., Competing Interests: Declaration of interests T.R.G. and J.Z. receive research funding from GlaxoSmithKline. T.R.G. receives research funding from Biogen. U.S., K.S., L. Stefánsdóttir, G.B., S.H.L., U.T., and G. T. are employed by deCODE genetics/Amgen Inc. A.M.V. is a consultant for Zoe Global Ltd. All other authors report no competing interests. All Regeneron Genetics Center banner authors are current employees and/or stockholders of Regeneron Pharmaceuticals., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Osteoarthritis (OA) is the most common form of arthritis and the leading cause of disability in the elderly. Of all the joints, genetic predisposition is strongest for OA of the hand; however, only few genetic risk loci for hand OA have been identified. Our aim was to identify novel genes associated with hand OA and examine the underlying mechanism., Methods: We performed a genome-wide association study of a quantitative measure of hand OA in 12 784 individuals (discovery: 8743, replication: 4011). Genome-wide significant signals were followed up by analysing gene and allele-specific expression in a RNA sequencing dataset (n=96) of human articular cartilage., Results: We found two significantly associated loci in the discovery set: at chr12 (p=3.5 × 10 -10 ) near the matrix Gla protein (MGP) gene and at chr12 (p=6.1×10 -9 ) near the CCDC91 gene. The DNA variant near the MGP gene was validated in three additional studies, which resulted in a highly significant association between the MGP variant and hand OA (rs4764133, Beta meta =0.83, P meta =1.8*10 -15 ). This variant is high linkage disequilibrium with a coding variant in MGP , a vitamin K-dependent inhibitor of cartilage calcification. Using RNA sequencing data from human primary cartilage tissue (n=96), we observed that the MGP RNA expression of the hand OA risk allele was significantly lowercompared with the MGP RNA expression of the reference allele (40.7%, p<5*10 -16 )., Conclusions: Our results indicate that the association between the MGP variant and increased risk for hand OA is caused by a lower expression of MGP , which may increase the burden of hand OA by decreased inhibition of cartilage calcification., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: To investigate familial aggregation of Sjögren's syndrome (SS) and the relative risks (RRs) of other autoimmune disease in relatives of patients with SS., Methods: We identified 23,658,577 beneficiaries enrolled in the Taiwan National Health Insurance system in 2010, of whom 12,754 had SS. We identified 21,009,551 parent-child relationships and 17,168,340 pairs of full siblings. The familial risks of SS and other autoimmune diseases, tetrachoric correlation, and familial transmission were estimated., Results: We identified 105 patients with SS who had an affected first-degree relative. The RR of SS was 18.99 (95% confidence interval [95% CI] 9.76-36.93) in siblings of patients with SS, 11.31 (95% CI 8.34-15.33) in offspring, and 12.46 (95% CI 9.34-16.62) in parents. Tetrachoric correlation coefficients were 0.53 (95% CI 0.41-0.65) for cotwins of affected individuals and 0.21 (95% CI 0.16-0.26) for full siblings. The familial transmission (heritability plus shared environmental contribution) was 0.54 (95% CI 0.44-0.77). In first-degree relatives of patients with SS, the RRs were 2.95 (95% CI 2.33-3.73) for rheumatoid arthritis, 6.25 (95% CI 5.15-7.58) for systemic lupus erythematosus, 2.39 (95% CI 0.77-7.41) for systemic sclerosis, 0.71 (95% CI 0.10-5.07) for idiopathic inflammatory myopathy, 1.97 (95% CI 1.29-3.02) for type 1 diabetes mellitus, 3.38 (95% CI 1.26-9.05) for multiple sclerosis, 1.67 (95% CI 0.83-3.33) for myasthenia gravis, 1.25 (95% CI 1.04-1.50) for psoriasis, 1.21 (95% CI 0.39-3.76) for inflammatory bowel disease, and 2.29 (95% CI 1.19-4.40) for vasculitis., Conclusion: The risk of SS and other autoimmune diseases is increased in relatives of patients with SS, and more than one-half of phenotypic variance in SS can be explained by familial factors., (© 2015 The Authors. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.)

Objective: To examine familial aggregation of gout and to estimate the heritability and environmental contributions to gout susceptibility in the general population., Methods: Using data from the National Health Insurance (NHI) Research Database in Taiwan, we conducted a nationwide cross-sectional study of data collected from 22 643 748 beneficiaries of the NHI in 2004; among them 1 045 059 individuals had physician-diagnosed gout. We estimated relative risks (RR) of gout in individuals with affected first-degree and second-degree relatives and relative contributions of genes (heritability), common environment shared by family members and non-shared environment to gout susceptibility., Results: RRs for gout were significantly higher in individuals with affected first-degree relatives (men, 1.91 (95% CI 1.90 to 1.93); women, 1.97 (95% CI 1.94 to 1.99)) and also in those with affected second-degree relatives (men, 1.27 (95% CI 1.23 to 1.31); women, 1.40 (95% CI 1.35 to 1.46)). RRs (95% CIs) for individuals with an affected twin, sibling, offspring, parent, grandchild, nephew/niece, uncle/aunt and grandparent were 8.02 (6.95 to 9.26), 2.59 (2.54 to 2.63), 1.96 (1.95 to 1.97), 1.93 (1.91 to 1.94), 1.48 (1.43 to 1.53), 1.40 (1.32 to 1.47), 1.31 (1.24 to 1.39), and 1.26 (1.21 to 1.30), respectively. The relative contributions of heritability, common and non-shared environmental factors to phenotypic variance of gout were 35.1, 28.1 and 36.8% in men and 17.0, 18.5 and 64.5% in women, respectively., Conclusions: This population-based study confirms that gout aggregates within families. The risk of gout is higher in people with a family history. Genetic and environmental factors contribute to gout aetiology, and the relative contributions are sexually dimorphic., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Osteoarthritis is the most common form of arthritis and is a major cause of pain and disability in the elderly. To search for sequence variants that confer risk of osteoarthritis of the hand, we carried out a genome-wide association study (GWAS) in subjects with severe hand osteoarthritis, using variants identified through the whole-genome sequencing of 2,230 Icelanders. We found two significantly associated loci in the Icelandic discovery set: at 15q22 (frequency of 50.7%, odds ratio (OR) = 1.51, P = 3.99 × 10(-10)) in the ALDH1A2 gene and at 1p31 (frequency of 0.02%, OR = 50.6, P = 9.8 × 10(-10)). Among the carriers of the variant at 1p31 is a family with several members in whom the risk allele segregates with osteoarthritis. The variants within the ALDH1A2 gene were confirmed in replication sets from The Netherlands and the UK, yielding an overall association of OR = 1.46 and P = 1.1 × 10(-11) (rs3204689).

Objective: To assess candidate genes for association with osteoarthritis (OA) and identify promising genetic factors and, secondarily, to assess the candidate gene approach in OA., Methods: A total of 199 candidate genes for association with OA were identified using Human Genome Epidemiology (HuGE) Navigator. All of their single-nucleotide polymorphisms (SNPs) with an allele frequency of >5% were assessed by fixed-effects meta-analysis of 9 genome-wide association studies (GWAS) that included 5,636 patients with knee OA and 16,972 control subjects and 4,349 patients with hip OA and 17,836 control subjects of European ancestry. An additional 5,921 individuals were genotyped for significantly associated SNPs in the meta-analysis. After correction for the number of independent tests, P values less than 1.58 × 10(-5) were considered significant., Results: SNPs at only 2 of the 199 candidate genes (COL11A1 and VEGF) were associated with OA in the meta-analysis. Two SNPs in COL11A1 showed association with hip OA in the combined analysis: rs4907986 (P = 1.29 × 10(-5) , odds ratio [OR] 1.12, 95% confidence interval [95% CI] 1.06-1.17) and rs1241164 (P = 1.47 × 10(-5) , OR 0.82, 95% CI 0.74-0.89). The sex-stratified analysis also showed association of COL11A1 SNP rs4908291 in women (P = 1.29 × 10(-5) , OR 0.87, 95% CI 0.82-0.92); this SNP showed linkage disequilibrium with rs4907986. A single SNP of VEGF, rs833058, showed association with hip OA in men (P = 1.35 × 10(-5) , OR 0.85, 95% CI 0.79-0.91). After additional samples were genotyped, association at one of the COL11A1 signals was reinforced, whereas association at VEGF was slightly weakened., Conclusion: Two candidate genes, COL11A1 and VEGF, were significantly associated with OA in this focused meta-analysis. The remaining candidate genes were not associated., (Copyright © 2014 by the American College of Rheumatology.)

Osteoarthritis (OA) is known to have an important genetic component and human genetic studies can help unravel the molecular mechanisms responsible for joint damage and nociception involved in OA. Genetic studies in humans have identified molecules involved in signaling cascades that are important for the pathology of the joint components such as the bone morphogenetic protein growth differentiation factor 5 (GDF5). Genomewide association scans (GWAS) in Asians have uncovered a likely role for structural extracellular matrix components (DVWA), and for molecules involved in immune response (HLA class II DQB1 and BTNL2) but these genes are not associated in Caucasian patients. In Caucasians a ~300 kilobase region in chromosome 7q22 containing several genes has been found to be reproducibly associated with OA. A recent European GWAS taking advantage of imputation techniques has uncovered a variant in the MCF2L gene as significantly associated with large joint OA. MCF2L is involved in neurotrophin mediated regulation of cell motility in the peripheral nervous system, and thus potentially implicated in nociception in OA. As the number of OA cases with genomewide genotyping increases it is expected that many more reproducible variants implicated in OA will be reported. This article is part of a Special Issue entitled "Osteoarthritis"., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Osteoarthritis (OA) is a prevalent, heritable degenerative joint disease with a substantial public health impact. We used a 1000-Genomes-Project-based imputation in a genome-wide association scan for osteoarthritis (3177 OA cases and 4894 controls) to detect a previously unidentified risk locus. We discovered a small disease-associated set of variants on chromosome 13. Through large-scale replication, we establish a robust association with SNPs in MCF2L (rs11842874, combined odds ratio [95% confidence interval] 1.17 [1.11-1.23], p = 2.1 × 10(-8)) across a total of 19,041 OA cases and 24,504 controls of European descent. This risk locus represents the third established signal for OA overall. MCF2L regulates a nerve growth factor (NGF), and treatment with a humanized monoclonal antibody against NGF is associated with reduction in pain and improvement in function for knee OA patients., (Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Objectives: Osteoarthritis (OA) is the most prevalent form of arthritis and accounts for substantial morbidity and disability, particularly in older people. It is characterised by changes in joint structure, including degeneration of the articular cartilage, and its aetiology is multifactorial with a strong postulated genetic component., Methods: A meta-analysis was performed of four genome-wide association (GWA) studies of 2371 cases of knee OA and 35 909 controls in Caucasian populations. Replication of the top hits was attempted with data from 10 additional replication datasets., Results: With a cumulative sample size of 6709 cases and 44 439 controls, one genome-wide significant locus was identified on chromosome 7q22 for knee OA (rs4730250, p=9.2 × 10⁻⁹), thereby confirming its role as a susceptibility locus for OA., Conclusion: The associated signal is located within a large (500 kb) linkage disequilibrium block that contains six genes: PRKAR2B (protein kinase, cAMP-dependent, regulatory, type II, β), HPB1 (HMG-box transcription factor 1), COG5 (component of oligomeric golgi complex 5), GPR22 (G protein-coupled receptor 22), DUS4L (dihydrouridine synthase 4-like) and BCAP29 (B cell receptor-associated protein 29). Gene expression analyses of the (six) genes in primary cells derived from different joint tissues confirmed expression of all the genes in the joint environment.

Osteoarthritis (OA) is the most common form of arthritis and a major cause of disability. This study evaluates the association in Caucasian populations of two single nucleotide polymorphisms (SNPs) mapping to the Human Leukocyte Antigen (HLA) region and deriving from a genome wide association scan (GWAS) of knee OA in Japanese populations. The frequencies for rs10947262 were compared in 36,408 controls and 5,749 knee OA cases from European-descent populations. rs7775228 was tested in 32,823 controls and 1,837 knee OA cases of European descent. The risk (major) allele at rs10947262 in Caucasian samples was not significantly associated with an odds ratio (OR)  = 1.07 (95%CI 0.94 -1.21; p = 0.28). For rs7775228 the meta-analysis resulted in OR = 0.94 (95%CI 0.81-1.09; p = 0.42) for the allele associated with risk in the Japanese GWAS. In Japanese individuals these two SNPs are in strong linkage disequilibrium (LD) (r(2) = 0.86) with the HLA class II haplotype DRB1*1502 DQA1*0103 DQB1*0601 (frequency 8%). In Caucasian and Chinese samples, using imputed data, these SNPs appear not to be in LD with that haplotype (r(2)<0.07). The rs10947262 and rs7775228 variants are not associated with risk of knee OA in European descent populations and they do not appear tag the same HLA class II haplotype as they do in Japanese individuals.

Purpose of Review: Osteoarthritis is the most common form of arthritis in the elderly and is influenced by both genetic and environmental risk factors. The scope of the present article is to offer an overview of recent developments in the genetic epidemiology of knee and hip osteoarthritis, with particular emphasis on published genomewide association studies (GWAS)., Recent Findings: Candidate gene studies and genomewide linkage studies have identified genes in the bone morphogenetic pathway (e.g. GDF5), the thyroid regulation pathway (DIO2) and apoptotic pathways as involved in genetic risk of large joint osteoarthritis. GWAS have reported structural genes (COL6A4), inflammation-related genes (PTGS2/PLA2G4A) and a locus on chr 7q22 (GPR22 and four other genes in the same linkage disequilibrium block) associated with osteoarthritis., Summary: Genetic studies have identified polymorphisms associated with osteoarthritis and related end-points. These include genes in signaling cascades involved in joint and bone biology, as well as genes in inflammatory pathways and a cluster of five genes in perfect linkage disequilibrium in the 7q22 region.

Osteoarthritis is a major musculoskeletal cause of disability in the elderly, but current therapeutic approaches are insufficient to prevent initiation and progression of the disease. Genetic studies in humans have identified molecules involved in signalling cascades that are important for the pathology of the joint components. These include the bone morphogenetic protein (BMP) signalling, the wingless-type signalling and the thyroid pathway as well as apoptotic-related molecules. There is emerging evidence indicating that inflammatory molecules related to cytokine production, prostaglandin and arachidonic acid metabolism are also involved in susceptibility to osteoarthritis. All of these pathways are likely targets for pharmacological intervention. Genetic variation also affects pain due to osteoarthritis highlighting molecular mechanisms for pain relief. Moreover, combinations of genetic markers can be used to identify individuals at high risk of osteoarthritis and risk of total joint arthroplasty failure, which should facilitate the application of preventive and disease management strategies., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Objective: The ANP32A gene encodes a tumor suppressor molecule that plays a regulatory role in apoptosis and interferes with canonical Wnt signaling in vitro. We undertook this study to test whether genetic variation at ANP32A was associated with osteoarthritis (OA) in women., Methods: Single-nucleotide polymorphisms (SNPs) in the ANP32A gene were genotyped in 438 control women, 425 women with total knee replacements (TKRs), and 537 women with total hip replacements (THRs) from the Nottingham case-control study as well as in 820 women from the population-based Chingford Study cohort for whom hip and knee radiographs were available. The most highly associated SNP was further tested in women from the Rotterdam Study (131 with THRs, 633 with knee OA, and 1,567 controls) and the TwinsUK Study cohort (67 with THRs, 43 with TKRs, and 358 controls), for a total of 2,170 patients with OA and 2,849 controls., Results: The ANP32A transcript was abundantly expressed in normal and OA articular cartilage. Three SNPs in the ANP32A gene were significantly associated in Nottingham patients with hip OA, but not knee OA. One of these (rs7164503) was associated with hip and knee OA in the Chingford Study cohort and with THR in the TwinsUK Study cohort, but the association was not statistically significant in the Rotterdam Study. When we combined hip data from all 4 cohorts, we found that the minor allele of rs7164503 was associated with a significantly lower risk of hip OA (Mantel-Haenszel odds ratio 0.67 [95% confidence interval 0.53-0.84], P < 3.8 x 10(-4)) and that a similar trend was observed for knee OA (Mantel-Haenszel odds ratio 0.87 [95% confidence interval 0.73-1.01], P < 0.055)., Conclusion: Our results provide evidence suggesting that ANP32A is involved in the pathogenesis of OA of the hip.

Osteoarthritis (OA) is the most prevalent form of arthritis in the elderly. A large body of evidence, including familial aggregation and classic twin studies, indicates that primary OA has a strong hereditary component that is likely polygenic in nature. Traits related to OA, such as longitudinal changes in cartilage volume and progression of radiographic features, are also under genetic control. In recent years several linkage analyses and candidate gene studies have been performed and unveiled some of the specific genes involved in disease risk, such as FRZB and GDF5. This article discusses the impact that future genome-wide association scans can have on our understanding of the pathogenesis of OA and on identifying individuals at high risk for developing severe OA.

Osteoarthritis (OA) is the most prevalent form of arthritis in the elderly. A large body of evidence, including familial aggregation and classic twin studies, indicates that primary OA has a strong hereditary component that is likely polygenic in nature. Furthermore, traits related to OA, such as longitudinal changes in cartilage volume and progression of radiographic features, are also under genetic control. In recent years, several linkage analysis and candidate gene studies have been performed and have unveiled some of the specific genes involved in disease risk, such as FRZB and GDF5. The authors discuss the impact that future genome-wide association scans can have on our understanding of the pathogenesis of OA and on identifying individuals at high risk for developing severe OA.

Our aim is to review methods to optimize detection of all disease genes in a genetic region. As a starting point, we assume there is sufficient evidence from linkage and/or association studies, based on significance levels or replication studies, for the involvement in disease risk of the genetic region under study. For closely linked markers, there will often be multiple associations with disease, and linkage analyses identify a region rather than the specific disease-predisposing gene. Hence, the first task is to identify the primary (major) disease-predisposing gene or genes in a genetic region, and single nucleotide polymorphisms thereof, that is, how to distinguish true associations from those that are just due to linkage disequilibrium with the actual disease-predisposing variants. Then, how do we detect additional disease genes in this genetic region? These two issues are of course very closely interrelated. No existing programs, either individually or in aggregate, can handle the magnitude and complexity of the analyses needed using currently available methods. Further, even with modern computers, one cannot study every possible combination of genetic markers and their haplotypes across the genome, or even within a genetic region. Although we must rely heavily on computers, in the final analysis of multiple effects in a genetic region and/or interaction or independent effects between unlinked genes, manipulation of the data by the individual investigator will play a crucial role. We recommend a multistrategy approach using a variety of complementary methods described below.

Objective: To assess whether the association of genetic polymorphisms with osteoarthritis (OA) in other populations could be replicated in a large, multicenter, mixed-sex, case-control study of clinical knee OA., Methods: Genetic polymorphisms in OA candidate genes were genotyped in 298 men and 305 women, ages 50-86 years, all of whom had a diagnosis of knee OA as assessed clinically and radiographically, and in 300 male and 299 female control subjects matched for age and ethnicity. Allele and haplotype frequencies for 5 genes (ASPN, CALM1, COL2A1, COMP, and FRZB) previously tested for association with hip and/or knee OA in other populations were compared between patients and control subjects, analyzing men and women separately., Results: The same FRZB 2-marker single-nucleotide polymorphism (SNP) haplotype associated with hip OA in other populations of Caucasian women was shown to increase the risk of knee OA among the women (but not the men) in the current study (odds ratio [OR] 2.87, P < 0.04). The CALM1 SNP, which affects the risk of hip OA in Japanese individuals, was not shown to be associated with susceptibility to OA in men or women. COL2A1 haplotypes were demonstrated to be associated with a decreased risk of knee OA in men (OR 0.68, P < 0.005) but not in women. COMP haplotypes that were associated with susceptibility to knee OA were different in men and women (P < 0.014 and P < 0.032, respectively). A meta-analysis of these data and those from previously published reports indicated a strong association between the FRZB G324 allele (P < 0.0003) and suggested that an ASPN allele is protective against the risk of knee OA in Caucasians (P < 0.02)., Conclusion: Our results indicate that genetic polymorphisms affecting knee OA vary between populations (Japanese versus Caucasian) and sexes and indicate a role for ASPN, COMP, FRZB, and COL2A1 in Caucasians.

Tumor necrosis factor (TNF) and lymphotoxin alpha (LT-alpha) are immunomodulators that have been hypothesized to contribute to susceptibility to type 1 diabetes (T1D). Several polymorphisms in the TNF and LT-alpha loci have been extensively studied for T1D association, with conflicting reports. In this study, we examined two TNF variants and one LT-alpha variant for T1D association in 283 Caucasian, multiplex T1D families for which complete human leukocyte antigen (HLA) genotyping data are available. Initially, association with T1D was seen for LT-alpha A1069G (intron A, p=0.011, rs909253) and TNF G(-308)A (p<1x10(-5), rs1800629), but no association was observed for TNF G(-238)A (rs361525). After adjusting the data for linkage disequilibrium (LD) with DRB1-DQB1 haplotypes, however, only one polymorphism, TNF G(-238)A showed significant association with T1D (p<0.006). When HLA-DR3 haplotypes were examined, the A allele of TNF G(-238)A was significantly overtransmitted to affected offspring (p<0.009). Including HLA-B data in the analysis revealed that TNF (-238)A is present exclusively on DR3 haplotypes that also carry HLA-B18. Transmission proportion of B18-DR3 haplotypes did not differ between those with TNF (-238)A and those with TNF (-238)G. Thus, variation at TNF does not affect the T1D risk for B18-DR3 haplotypes, and the apparent association of TNF(-238)A with T1D may simply reflect its presence on a high-risk haplotype.

Objective: To perform a large-scale association analysis of single-nucleotide polymorphisms (SNPs) in patients with radiographically defined osteoarthritis (OA) of the knee., Methods: We examined >25,000 SNPs located within approximately 14,000 genes for associations with radiographically defined knee OA, using polymerase chain reaction and MassExtend amplification techniques. Allele frequencies were estimated initially in DNA pools from 335 female patients with knee OA and 335 asymptomatic and radiographically negative female control subjects. All were of northern European ancestry. Significant allele frequency differences were validated by genotyping of individual DNA samples. Confirmed significant findings were verified in 2 additional case-control samples from the UK (443 cases and 303 controls) and Newfoundland (346 cases and 264 controls). Chondrosarcoma cell lines were used to test for potential differences in gene expression., Results: The marker most strongly associated with the risk of knee OA was rs912428, a C/T polymorphism in intron 1 of LRCH1, a gene on chromosome 13q14 that encodes a novel protein of as-yet-unknown function. The frequency of the T allele compared with controls was consistently increased by 40% across all 3 case-control groups. Additional subanalyses in case-control samples with hip OA and hand OA suggested similar trends, but did not reach statistical significance. Association fine-mapping using 10 additional SNPs in LRCH1 confirmed intron 1 as the region of highest association but failed to reveal variations with significance stronger than the marker SNP, as did the haplotype analysis. LRCH1 was not up-regulated or overexpressed in chondrosarcoma cell lines exposed to inflammatory stimuli, suggesting a possible structural role., Conclusion: A genetic variant in LRCH1 was consistently associated with knee OA in 3 samples from 2 populations. Our results also suggest that the same association with OA may exist at other sites. Additional genetic and experimental work is needed to elucidate the precise mechanism by which the LRCH1 gene influences OA risk.

Objective: Osteoarthritis (OA) is recognized to have a genetic component, and in this study, we aimed to replicate in a case-control study of men and women with clinical knee OA genetic associations in 12 candidate genes previously reported to be associated with OA., Methods: Twenty-five single-nucleotide polymorphisms were genotyped in 298 men and 305 women ages 50-86 who were diagnosed as having knee OA, as assessed both clinically and radiographically, and in 297 men and 299 women matched for age and ethnicity (controls). Standardized anteroposterior radiographs of the knee in extension were performed on each of the cases, and all cases met the American College of Rheumatology criteria for OA of the knee. Genotype and haplotype frequencies in cases and controls were compared separately in men and women. The 12 genes tested were AACT, ADAM12, BMP2, CD36, CILP, COX2, ESR1, NCOR2, OPG, TNA, TNFAIP6, and VDR., Results: Eight of the candidate genes were associated in women and 5 in men, and only 3 genes (TNFAIP6, NCOR2, and CD36) were not significantly associated in either sex. The strongest associations in terms of odds ratios (ORs) were a haplotype in ADAM12 (OR 7.1 [95% confidence interval (95% CI) 3.3-33.8]) and a haplotype in ESR1 (OR 3.6 [95% CI 1.18-10.98]) in women. The same ADAM12 haplotype (OR 2.54 [95% CI 1.2-5.4]) and a haplotype in the CILP gene (OR 0.38 [95% CI 0.23-0.62]) were the strongest associations in men., Conclusion: We found that genes previously identified by their association with subclinical features of knee OA or progression were also associated with clinical knee OA. These genetic associations may identify individuals at a particularly high risk of developing knee OA.

Study Design: A candidate gene association study in a longitudinal cohort., Objective: To investigate the association between polymorphisms at 25 candidate genes and progression of individual radiographic features of lumbar disc degeneration (LDD)., Summary of Background Data: LDD is characterized radiographically by the presence of osteophytes and disc space narrowing and is known to have a genetic component. Because of the high prevalence of radiographic features, progression may be a more useful phenotype clinically to study than prevalence itself., Methods: We tested the effect on radiographic progression of LDD of polymorphisms in 25 genes, 24 of which had been previously tested with regards to knee osteoarthritis. The progression traits used were the change in radiographic grade over 9 years in osteophytes, disc space narrowing, and summary Kellgren-Lawrence grade. Lumbar spine radiographs (L1-L5) at baseline and at follow-up were read for 720 women genotyped at the 25 genes participating in the Chingford study., Results: Polymorphisms in MMP3, TIMP1, and COX2, which encode molecules involved in inflammatory pathways, were associated with radiographic progression of LDD. The strongest associations observed (statistically significant after correcting for multiple comparisons) were between COX2 and change in osteophyte grade (P < 0.001) and Kellgren-Lawrence grade (P < 2 x 10(-5)), and between the genes for vitamin D receptor (P < 0.002) and a thrombospondin (THSD2) (P < 0.002) and change in osteophyte grade., Conclusions: Our results suggest a role for genes regulating inflammatory pathways in the radiographic progression of spine degeneration. This could prove a fruitful area for future therapeutics for the spine and other joints.

Alleles of human leukocyte antigen (HLA) class II genes are well known to affect susceptibility to type 1 diabetes (T1D), but less is known about the contribution of HLA class I alleles to T1D susceptibility. In this study, molecular genotyping was performed at the HLA-B and HLA-C loci for 283 multiplex Caucasian families, previously typed for HLA-A and the class II loci. Allele frequencies were compared between affected siblings and affected family-based controls. Linkage disequilibrium coefficients were calculated for HLA-B-HLA-C haplotypes and for class I-lass II haplotypes. After adjustment for linkage disequilibrium, the following alleles remain associated with T1D: B*1801, B*3906, B*4403, C*0303, C*0802, and C*1601. B and C allele associations were tested for certain T1D-associated DRB1-DQB1 haplotypes, with the following results: B*3801 is protective on DRB1*0401-DQB1*0302 haplotypes, both C*0701 and C*0702 are predisposing on DRB1*0404-DQB1*0302 haplotypes, and B*3906 is predisposing on DRB1*0801-DQB1*0402 haplotypes. As with previous results for HLA-A, HLA-B and HLA-C are associated with age at T1D onset (mean 11.6 +/- 0.3 years). The protective allele B*4403 was associated with older age at onset (15.1 years; p < 0.04), and the predisposing alleles C*0702 and B*3906 were associated with younger age at onset (9.5 years, p < 0.001; and 7.8 years, p < 0.002, respectively). These data support a role for HLA class I alleles in susceptibility to and age at onset of T1D.

The PTPN22 (protein tyrosine phosphatase N22) gene encodes the protein tyrosine phosphatase Lyp. One function of Lyp is downregulation of T-cell signaling through its interaction with the negative regulatory kinase C-terminal Src tyrosine kinase (Csk). A single nucleotide polymorphism in the PTPN22 gene, C1858T, encodes products with different Csk binding affinities. Disease association of the PTPN22 1858T allele has been reported in case-control studies of three different autoimmune disorders: type 1 diabetes (T1D), rheumatoid arthritis, and systemic lupus erythematosus. In this study, a set of 341 white, multiplex T1D families were genotyped for the C1858T single nucleotide polymorphism of PTPN22, and transmission disequilibrium test analysis revealed significant association (p = 0.005) of the T allele with T1D. No effects of parent of origin, sex of patient, or human leukocyte antigen genotype (high-risk human leukocyte antigen DR3/DR4 vs non-DR3/DR4) were observed. However, transmission of the T allele was significantly increased in the subset of patients who also carried at least one copy of the TCF7 883A allele, another allele that is important in regulating T-cell responses and that is associated with T1D. These results are consistent with the hypothesis that individuals lacking the C allele of PTPN22 may have reduced capacity to downregulate T-cell responses and may therefore be more susceptible to autoimmunity.

Genetic associations between type 1 diabetes and alleles at the HLA class II locus DPB1 have been previously reported. Observed associations could be due to variation in the DPB1 locus itself or to linkage disequilibrium (LD) between DPB1 alleles and other susceptibility loci. One measure of whether the association of an allele with a disease reflects a true effect of the locus or is simply due to LD is the observation of that association in multiple ethnic groups. Previous type 1 diabetes associations have been reported for DPB1*0301 and DPB1*0202 (predisposing) and for DPB1*0402 (protective). In this study, results are reported from testing these associations in three different sample sets: 1) Puerto Rican case and control subjects, 2) Mexican-American simplex families, and 3) high-risk (DR3/DR4) individuals with and without an affected relative. DPB1*0301 was associated in all three groups, even after accounting for LD with DRB1-DQB1. DPB1*0202 and DPB1*0402 were positively and negatively associated, respectively, in two of the three populations. These results suggest that the observed DPB1 associations, especially that of the DPB1*0301 allele, with type 1 diabetes are likely to be true associations. This supports the concept that multiple genes in the HLA region can affect type 1 diabetes susceptibility.

In the search for genes involved in type 1 diabetes (T1D), other than the well-established risk alleles at the human leukocyte antigen loci, we have investigated the association and interaction of polymorphisms in genes involved in the IL4/IL13 pathway in a sample of 90 Filipino patients with T1D and 94 controls. Ten single-nucleotide polymorphisms (SNPs), including two promoter SNPs in the IL4R locus on chromosome 16p11, one promoter SNP in the IL4 locus on chromosome 5q31, and four SNPs--including two promoter SNPs--in the IL13 locus on chromosome 5q31 were examined for association, linkage disequilibrium, and interaction. We found that both individual SNPs (IL4R L389L; odds ratio [OR] 0.34; 95% confidence interval [CI] 0.17-0.67; P=.001) and specific haplotypes both in IL4R (OR 0.10; 95% CI 0-0.5; P=.001) and for the five linked IL4 and IL13 SNPs (OR 3.47; P=.004) were strongly associated with susceptibility to T1D. Since IL4 and IL13 both serve as ligands for a receptor composed, in part, of the IL4R alpha chain, we looked for potential epistasis between polymorphisms in the IL4R locus on chromosome 16p11 and the five SNPs in the IL4 and IL13 loci on chromosome 5q31 and found, through use of a logistic-regression model, significant gene-gene interactions (P=.045, corrected for multiple comparisons by permutation analysis). Our data suggest that the risk for T1D is determined, in part, by polymorphisms within the IL4R locus, including promoter and coding-sequence variants, and by specific combinations of genotypes at the IL4R and the IL4 and IL13 loci.

Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10-8) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs496547), while the other two (DOT1L and SUPT3H/RUNX2) were previously identified. A systematic prioritization for underlying causal genes was performed using diverse lines of evidence. Exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. In addition, TGFA, FGFR3 and PIK3R1 were differentially expressed in OA cartilage lesions versus non-lesioned cartilage in the same individuals. In conclusion, we identified four novel loci (TGFA, PIK3R1, FGFR3 and TREH) and confirmed two loci known to be associated with cartilage thickness.The identified associations were not caused by rare exonic variants. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies.

ObjectivesTo identify genetic associations with hip osteoarthritis (HOA), we performed a meta-analysis of genome-wide association studies (GWAS) of HOA.MethodsThe GWAS meta-analysis included approximately 2.5 million imputed HapMap single nucleotide polymorphisms (SNPs). HOA cases and controls defined radiographically and by total hip replacement were selected from the Osteoporotic Fractures in Men (MrOS) Study and the Study of Osteoporotic Fractures (SOF) (654 cases and 4697 controls, combined). Replication of genome-wide significant SNP associations (p ≤5×10(-8)) was examined in five studies (3243 cases and 6891 controls, combined). Functional studies were performed using in vitro models of chondrogenesis and osteogenesis.ResultsThe A allele of rs788748, located 65 kb upstream of the IGFBP3 gene, was associated with lower HOA odds at the genome-wide significance level in the discovery stage (OR 0.71, p=2×10(-8)). The association replicated in five studies (OR 0.92, p=0.020), but the joint analysis of discovery and replication results was not genome-wide significant (p=1×10(-6)). In separate study populations, the rs788748 A allele was also associated with lower circulating IGFBP3 protein levels (p=4×10(-13)), suggesting that this SNP or a variant in linkage disequilibrium could be an IGFBP3 regulatory variant. Results from functional studies were consistent with association results. Chondrocyte hypertrophy, a deleterious event in OA pathogenesis, was largely prevented upon IGFBP3 knockdown in chondrocytes. Furthermore, IGFBP3 overexpression induced cartilage catabolism and osteogenic differentiation.ConclusionsResults from GWAS and functional studies provided suggestive links between IGFBP3 and HOA.

ObjectivesOsteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects.MethodsWe performed a two-stage meta-analysis on more than 78,000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for 'in silico' or 'de novo' replication. Besides the main analysis, a stratified by sex analysis was performed to detect possible sex-specific signals. Meta-analysis was performed using inverse-variance fixed effects models. A random effects approach was also used.ResultsWe accumulated 11,277 cases of radiographic and symptomatic hip OA. We prioritised eight single nucleotide polymorphism (SNPs) for follow-up in the discovery stage (4349 OA cases); five from the combined analysis, two male specific and one female specific. One locus, at 20q13, represented by rs6094710 (minor allele frequency (MAF) 4%) near the NCOA3 (nuclear receptor coactivator 3) gene, reached genome-wide significance level with p=7.9×10(-9) and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p=5.6×10(-8)) and follow-up studies (p=7.3×10(-4)). We showed that this gene is expressed in articular cartilage and its expression was significantly reduced in OA-affected cartilage. Moreover, two loci remained suggestive associated; rs5009270 at 7q31 (MAF 30%, p=9.9×10(-7), OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2×10(-6), OR=1.27 in male specific analysis).ConclusionsNovel genetic loci for hip OA were found in this meta-analysis of GWAS.