Abstract
Osteoarthritis is a common complex disease imposing a large public-health burden. Here, we performed a genome-wide association study for osteoarthritis, using data across 16.5 million variants from the UK Biobank resource. After performing replication and meta-analysis in up to 30,727 cases and 297,191 controls, we identified nine new osteoarthritis loci, in all of which the most likely causal variant was noncoding. For three loci, we detected association with biologically relevant radiographic endophenotypes, and in five signals we identified genes that were differentially expressed in degraded compared with intact articular cartilage from patients with osteoarthritis. We established causal effects on osteoarthritis for higher body mass index but not for triglyceride levels or genetic predisposition to type 2 diabetes.
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Acknowledgements
This research was conducted by using the UK Biobank Resource under application no. 9979. This work was funded by the Wellcome Trust (WT098051). We are grateful to R. Brooks, J. Choudhary and T. Roumeliotis for their contribution to the functional genomics data collection. The Human Research Tissue Bank is supported by the NIHR Cambridge Biomedical Research Centre. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Organization for Health Research and Development (ZonMw); the Netherlands Genomics Initiative (NGI)/Netherlands Organisation of Scientific Research (NWO); the Netherlands Consortium for Healthy Aging (NCHA), Research Institute for Diseases in the Elderly (RIDE); the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam.
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Association analyses: E. Zengini, K.H., I.T., L.S., J.S., S.H. and A.G. Mendelian randomization: F.P.H. and G.D.S. Functional genomics sample collection: A.McC., J.M.W. and E. Zeggini. Functional genomics analyses: J.S. and L.S. Endophenotype analyses: C.G.B., A.G.U. and J.B.J.v.M. Replication analyses: U.S., T.I., H.J., U.T. and K.S. Bioinformatics: A.G., D.S. and B.K. Student supervision: K.H., G.C.B., G.D.S., J.M.W. and E. Zeggini. Manuscript writing: E. Zengini, K.H., I.T., J.S., F.P.H., L.S., C.G.B., U.S., D.S., J.B.J.v.M., G.D.S., J.M.W. and E. Zeggini.
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U.T., U.S. and K.S. are employees of deCODE genetics/Amgen.
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Supplementary Figure 1
Study-design flowchart. OA: Osteoarthritis; UKBB: UK Biobank; n: sample size; SNP: single nucleotide polymorphism; QC: quality control; 1000G: 1000 Genomes Project; AF: allele frequency; PC: principal component.
Supplementary Figure 2 Manhattan plots
a) Self-reported OA; b) Hospital diagnosed OA; c) Hospital diagnosed hip OA; d) Hospital diagnosed knee OA; e) Hospital diagnosed hip and/or knee OA; the horizontal line denotes the genome-wide significance threshold. OA: osteoarthritis.
Supplementary Figure 3 QQ plots
a) Self-reported OA; b) Hospital diagnosed OA; c) Hospital diagnosed hip OA; d) Hospital diagnosed knee OA; e) Hospital diagnosed hip and/or knee OA. OA: Osteoarthritis; N: number of variants analysed following quality control; MAF: minor allele frequency; Lambda: genomic inflation factor.
Supplementary Figure 4 Genome-wide-association summary statistics of the self-reported and sensitivity analysis for self-reported OA
a) qq plot for self-reported OA; b) Manhattan plot for self-reported OA; c) qq plot for the sensitivity analysis of self-reported OA; d) Manhattan plot for the sensitivity analysis of self-reported OA. OA: Osteoarthritis; N: number of variants analysed following quality control; MAF: minor allele frequency; Lambda: genomic inflation factor; the horizontal line denotes the genome-wide significance threshold.
Supplementary Figure 5 Correlation across annotations and corresponding correlations across PPAs in an exemplary fine-mapped region (indexed by rs2820436)
a: Histogram of all annotations (CADD, CADD-Phred, Eigen, Eigen-Phred, EigenPC, EigenPC-Phred, Combined CADD-Phred and Eigen-Phred) and scatter plots between pairs of annotations. b: Pearson correlation coefficient of the posterior probability of association (PPA) across variants in the fine-mapped region for the different annotations used.
Supplementary Figure 6 Gene-set representation onto protein–protein-interaction networks
Large coloured circles represent the proteins of each gene set, while grey small circles represent proteins found in the InWeb database (high-confidence interaction set) that have a direct (proteins that directly bind each other) or indirect (any other proteins connected to the direct network) connectivity. a) Anatomical structure morphogenesis b) Ion channel transport c) Activation of MAPK activity d) Histidine metabolism e) Recruitment of mitotic centrosome proteins and complexes.
Supplementary Figure 7 LD-regression Venn diagram
Using LD regression, we identify 23 phenotypes with significant genetic correlation with self-reported OA, 31 with hospital diagnosed OA, 26 with hospital diagnosed hip and/or knee OA, 23 with hospital diagnosed knee OA, and 4 with hospital diagnosed hip OA, with large overlap between the identified phenotypes (35 phenotypes in total; significance at 5% FDR). OA: osteoarthritis.
Supplementary Figure 8 ORs and risk-allele frequencies for established and novel OA-associated variants
The sibling relative risk ratio (λs) for each variant is shown by the different size of each circle. The darker color of the circles shows the percentage of variance explained on the liability scale (h2L) (calculated assuming 10% prevalence of OA). Totals of λs and h2L are shown at the top. OA: osteoarthritis.
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–8, Supplementary Note and Supplementary Tables 1, 4–6, 8–10, 19–21 and 28–30
Supplementary Table 27: Results of one-sample MR analyses in UK Biobank
Regression coefficients are shown for continuous exposure phenotypes, and odds ratio are shown for binary exposure phenotypes. MR: Mendelian randomization; OA: osteoarthritis; OR: odds ratio; SE: standard error; CI: confidence interval; N: sample size
Supplementary Table 2
ICD10 code exclusion criteria for the definition of controls
Supplementary Table 3
ICD10 code inclusion criteria for the definition of cases
Supplementary Table 7: Association summary statistics and power calculations for established OA loci present in UK Biobank
RA, risk allele; RAF, risk allele frequency; OR, odds ratio; CI, confidence interval; OA, osteoarthritis; EA, effect allele; EAF, effect allele frequency; N/A, not available a: variant studied separately in Asian and European populations b: RA is defined as the allele with OR >1 in the respective study c: Allele on reverse strand d: Power is calculated on the basis of the EAF and OR estimates from the UK Biobank OA datasets and assuming 4 controls per case e: Power is calculated on the basis of the reported OR estimates from each discovery study (referenced in the last column) and effect allele frequencies from the UK Biobank OA datasets respectively. For rs143383 we used the OR from the European population. f: Power is calculated on the basis of the replication OR estimates from each discovery study and effect allele frequencies from the UK Biobank OA datasets, respectively. For rs11842874 we used the OR from the "arcOGEN replication set1" replication dataset. For rs12901071 we used the relevant OR from the deCODE replication dataset. For rs143383 we used the relevant OR from the European population and particularly the OR from the "Ten studies from large-scale meta-analysis" replication cohort. For rs7639618 we used the OR from the Japanese replication dataset. g: The number of cases required for 80% power is calculated on the basis of EAF and OR estimates from the UK Biobank OA datasets and assuming 4 controls per case
Supplementary Table 11: Association summary statistics for the 173 prioritised SNPs in the discovery, replication and overall meta-analysis for self-reported OA
OA: Osteoarthritis; EA: Effect allele; EAF: Effect allele frequency; OR: Odds ratio; PV: p-value; chr: chromosome
Supplementary Table 12: Association summary statistics for the 173 prioritised SNPs in the discovery, replication and overall meta-analysis for hospital diagnosed OA
OA: osteoarthritis; EA: Effect allele; EAF: Effect allele frequency; OR: Odds ratio; PV: p-value; chr: chromosome
Supplementary Table 13: Association summary statistics for the 173 prioritised SNPs in the discovery, replication and overall meta-analysis for hospital diagnosed knee and/or hip OA
OA: osteoarthritis; EA: Effect allele; EAF: Effect allele frequency; OR: Odds ratio; PV: p-value; chr: chromosome
Supplementary Table 14: Association summary statistics for the 173 prioritised SNPs in the discovery, replication and overall meta-analysis for hospital diagnosed hip OA
OA: osteoarthritis; EA: Effect allele; EAF: Effect allele frequency; OR: Odds ratio; PV: p-value; chr: chromosome
Supplementary Table 15: Association summary statistics for the 173 prioritised SNPs in the discovery, replication and overall meta-analysis for hospital diagnosed knee OA
OA: osteoarthritis; EA: Effect allele; EAF: Effect allele frequency; OR: Odds ratio; PV: p-value; chr: chromosome
Supplementary Table 16: eQTL analysis in GTEx
Significant eQTL associations (at 5% FDR) for the 9 osteoarthritis signals as provided by the GTEx portal
Supplementary Table 17: Detailed fine-mapping results for the OA-associated loci
For each variant (columns A-D), we report its association summary statistics in UK Biobank (G-K), its predicted consequence (L) and the nearest gene (M), as well as the region centred around the variant used for the fine mapping (N-O). For each region, we report the Bayes’ factor (F) and the posterior probability that there be at least 1 causal variant in the region (E), followed by the variants (P) in the 95% credible intervals (defined to contain the minimum set of variants that jointly have at least 95% probability of including the causal variant). Summary statistics (S-W), Bayes’ factors (Q) and the posterior probabilities of association (PPA, column R) of each variant in the credible intervals are also reported. For regions in which the sum of probabilities of causality of all variants in the fine-mapped region is less than 0.95, we report the lower confidence interval achieved. EA: effect allele; NEA: non-effect allele; EAF: affect allele frequency; SE: standard error; N: sample size; BF: Bayes factor; PPA: posterior probability of association; OA: osteoarthritis
Supplementary Table 18: Fine-mapping results for the OA-associated loci
For each index variant (columns A-D), we report its predicted consequence (E) and the nearest protein coding gene (F). For each region constructed around the index variant, we report the Bayes’ factor (H) and the posterior probability that there be at least 1 causal variant in the region (G). Column I reports the number of variants in the resulting 95% credible intervals (defined to contain the minimum set of variants that jointly have at least 95% probability of including the causal variant). For each region, the number of variants in the credible interval with posterior probability >0.1, and their combined probability are listed in column J and K, respectively. Properties (L-Q, T-X), summary statistics (Y-AA), Bayes’ factors (R) and the posterior probabilities of association (S) of the top variants in the credible intervals are also reported. Only variants with probability of causality >0.1 are shown, or the top variant if its probability of causality is
Supplementary Table 22: Description of studies used to identify genetic instruments for MR analyses
MR: Mendelian randomization. aNot available in MR-Base for this record, so this value was extracted from another GWAS of the same phenotype (PMID 22504420) available in MR-Base
Supplementary Table 23: Summary association results used in the two-sample MR analyses
MR: Mendelian randomization; EA: effect allele; NEA: non-effect allele; EAF: effect allele frequency; SE: standard error; OA: osteoarthritis
Supplementary Table 24: Summary statistics of each set of genetic instruments used in the two-sample MR analyses
MR: Mendelian randomization; OA: osteoarthritis
Supplementary Table 25: Causal OR estimates of OA for each exposure phenotype from two-sample MR analyses
For exposure phenotypes with at least 10 genetic instruments, all methods were applied. For exposure phenotypes with less than 10 genetic instruments, only the inverse-variance weighting method was applied to calculate a pooled causal effect estimate, and only the heterogeneity test was used to assess horizontal pleiotropy. For exposure phenotypes with only one genetic instrument, the ratio method was used to calculate the causal effect estimate. bStandard error of the ln(OR). ϕ: tunning parameter of the mode-based estimate. The smaller the value of ϕ, the more stringent the analysis is. OR: odds ratio; OA: osteoarthritis; MR: Mendelian randomization; SE: standard error; CI: confidence interval
Supplementary Table 26: Power (%) to detect different OR of OA in MR analyses using the inverse-variance weighting method
OR: odds ratio; OA: osteoarthritis; MR: Mendelian randomization
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Zengini, E., Hatzikotoulas, K., Tachmazidou, I. et al. Genome-wide analyses using UK Biobank data provide insights into the genetic architecture of osteoarthritis. Nat Genet 50, 549–558 (2018). https://doi.org/10.1038/s41588-018-0079-y
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DOI: https://doi.org/10.1038/s41588-018-0079-y
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