Genome-Wide Association Study of Radiographic Knee Osteoarthritis in North American Caucasians

Michelle S. Yau, Laura M. Yerges-Armstrong, Youfang Liu, Cora E. Lewis, David J. Duggan, Jordan B. Renner, James Torner, David T. Felson, Charles E. McCulloch, C. Kent Kwoh, Michael C. Nevitt, Marc C. Hochberg, Braxton D. Mitchell, Joanne M. Jordan, Rebecca D. Jackson

Research output: Contribution to journalArticle

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Abstract

Objective: A major barrier to genetic studies of osteoarthritis (OA) is the need to obtain large numbers of individuals with standardized radiographic evaluations for OA. To address this gap, we performed a genome-wide association study (GWAS) of radiographically defined tibiofemoral knee OA in 3,898 cases and 3,168 controls from 4 well-characterized North American cohorts, and we performed replication analysis of previously reported OA loci. Methods: We performed meta-analysis using a 2-stage design. Stage 1 (discovery) consisted of a GWAS meta-analysis of radiographic knee OA carried out in the Osteoarthritis Initiative and the Johnston County Osteoarthritis Project. Knee OA was defined as definite osteophytes and possible joint space narrowing or total joint replacement in one or both knees. Stage 2 (validation) was performed in the Multicenter Osteoarthritis Study and the Genetics of Osteoarthritis study. We genotyped lead meta-analysis variants (P ≤ 1 × 10−4) from stage 1 and tested the association between these variants and knee OA. We then combined results from all cohorts in a meta-analysis. Results: Lead variants from stage 1, representing 49 unique loci, were analyzed in stage 2; none met genome-wide significance in the combined analysis of stage 1 and stage 2. We validated 1 locus (rs4867568 near LSP1P3) with nominal significance (P < 0.05), which was also our top finding in the combined meta-analysis (odds ratio [OR] 0.84 [95% confidence interval (95% CI) 0.79–0.91], P = 3.02 × 10−6). We observed nominally significant associations (P < 0.05) with 3 previously reported OA loci: rs143383 in GDF5 (OR 1.12 [95% CI 1.04–1.21], P = 2.13 × 10−3), rs835487 in CHST11 (OR 0.93 [95% CI 0.85–0.99], P = 0.03), and rs8044769 in FTO (OR 1.10 [95% CI 1.03–1.19], P = 6.13 × 10−3). Conclusion: These findings provide suggestive evidence of a novel knee OA locus and confirm previously reported associations in GDF5, CHST11, and FTO.

LanguageEnglish (US)
Pages343-351
Number of pages9
JournalArthritis and Rheumatology
Volume69
Issue number2
DOIs
StatePublished - Feb 1 2017

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Knee Osteoarthritis
Genome-Wide Association Study
Osteoarthritis
Meta-Analysis
Odds Ratio
Confidence Intervals
Replacement Arthroplasties
Osteophyte
Multicenter Studies
Knee
Joints
Genome

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology

Cite this

Yau, M. S., Yerges-Armstrong, L. M., Liu, Y., Lewis, C. E., Duggan, D. J., Renner, J. B., ... Jackson, R. D. (2017). Genome-Wide Association Study of Radiographic Knee Osteoarthritis in North American Caucasians. Arthritis and Rheumatology, 69(2), 343-351. DOI: 10.1002/art.39932

Genome-Wide Association Study of Radiographic Knee Osteoarthritis in North American Caucasians. / Yau, Michelle S.; Yerges-Armstrong, Laura M.; Liu, Youfang; Lewis, Cora E.; Duggan, David J.; Renner, Jordan B.; Torner, James; Felson, David T.; McCulloch, Charles E.; Kwoh, C. Kent; Nevitt, Michael C.; Hochberg, Marc C.; Mitchell, Braxton D.; Jordan, Joanne M.; Jackson, Rebecca D.

In: Arthritis and Rheumatology, Vol. 69, No. 2, 01.02.2017, p. 343-351.

Research output: Contribution to journalArticle

Yau, MS, Yerges-Armstrong, LM, Liu, Y, Lewis, CE, Duggan, DJ, Renner, JB, Torner, J, Felson, DT, McCulloch, CE, Kwoh, CK, Nevitt, MC, Hochberg, MC, Mitchell, BD, Jordan, JM & Jackson, RD 2017, 'Genome-Wide Association Study of Radiographic Knee Osteoarthritis in North American Caucasians' Arthritis and Rheumatology, vol. 69, no. 2, pp. 343-351. DOI: 10.1002/art.39932
Yau MS, Yerges-Armstrong LM, Liu Y, Lewis CE, Duggan DJ, Renner JB et al. Genome-Wide Association Study of Radiographic Knee Osteoarthritis in North American Caucasians. Arthritis and Rheumatology. 2017 Feb 1;69(2):343-351. Available from, DOI: 10.1002/art.39932
Yau, Michelle S. ; Yerges-Armstrong, Laura M. ; Liu, Youfang ; Lewis, Cora E. ; Duggan, David J. ; Renner, Jordan B. ; Torner, James ; Felson, David T. ; McCulloch, Charles E. ; Kwoh, C. Kent ; Nevitt, Michael C. ; Hochberg, Marc C. ; Mitchell, Braxton D. ; Jordan, Joanne M. ; Jackson, Rebecca D./ Genome-Wide Association Study of Radiographic Knee Osteoarthritis in North American Caucasians. In: Arthritis and Rheumatology. 2017 ; Vol. 69, No. 2. pp. 343-351
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abstract = "Objective: A major barrier to genetic studies of osteoarthritis (OA) is the need to obtain large numbers of individuals with standardized radiographic evaluations for OA. To address this gap, we performed a genome-wide association study (GWAS) of radiographically defined tibiofemoral knee OA in 3,898 cases and 3,168 controls from 4 well-characterized North American cohorts, and we performed replication analysis of previously reported OA loci. Methods: We performed meta-analysis using a 2-stage design. Stage 1 (discovery) consisted of a GWAS meta-analysis of radiographic knee OA carried out in the Osteoarthritis Initiative and the Johnston County Osteoarthritis Project. Knee OA was defined as definite osteophytes and possible joint space narrowing or total joint replacement in one or both knees. Stage 2 (validation) was performed in the Multicenter Osteoarthritis Study and the Genetics of Osteoarthritis study. We genotyped lead meta-analysis variants (P ≤ 1 × 10−4) from stage 1 and tested the association between these variants and knee OA. We then combined results from all cohorts in a meta-analysis. Results: Lead variants from stage 1, representing 49 unique loci, were analyzed in stage 2; none met genome-wide significance in the combined analysis of stage 1 and stage 2. We validated 1 locus (rs4867568 near LSP1P3) with nominal significance (P < 0.05), which was also our top finding in the combined meta-analysis (odds ratio [OR] 0.84 [95{\%} confidence interval (95{\%} CI) 0.79–0.91], P = 3.02 × 10−6). We observed nominally significant associations (P < 0.05) with 3 previously reported OA loci: rs143383 in GDF5 (OR 1.12 [95{\%} CI 1.04–1.21], P = 2.13 × 10−3), rs835487 in CHST11 (OR 0.93 [95{\%} CI 0.85–0.99], P = 0.03), and rs8044769 in FTO (OR 1.10 [95{\%} CI 1.03–1.19], P = 6.13 × 10−3). Conclusion: These findings provide suggestive evidence of a novel knee OA locus and confirm previously reported associations in GDF5, CHST11, and FTO.",
author = "Yau, {Michelle S.} and Yerges-Armstrong, {Laura M.} and Youfang Liu and Lewis, {Cora E.} and Duggan, {David J.} and Renner, {Jordan B.} and James Torner and Felson, {David T.} and McCulloch, {Charles E.} and Kwoh, {C. Kent} and Nevitt, {Michael C.} and Hochberg, {Marc C.} and Mitchell, {Braxton D.} and Jordan, {Joanne M.} and Jackson, {Rebecca D.}",
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AU - Yau,Michelle S.

AU - Yerges-Armstrong,Laura M.

AU - Liu,Youfang

AU - Lewis,Cora E.

AU - Duggan,David J.

AU - Renner,Jordan B.

AU - Torner,James

AU - Felson,David T.

AU - McCulloch,Charles E.

AU - Kwoh,C. Kent

AU - Nevitt,Michael C.

AU - Hochberg,Marc C.

AU - Mitchell,Braxton D.

AU - Jordan,Joanne M.

AU - Jackson,Rebecca D.

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N2 - Objective: A major barrier to genetic studies of osteoarthritis (OA) is the need to obtain large numbers of individuals with standardized radiographic evaluations for OA. To address this gap, we performed a genome-wide association study (GWAS) of radiographically defined tibiofemoral knee OA in 3,898 cases and 3,168 controls from 4 well-characterized North American cohorts, and we performed replication analysis of previously reported OA loci. Methods: We performed meta-analysis using a 2-stage design. Stage 1 (discovery) consisted of a GWAS meta-analysis of radiographic knee OA carried out in the Osteoarthritis Initiative and the Johnston County Osteoarthritis Project. Knee OA was defined as definite osteophytes and possible joint space narrowing or total joint replacement in one or both knees. Stage 2 (validation) was performed in the Multicenter Osteoarthritis Study and the Genetics of Osteoarthritis study. We genotyped lead meta-analysis variants (P ≤ 1 × 10−4) from stage 1 and tested the association between these variants and knee OA. We then combined results from all cohorts in a meta-analysis. Results: Lead variants from stage 1, representing 49 unique loci, were analyzed in stage 2; none met genome-wide significance in the combined analysis of stage 1 and stage 2. We validated 1 locus (rs4867568 near LSP1P3) with nominal significance (P < 0.05), which was also our top finding in the combined meta-analysis (odds ratio [OR] 0.84 [95% confidence interval (95% CI) 0.79–0.91], P = 3.02 × 10−6). We observed nominally significant associations (P < 0.05) with 3 previously reported OA loci: rs143383 in GDF5 (OR 1.12 [95% CI 1.04–1.21], P = 2.13 × 10−3), rs835487 in CHST11 (OR 0.93 [95% CI 0.85–0.99], P = 0.03), and rs8044769 in FTO (OR 1.10 [95% CI 1.03–1.19], P = 6.13 × 10−3). Conclusion: These findings provide suggestive evidence of a novel knee OA locus and confirm previously reported associations in GDF5, CHST11, and FTO.

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