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Meta-Analysis

A variant in MCF2L is associated with osteoarthritis

Aaron G Day-Williams et al. Am J Hum Genet. .

Abstract

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.

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Figures

Figure 1
Figure 1
Overview of Study Design
Figure 2
Figure 2
Forest Plot of OA Association and Meta-Analysis Results for rs11842874 The purple squares designate the estimated Odds Ratio (OR) for each individual study and the error bars extending out on both sides show the 95% confidence interval for the OR estimate. The pink diamond designates the estimated OR of the fixed effects meta-analysis of all the studies.
Figure 3
Figure 3
Comparison of Regional Association Plots at the Chromosome 13 Association Signal Evidence for association in the rs11842874 region for (A) arcOGEN GWAS directly typed analysis, (B) arcOGEN HapMap3 imputation analysis, and (C) arcOGEN 1KGP final pilot 1 release imputation analysis. The x axis shows the build 36 chromosome 13 base position ± 500 kb of rs11842874. The left y axis is the −log (p value) of SNPs in the region, and the right y axis is the recombination rate (cM/Mb) as calculated from the pilot 1 release of the 1KGP. Each diamond represents a variant and is colored according to its correlation (r2) with rs11842874. The green arrows below provide an overview of the genes in the region and their transcriptional direction. Imputed variants are denoted by circles and directly typed variants are denoted by diamonds.
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