Association of the GDF5 and COL27A1 Genes with Knee Pain in UK Biobank (N = 171, 516) Based on a Genome-Wide Association Study

Abstract

Objective: Knee pain is one of the most common musculoskeletal complaints that brings people to medical attention. We sought to identify the genetic variants associated with pain in 171,516 subjects from the UK Biobank cohort and replicate them using cohorts from 23andMe, the Osteoarthritis Initiative (OAI), and the Johnston County Osteoarthritis Study (JoCo). Methods: We performed a genome-wide association study of pain in the UK Biobank, where pain was ascertained through self-report and defined as knee pain in the last month interfering with usual activities. A total of 22,204 cases and 149,312 controls were included in the discovery analysis. We tested our top and independent SNPs (P < 5 x 10-8) for replication in 23andMe, OAI, and JoCo, then performed a joint meta-analysis between discovery and replication cohorts using GWAMA. We calculated the narrow-sense heritability of pain using Genome-wide Complex Trait Analysis (GCTA). Results: We identified 2 loci that reached genome-wide significance, rs143384 located in the GDF5 (P = 1.32 x 10-12), a gene previously implicated in osteoarthritis, and rs2808772, located near COL27A1 (P = 1.49 x 10-8). These findings were subsequently replicated in independent cohorts and increased in significance in the joint meta-analysis (rs143384: P = 4.64 x 10-18; rs2808772: P = 2.56 x 10-11). The narrow sense heritability of pain was 0.08. Conclusion: In this first reported genome-wide association meta-analysis of pain, we identified and replicated two loci in or near GDF5 and COL27A1 that are associated with pain. Funding Statement: This work was supported by the STRADL project (Wellcome Trust, grant number: 104036/Z/14/Z). The Osteoarthritis Initiative (OAI) was public-private partnership comprised of five contracts (N01-AR-2-2258; N01-AR-2-2259; N01-AR-2-2260; N01- AR-2-2261; N01-AR-2-2262) funded by the NIH. The the Johnston County Osteoarthritis Study (JoCo) was supported in part by S043, S1734, & S3486 from the CDC/Association of Schools of Public Health; 5-P60-AR30701 & 5-P60- AR49465-03 from NIAMS/NIH; genotyping was supported by Algynomics, Inc. Additional support was obtained from NIH grant P30-DK072488. Declaration of Interests: J.S., A.A., and members of the 23andMe Research Team are employees of 23andMe, Inc., and hold stock or stock options in 23andMe. Other coauthors have no conflicts of interest. Ethics Approval Statement: Ethical approval was granted by the National Health Service National Research Ethics Service (reference 11/NW/0382). All participants included in the analyses provided informed consent and answered surveys online according to 23andMe’s human subjects protocol, which was reviewed and approved by Ethical & Independent Review Services, a private institutional review board.