Genome-wide linkage analysis of quantitative biomarker traits of osteoarthritis in a large, multigenerational extended family

Abstract

Objective: The genetic contributions to the multifactorial disorder osteoarthritis (OA) have been increasingly recognized. The goal of the current study was to use OA-related biomarkers of severity and disease burden as quantitative traits to identify genetic susceptibility loci for OA.

Methods: In a large multigenerational extended family (n = 350), we measured 5 OA-related biomarkers: hyaluronan (HA), cartilage oligomeric matrix protein (COMP), N-propeptide of type IIA collagen (PIIANP), C-propeptide of type II procollagen (CPII), and type II collagen neoepitope (C2C). Single-nucleotide polymorphism markers (n = 6,090) covering the whole genome were genotyped using the Illumina HumanLinkage-12 BeadChip. Variance components analysis, as implemented in the Sequential Oligogenic Linkage Analysis Routines, was used to estimate heritabilities of the quantitative traits and to calculate 2-point and multipoint logarithm of odds (LOD) scores using a polygenic model.

Results: After adjusting for age and sex, we found that 4 of the 5 biomarkers exhibited significant heritability (PIIANP 0.57, HA 0.49, COMP 0.43, C2C 0.30; P < or = 0.01 for all). Fourteen of the 19 loci that had multipoint LOD scores of >1.5 were near to or overlapped with previously reported OA susceptibility loci. Four of these loci were identified by more than 1 biomarker. The maximum multipoint LOD scores for the heritable quantitative biomarker traits were 4.3 for PIIANP (chromosome 8p23.2), 3.2 for COMP (chromosome 8q11.1), 2.0 for HA (chromosome 6q16.3), and 2.0 for C2C (chromosome 5q31.2).

Conclusion: Herein, we report the first evidence of genetic susceptibility loci identified by OA-related biomarkers in an extended family. Our results demonstrate that serum concentrations of PIIANP, HA, COMP, and C2C have substantial heritable components, and using these biomarkers, several genetic loci potentially contributing to the genetic diversity of OA were identified.

Figure 1. Quantitative trait loci (QTL) mapping for the 4 highly heritable OA-related biomarkers in 22 chromosomes (multipoint LOD scores)

A. PIIANP (type IIA collagen N-propeptide); B. COMP (cartilage oligomeric matrix protein); C. HA (hyaluronan); D. C₂C (neoepitope from cleavage of CII); significant linkage if LOD >3.0 and suggestive of linkage if LOD >1.5. All figure panels were generated with HaploView software.

Figure 2. Potential OA candidate genes on chromosome 6, 8, and 14

Genes listed in bold over the peaks represent potential novel candidate genes associated with biomarkers of OA in this study that have potential biological relevance for OA based on the literature. Genes listed without bold type over the peaks represent candidate genes linked previously to OA. The # sign indicates that the genes are less than 10 cM from the border of the 1-LOD drop support interval. ANGPT2=angiopoietin 2; DEFB4=beta-defensin 4; ANK1=ankyrin 1; PLAT=plasminogen activator, tissue; PLAG1= pleomorphic adenoma gene 1; COL22A1=collagen, type XXII, alpha 1; WISP1=wnt-1-induced secreted protein 1; HFE=hemochromatosis; COL11A2=collagen, type XI, alpha 2; TNF=tumor necrosis factor; COL10A1=collagen, type X, alpha 1; ESR2=Estrogen receptor 2; DIO2=Type II iodothyronine deiodinase; FLRT2=Fibronectin leucine-rich transmembrane protein 2.