title: 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Hsiang-Cheng
authors.initials: HC
authors.lastname: Chen
authors.forename: Virginia Byers
authors.initials: VB
authors.lastname: Kraus
authors.forename: Yi-Ju
authors.initials: YJ
authors.lastname: Li
authors.forename: Sarah
authors.initials: S
authors.lastname: Nelson
authors.forename: Carol
authors.initials: C
authors.lastname: Haynes
authors.forename: Jessica
authors.initials: J
authors.lastname: Johnson
authors.forename: Thomas
authors.initials: T
authors.lastname: Stabler
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Hauser
authors.forename: Simon G
authors.initials: SG
authors.lastname: Gregory
authors.forename: William E
authors.initials: WE
authors.lastname: Kraus
authors.forename: Svati H
authors.initials: SH
authors.lastname: Shah
mesh_terms: D015415:Biomarkers / Q000097:blood*; D064236:Cartilage Oligomeric Matrix Protein; D024043:Collagen Type II / Q000032:analysis; D016326:Extracellular Matrix Proteins / Q000032:analysis; D008040:Genetic Linkage; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006023:Glycoproteins / Q000032:analysis; D006801:Humans; D006820:Hyaluronic Acid / Q000032:analysis; D008126:Lod Score; D064235:Matrilin Proteins; D010003:Osteoarthritis / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide
chemical_list: D015415:Biomarkers; D064236:Cartilage Oligomeric Matrix Protein; D024043:Collagen Type II; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D064235:Matrilin Proteins; C577553:TSP5 protein, human; D006820:Hyaluronic Acid