title: Use of supplementary phenotype to identify additional rheumatoid arthritis loci in a linkage analysis of 342 UK affected sibling pair families.
abstract: BACKGROUND
  Although rheumatoid arthritis has been shown to have moderately strong genetic component, both linked loci identified in linkage analyses and susceptibility variants from association studies are short of adequately accounting for a comprehensive catalogue of the molecular factors underlying this complex disease. The objective of this study was to use supplementary phenotype based on cumulative hazard of rheumatoid arthritis to identify linkage evidence for new and additional rheumatoid arthritis loci in a genome-wide linkage analysis of 342 affected sibling pair families from the United Kingdom.
  
  
  METHODS
  Using proportional hazards model, we estimated cumulative hazard of rheumatoid arthritis and then used it as a quantitative trait in a non-parametric multipoint variance component linkage analysis with 353 microsatellite markers distributed across the 22 autosomal chromosomes.
  
  
  RESULTS
  We identified 3 new loci with genome-wide suggestive linkage evidence for rheumatoid arthritis on 9q21.13, 15p11.1 and 20q13.33. Our results also confirmed previously reported linkage evidence in the HLA-DRB1 region on chromosome 6 and on locus 1q32.1.
  
  
  CONCLUSIONS
  This study demonstrates the potential for information gain through the use of supplementary phenotypes in genetic study of complex diseases to identify new and additional potential linked loci that are not detected by linkage analysis of traditional phenotypes; and our results provide further evidence of the involvement of multiple loci in the genetic aetiology of rheumatoid arthritis.
authors.affiliation: Department of Preventive Medicine and Epidemiology, Loyola University Chicago, Chicago, IL, USA. btayo@lumc.edu
authors.forename: Bamidele O
authors.initials: BO
authors.lastname: Tayo
authors.forename: Yulan
authors.initials: Y
authors.lastname: Liang
authors.forename: Arpad
authors.initials: A
authors.lastname: Kelemen
authors.forename: Austin
authors.initials: A
authors.lastname: Miller
authors.forename: Maurizio
authors.initials: M
authors.lastname: Trevisan
authors.forename: Richard S
authors.initials: RS
authors.lastname: Cooper
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D009679:Nuclear Family; D010641:Phenotype; D016016:Proportional Hazards Models; D006113:United Kingdom