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Whole-genome single nucleotide polymorphism-based linkage analysis in spondyloarthritis multiplex families reveals a new susceptibility locus in 13q13
  1. Félicie Costantino1,2,3,
  2. Emmanuel Chaplais1,3,
  3. Tifenn Leturcq1,3,
  4. Roula Said-Nahal2,
  5. Ariane Leboime2,
  6. Elena Zinovieva1,3,
  7. Diana Zelenika4,
  8. Ivo Gut4,
  9. Céline Charon4,
  10. Gilles Chiocchia1,3,
  11. Maxime Breban1,2,3,
  12. Henri-Jean Garchon1,3,5
  1. 1INSERM U1173, UFR Simone Veil, Versailles-Saint Quentin University, Saint-Quentin en Yvelines, France
  2. 2Rheumatology Division, Ambroise Paré Hospital (AP-HP), Boulogne-Billancourt, France
  3. 3Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence, Paris, France
  4. 4National Genotyping Center (CNG/CEA), Evry, France
  5. 5Genetics Division, Ambroise Paré Hospital (AP-HP), Boulogne-Billancourt, France
  1. Correspondence to Professor Henri-Jean Garchon, UFR Simone Veil, 2 avenue de la source de la Bièvre, Montigny le Bretonneux 78180, France; henri-jean.garchon{at}


Objective Spondyloarthritis (SpA) is a chronic inflammatory disorder with high heritability but with complex genetics. Apart from HLA-B27, most of the underlying genetic components remain to be identified. We conducted a whole-genome high-density non-parametric linkage analysis to identify new genetic factors of susceptibility to SpA.

Methods 914 subjects including 462 with SpA from 143 multiplex families were genotyped using Affymetrix 250K microarrays. After quality control, 189 368 single nucleotide polymorphisms (SNPs) were kept for further analyses. Both non-parametric and parametric linkage analyses were performed using Merlin software. Association was tested with Unphased.

Results Non-parametric linkage analysis identified two regions significantly linked to SpA: the major histocompatibility complex (LODmax=24.77) and a new 13q13 locus (LODmax=5.03). Additionally, eight loci achieved suggestive LOD scores, including the previously identified SPA2 locus at 9q33 (LODmax=3.51). Parametric analysis supported a codominant model in 13q13 with a maximum heterogeneity LOD, ‘HLOD’ score of 3.084 (α=0.28). Identification of meiotic recombination events around the 13q13 linkage peak in affected subjects from the 43 best-linked families allowed us to map the disease interval between 38.753 and 40.040 Mb. Family-based association analysis of the SNPs inside this interval in the best-linked families identified a SNP near FREM2 (rs1945502) which reached a p value close to statistical significance (corrected p=0.08).

Conclusion We report here for the first time a significant linkage between 13q13 and SpA. Identification of susceptibility factor inside this chromosomal region through targeted sequencing in linked families is underway.

  • Ankylosing Spondylitis
  • Spondyloarthritis
  • Gene Polymorphism
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