Comprehensive linkage and association analyses identify haplotype, near to the TNFSF15 gene, significantly associated with spondyloarthritis - PubMed (original) (raw)

. 2009 Jun;5(6):e1000528.

doi: 10.1371/journal.pgen.1000528. Epub 2009 Jun 19.

Catherine Bourgain, Amir Kadi, Franck Letourneur, Brigitte Izac, Roula Said-Nahal, Nicolas Lebrun, Nicolas Cagnard, Agathe Vigier, Sébastien Jacques, Corinne Miceli-Richard, Henri-Jean Garchon, Simon Heath, Céline Charon, Delphine Bacq, Anne Boland, Diana Zelenika, Gilles Chiocchia, Maxime Breban

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Comprehensive linkage and association analyses identify haplotype, near to the TNFSF15 gene, significantly associated with spondyloarthritis

Elena Zinovieva et al. PLoS Genet. 2009 Jun.

Abstract

Spondyloarthritis (SpA) is a chronic inflammatory disorder with a strong genetic predisposition dominated by the role of HLA-B27. However, the contribution of other genes to the disease susceptibility has been clearly demonstrated. We previously reported significant evidence of linkage of SpA to chromosome 9q31-34. The current study aimed to characterize this locus, named SPA2. First, we performed a fine linkage mapping of SPA2 (24 cM) with 28 microsatellite markers in 149 multiplex families, which allowed us to reduce the area of investigation to an 18 cM (13 Mb) locus delimited by the markers D9S279 and D9S112. Second, we constructed a linkage disequilibrium (LD) map of this region with 1,536 tag single-nucleotide polymorphisms (SNPs) in 136 families (263 patients). The association was assessed using a transmission disequilibrium test. One tag SNP, rs4979459, yielded a significant P-value (4.9 x 10(-5)). Third, we performed an extension association study with rs4979459 and 30 surrounding SNPs in LD with it, in 287 families (668 patients), and in a sample of 139 cases and 163 controls. Strong association was observed in both familial and case/control datasets for several SNPs. In the replication study, carried with 8 SNPs in an independent sample of 232 cases and 149 controls, one SNP, rs6478105, yielded a nominal P-value<3 x 10(-2). Pooled case/control study (371 cases and 312 controls) as well as combined analysis of extension and replication data showed very significant association (P<5 x 10(-4)) for 6 of the 8 latter markers (rs7849556, rs10817669, rs10759734, rs6478105, rs10982396, and rs10733612). Finally, haplotype association investigations identified a strongly associated haplotype (P<8.8 x 10(-5)) consisting of these 6 SNPs and located in the direct vicinity of the TNFSF15 gene. In conclusion, we have identified within the SPA2 locus a haplotype strongly associated with predisposition to SpA which is located near to TNFSF15, one of the major candidate genes in this region.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1

Figure 1. Study design.

(A) shows the different stages of the study displayed according to their chronological order from left to right. Frames in blue describe the familial and case/control samples used for each different step. Frames in orange describe the sets of markers, the limits of the intervals covered by these markers on chromosome 9 (in distance from the p-telomere), and the techniques used for single-nucleotide polymorphisms initial genotyping. Frames in green describe the type of genetic analysis performed, the statistic, and the program used in each case. (B) shows compositions of family and case/control samples used in each step of the study. The three first columns show for each step of the study which familial, and case and/or control sample respectively, was used. The far right column displays, for each genotyped sample, the step of the study in which it was involved. The overlay parts of the samples are matched. Ex: Of the 136 families included in the LD mapping association study, 36 were also used in the fine mapping linkage study and in the initial whole genome and extension screen. NB: Both case/control samples were composed of independent individuals not tested elsewhere. Abbreviations: LD: linkage disequilibrium, SpA: spondyloarthritis, SNP: single-nucleotide polymorphism.

Figure 2

Figure 2. Results of linkage disequilibrium mapping association study.

(A) shows results of both fine mapping linkage step (right y axis) and LD mapping step (left y axis). Linkage results are shown in red, with the dashed straight line symbolizing the 0.05 Bonferroni corrected significance threshold. Family-based association results are displayed in blue, with each diamond corresponding to a studied tag SNP. The dotted straight line shows the 0.075 Bonferroni corrected significance threshold. In green are represented the locations of the TNFSF15 gene, associated with Crohn's disease and of the TRAF1-C5 locus associated with rheumatoid arthritis. (B) shows a zoomed view of the 135 kb region of interest delineated by frames in (A). Each diamond, corresponding to a studied tag SNP, appears coded by color and size, according to its linkage disequilibrium correlation coefficient (r2) with the most significantly associated tag SNP (rs4979459), as displayed in the legend. (C) shows linkage disequilibrium structure across the 135 kb region zoomed in (B), based on r2 coefficient calculated with the CEU HapMap database. The intron exon structure of the TNFSF15 gene lying within this locus is represented at the top of (C). The genotyped tag SNPs shown in (B) are indicated with red bars. Three of these tag SNPs lie within the TNFSF15 gene.

Figure 3

Figure 3. Quantile-quantile (Q-Q) plots comparing the distributions of observed versus expected _P_-values.

(A) shows the LD mapping Q-Q plot. The blue squares represent the observed _P_-values. The grey line represents the null hypothesis of no true association. (B) shows the extension study mapping Q-Q plot. The green circles and the red triangles represent the observed _P_-values for the family-based and case/control studies respectively. The grey line represents the null hypothesis of no true association.

Figure 4

Figure 4. Linkage disequilibrium (LD) plot for the eight single-nucleotide polymorphisms genotyped in the replication study.

LD calculations were based on pairwise r2 values of our entire case/control dataset. These values are displayed, in percentage, in the grey boxes. The red triangle indicates the LD block, computed by the program HAPLOVIEW, which was further used for haplotypic association with the program PLINK.

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