Abstract
We performed a genome-wide search for pairs of susceptibility loci that jointly contribute to rheumatoid arthritis in families recruited by the North American Rheumatoid Arthritis Consortium. A complete two-dimensional (2D) non-parametric linkage scan was carried out using 380 autosomal microsatellite markers in 511 families. At each 2D peak we obtained the most likely underlying genetic model explaining the two-locus effects, defining epistasis as a departure from an additive or a multiplicative two-locus penetrance function. The highest peak in the surface identified an epistatic interaction between loci 6p21 and 16p12 (two-locus lod score = 18.02, epistasis P < 0.012). Significant and suggestive two-locus effects were also obtained for region 6p21 in combination with loci 18q21, 8p23, 1q41, and 6p22, while the highest 2D peaks excluding region 6p21 were observed at locus pairs 8p23-18q21 and 1p21-18q21. The 2D peaks were further examined using combined microsatellite and single-nucleotide polymorphism (SNP) marker genotypes in 744 families. The two-locus evidence for linkage increased for region pairs 6p21-18q12, 6p21-16p12, 6p21-8p23, 1q41-6p21, and 6p21-6p22, but decreased for pairs of regions that did not include locus 6p21. In conclusion, we obtained evidence for multi-locus interactions in rheumatoid arthritis that are mediated by the major susceptibility locus at 6p21.
Highlights
Multiple loci are likely to influence susceptibility to rheumatoid arthritis (RA)
The aim of this study was to carry out a genomewide search for pairs of loci that jointly contribute to RA under two-locus genetic models that include epistasis
We performed a two-dimensional (2D) nonparametric linkage scan in sibling pairs affected with RA from the families in the North American Rheumatoid Arthritis Consortium (NARAC) collection
Summary
Genome-wide scans for multiple interacting loci have been performed in model organisms [1] and more recently for complex human traits [2,3]. A systematic genome-wide search for pair-wise interactions in RA has not yet been performed. The aim of this study was to carry out a genomewide search for pairs of loci that jointly contribute to RA under two-locus genetic models that include epistasis. We performed a two-dimensional (2D) nonparametric linkage scan in sibling pairs affected with RA from the families in the North American Rheumatoid Arthritis Consortium (NARAC) collection. We detected a genome-wide significant epistatic interaction between loci 6p21 and 16p12, as well as several other pairs of loci that contribute to RA jointly and include locus 6p21
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