Closely linked cis-acting modifier of expansion of the CGG repeat in high risk FMR1 haplotypes.
Bottom Line: We found expansion status to be strongly associated with a approximately 50-kb region proximal to the fragile site.However, stratification of chromosomes by risk subgroups enabled us to identify a common SNP variant which cosegregates with the subset of D group haplotypes at highest risk of expansion (chi(1)(2)=17.84, p=0.00002).We have verified that this SNP acts as a marker of repeat expansion in three independent samples.
Affiliation: Genetic Epidemiology Group, Human Genetics (MP808), Southampton General Hospital, Southampton, United Kingdom. email@example.comShow MeSH
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Mentions: Genotype data for 29 SNPs and one dichotomized microsatellite were determined for the entire sample (Table 1). SNP coverage extended approximately 650 kb, from˜400 kb proximal to the FRAXA repeat to ˜200 kb distal. By considering all chromosomes expanded at the FRAXA locus (CGG>40) as affected and all nonexpanded (CGG≤40) chromosomes as controls, we examined these data for evidence of significant association between the fragile X repeat and any possible cis–acting factors. Data from all 30 markers were formatted for an association analysis using the LOCATE program [Maniatis et al., 2004]. Individually, many of the SNPs showed significant association with repeat expansion but the highest single chi–squared statistic was observed for a locally ascertained SNP ss71651738 (local id WEX70) (χ21=178.71). Composite likelihood analysis of these data indicated a point location at 356 kb on the local map with a 95% CI for association of approximately 55 kb extending from 328.68 kb to 383.62 kb (Fig. 1). The maximum LOD score identified for the likelihood curve was 38.37 indicating very strong evidence in favor of some determinant 5′ of FRAXA that predisposed to larger repeat sizes. In order to elucidate the precise nature of this putative cis effect, we initiated an in–depth study of the 55 kb CI indicated by the association results.
Affiliation: Genetic Epidemiology Group, Human Genetics (MP808), Southampton General Hospital, Southampton, United Kingdom. firstname.lastname@example.org