Open Access Highly Accessed Research article

Genome-wide analysis validates aberrant methylation in fragile X syndrome is specific to the FMR1 locus

Reid S Alisch25, Tao Wang12, Pankaj Chopra2, Jeannie Visootsak24, Karen N Conneely2 and Stephen T Warren234*

Author Affiliations

1 Genetics and Molecular Biology Graduate Program, Emory University, Atlanta, GA, 30322, USA

2 Departments of Human Genetics, Emory University School of Medicine, 615 Michael Street, Atlanta, GA, 30322, USA

3 Departments of Biochemistry, Emory University School of Medicine, 615 Michael Street, Atlanta, GA, 30322, USA

4 Departments of Pediatrics, Emory University School of Medicine, 615 Michael Street, Atlanta, GA, 30322, USA

5 Current address: Department of Psychiatry, University of Wisconsin–Madison, Madison, WI, 53719, USA

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BMC Medical Genetics 2013, 14:18  doi:10.1186/1471-2350-14-18

Published: 29 January 2013

Additional files

Additional file 1: Figure S3:

Permutation analysis of FXS-associated loci. Scatterplot of permuted (1000 permutations) FXS-associated P-values (x-axis) compared to asymptotic P-values (y-axis) calculated using the linear model (Pearson R = 0.997).

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Additional file 2: Table S1:

Summary of the linear mixed-effects regression model. Column headers include: Illumina identification name (cpgids); Bonferroni-corrected P-values (bonferroni); False discovery rate P-values (fdr); Uncorrected P-value (raw_pvalue); Permutation P-value (perm_pvalue); Chromosome location (CHR); HG19 Map position (MAPINFO); and RefSeq gene name (UCSC_RefGene_Name).

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Additional file 3: Table S2:

Summary of the mean differences in methylation between FXS and control individuals. Column headers include: Illumina identification name (cpgids); Mean raw beta-values for fragile X patients (Mean FXS); Mean raw beta-values for control individuals (Mean controls); Chromosome location (CHR); HG19 Map position (MAPINFO); and RefSeq gene name (UCSC_RefGene_Name).

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Additional file 4: Figure S1:

Sample age distribution. The frequency (y-axis) of FXS (orange) and control (blue) individuals at each age (x-axis), with mean ages denoted by the vertical dashed lines.

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Additional file 5: Figure S2:

Methylation levels and significance of non-FMR1 FXS-associated loci. Top two panels show the methylation levels (y-axis) in FXS (orange squares) and control (blue crosses) individuals at several loci near the two significant non-FMR1 FXS-associated loci. Bottom two panels depict the P-values (−log(P-value); y-axis) for each probe generated by the mixed-effect linear model. Red line indicates the Bonferroni cutoff of 0.05. Only one probe from each region shown is significant at P <0.05. Position of probes (x-axis) in all four panels is relative to HG-19 coordinates for chromosomes 19 and 6, KLK15 and MICA, respectively.

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Additional file 6: Table S3:

Summary of the linear mixed-effects regression model using the data set filtered for all CGG trinucleotide repeats containing at least eight consecutive repeats (N = 136 tracts; N = 452 probes). Column headers include: Illumina identification name (cpgids); Bonferroni-corrected P-values (bonferroni); False discovery rate P-values (fdr); Uncorrected P-value (raw_pvalue); Permutation P-value (perm_pvalue); Chromosome location (CHR); HG19 Map position (MAPINFO); and RefSeq gene name (UCSC_RefGene_Name).

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Additional file 7: Figure S4:

Methylation levels of ZFHX3. All panels show the methylation levels (y-axis) in FXS (orange squares) and control (blue crosses) individuals at loci annotated to ZFHX3. Top panel (All CpG probes) shows the methylation levels of all the probes annotated to ZFHX3. Middle panel (Probes in a CGG repeat) displays only those ZFHX3 probes (4) that reside in a CGG trinucleotide repeat containing at least eight consecutive repeats. The bottom panel (Significant CGG repeat probes) shows the two ZFHX3-annotated probes that are significantly different (Bonferroni <0.05) between FXS and control individuals. Position of probes (x-axis) in all three panels is relative to HG-19 coordinates for chromosome 16.

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Additional file 8: Table S4:

Summary of the linear mixed-effects regression model using the iPS cell data set filtered loci that satisfied an FDR <0.05 in the peripheral blood analysis (N = 1183 probes). Column headers include: Illumina identification name (cpgids); Bonferroni-corrected P-values (bonferroni); False discovery rate P-values (fdr); Uncorrected P-value (raw_pvalue); Chromosome location (CHR); HG19 Map position (MAPINFO); and RefSeq gene name (UCSC_RefGene_Name).

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