NAHR deletion rate at the <i>CMT1A</i> locus in MZ co-twins.

<p>The estimates of deletion rate for each co-twin are plotted against one another, with 95% confidence intervals for each estimate also shown.</p

NAHR deletion rate at the <i>CMT1A</i> locus in all the sperm samples analysed with men grouped according to <i>PRDM9</i> zinc finger motif-binding status.

<p>Men homozygous for alleles recognising the canonical motif (shown in red) or heterozygous for alleles recognising the canonical and non-canonical motifs (shown in blue) are grouped separately and shown in ascending order. The 95% confidence intervals for each estimate of deletion rate are shown.</p

NAHR deletion rate at the <i>CMT1A</i> locus plotted against age at the time the sample was provided.

<p>In cases where multiple individuals have the same age the points are plotted slightly offset from each other on the x-axis. The 95% confidence intervals for each estimate of deletion rate are shown.</p

Manhattan plot for the FBAT-CNV P-values.

<p>The y-axis shows the distribution of –log₁₀(p) where p is the FBAT-CNV test association test P-value for all CNV loci passing quality control filters (Methods). The x-axis shows chromosomes numbered from 1 (left) to X (right).</p

Differences between case-control and FBAT-CNV association tests.

<p>A- In a case-control analysis, technical variability may affect the CNV intensity data between cases and controls. Therefore, it is necessary to call the discrete genotypes, potentially allowing for genotype uncertainty in the association tests. Mixture models are typically used for calling, as illustrated by the colored lines on top of the histograms. Intensity data must therefore be sufficiently separated to make these discrete calls (CNV data in this example obtained from both control groups in the WTCCC study <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004367#pgen.1004367-WTCCC1" target="_blank">[28]</a>). B- With the FBAT-CNV framework, one compares the average parental CNV signal with the signal for affected offspring. Consistent deviation of affected offspring intensity data compared to parental average indicates biased transmission of CNV alleles. As the test is solely based on the intensity data, and no systematic bias is expected between parents and offspring, it is not necessary to make discrete calls (CNV data obtained from INS VNTR first principal component).</p

Top ten T1D associated CNVs after removing known loci and technical artifacts.

<p>The last column lists the genes for which at least one exon overlaps the defined CNV region. P-value refers to the FBAT association test for autosomal CNVs, and to the FBAT-X association test otherwise.</p

Decomposition of multi-probe CNV data at the <i>INS</i> VNTR locus into first two principal components PC1 and PC2.

<p>Principal components PC1 and PC2 summarize the multi-probe CNV data at the <i>INS</i> VNTR locus. Colors (green/red/black) were chosen based on the genotypes of the SNP rs689 (AA/AT/TT), which captures the class I-class III separation.</p

Quantile-quantile plot comparing the expected versus the observed distribution of the FBAT-CNV P-values.

<p>These plots show the distribution of -2log₁₀(p), which is, under the null, distributed as chi-square with 2 degrees-of-freedom. IgG/TCR loci are discussed elsewhere and not included in these plots. A – N = 3,286 CNVs that passed quality controls and were tested for association. Loci overlapping the MHC region are marked in blue. Loci mapping to, or in strong LD with, the <i>INS</i> VNTR region are marked in red. B – N = 3,214 CNVs passed quality controls and did not overlap or tagged the <i>INS</i> VNTR and the MHC region. C – N = 448 VNTRs targeted by the CGH array that passed quality controls. <i>INS</i> VNTR CNV regions are marked in red as in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004367#pgen-1004367-g003" target="_blank">Figure 3A</a>.</p

Summary of the CNVs included in the array design and tested for T1D association using FBAT-CNV.

<p>CNVs originate from two main sources: the GSV map of common CNVs <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004367#pgen.1004367-Conrad2" target="_blank">[27]</a> and the 1,000 Genomes sequence data. Tested CNVs also include 365 novel insertion CNVs obtained from the Venter genome. Detailed description of the array design is provided in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004367#pgen.1004367.s016" target="_blank">Text S1</a>.</p

Spurious associations at TCR and IGH loci.

<p>Age at sampling (x-axis) versus CNV intensity signal (y-axis) for the three most associated Immunoglobin Heavy (IGH) and T cell receptor (TCR) loci CNVs. Each point represents an individual in the study (irrespective of familial/T1D status). Blue crosses indicate DNA extracted from LCLs (N = 551) and red crosses DNA extracted from blood (N = 2,981). Red and blue lines have been fitted to the LCL/blood data using cubic splines. A - CNVR6085.1 (chr14:21977832-21987926) mapping to TCR alpha and TCR delta locus on chr14, FBAT-CNV P = 3.6 10⁻⁶³. The plot shows correlation between age at sampling and probe intensity for DNA extracted from blood samples. B - CNVR3590.1 (chr7:142194021-142204412) mapping to TCR beta locus on chr7, FBAT-CNV P = 4.4 10⁻³¹. The plot shows correlation between age at sampling and probe intensity for DNA extracted from blood samples. C - CNVR6294.22 (chr14:105433837-105441555) mapping to Ig heavy chain locus on chr14, FBAT-CNV P = 6.5 10⁻⁵. No age-dependent effect was detected at this locus.</p