Measure of the impact of the number of bootstrap samples on the size and the relevance of the candidate haplotypes space for the APOE gene

<p><b>Copyright information:</b></p><p>Taken from "ISHAPE: new rapid and accurate software for haplotyping"</p><p>http://www.biomedcentral.com/1471-2105/8/205</p><p>BMC Bioinformatics 2007;8():205-205.</p><p>Published online 15 Jun 2007</p><p>PMCID:PMC1919397.</p><p></p> Black line and left scale are for ICR (capture rate of true haplotypes configurations). Dashed line and right scale are for ANCR (average number of candidates per genotype)

Statistical significance of our associations.

<p>Histogram of the number of SNPs that pass the significance criterion for this study using phenotype and SNP randomisations. These results provide us with a way to estimate the sensitivity of our study (diamond): it would be extremely unlikely for our eight independent findings to arise by chance alone (<i>p</i> = 0.001).</p

List of the significant associations (<i>p</i> ≤ 0.05) with slow and non-progression.

<p>(*) Note that rs3749971 is in linkage disequilibrium with rs3130350 and is therefore not considered an independent finding in our statistics (see text).</p><p>Alleles, allele frequencies (AF), positional data and genetic modes are provided with the results of the statistical inferences. Opposite signs for the β coefficients are required for an association to be replicated in the GRIV (non-progression) and ACS cohorts (time to AIDS93).</p

Schematic summary of our methodology.

<p>The data from three databases are integrated to provide us with functional SNPs likely to be associated with changes in gene transcription in the tissue of interest. Using the SNAP Pairwise LD server, we only kept independent SNPs by removing superfluous SNPs that were in linkage disequilibrium (<i>r</i>² ≥ 0.2). Among those SNPs, associations with slow and non-progression towards AIDS are sought and replicated. Randomisations are carried out in order to evaluate the statistical robustness of our results. Finally, the genetic associations are used to link progression to AIDS and gene expression in candidate genes.</p

List of SNP/gene pairs associated with AIDS progression.

<p>(*) Note that rs3749971 is in linkage disequilibrium with rs3130350 and is therefore not considered an independent finding (see text).</p><p>The genetic association is linked back to its association with gene expression levels to provide an association between transcription levels (we use the word ‘regulation’ for convenience’s sake) and AIDS progression.</p

Analysis of bulk SNP effects shows no evidence for enrichment of association signal across data sets.

<p>LD pruned SNP sets falling below various p-value thresholds (grey shades, x-axis) were selected based on association results calculated in five of six groups (discovery set). Per individual scores were calculated in a non-overlapping test set (Group 3) by summing the beta-weighted dosage of all SNPs in that set. Model p-value (listed above bars) and variance explained (using Nagelkerke's pseudo R², y-axis) were calculated by regressing phenotype on per individual score using logistic regression.</p

Results for 22 SNPs previously reported to affect HIV-1 acquisition sorted by reported effect and genomic location.

<p>Reported effects correspond to the A1 allele.</p><p>Frequency and odds ratio (OR) are calculated for the A1 allele with an OR>1 indicating a higher frequency of A1 in the HIV-1 infected sample.</p

Association results for approximately 8 million common DNA variants tested for an impact on HIV-1 acquisition.

<p>A) Quantile-quantile plot of association results after meta-analysis across the six groups. For each variant tested, the observed −log₁₀ p-value is plotted against the null expectation (dashed line). P-values lower than 5×10⁻⁸ are truncated for visual effect. B) Manhattan plot of association results where each variant is plotted by genomic position (x-axis) and −log₁₀ p-value (y-axis). Only variants in the MHC region on chromosome 6 have p-values below genome-wide significance (p<5×10⁻⁸ dashed line, large diamonds).</p

Common DNA variants within the MHC region that are associated with HIV-1 acquisition comparing 6,334 HIV-1 infected patients to 7,247 population controls are driven by HIV-1 controllers and not maintained when restricting to patients with known dates of seroconversion.

<p>A) Regional association plot of the locus containing genome-wide significant SNPs after meta-analysis. The signal of association is centered on the <i>HLA-B/HLA-C</i> genes. The association result for the top SNP, rs4418214, is indicated by the purple diamond, with dark blue indicating SNPs in high LD (r²>0.8), light blue indicating moderate LD (r² between 0.2 and 0.8) and grey indicating low or no LD (r²<0.2) with rs4418214. The dashed line indicates genome-wide significance (p<5×10⁻⁸). The location of classical class I and class II HLA genes (green arrows) is given as reference. B) Forest plot of effect estimates for the C allele at rs4418214 with 95% confidence intervals per group (box and whiskers) and after meta-analysis (diamond). The majority of the association signal is contributed by Groups 3 and 4, which are enriched for HIV-1 controllers. C) Regional association plot of the same variants as in A) but restricting analysis to include only individuals with a known date of seroconversion to limit frailty bias.</p