Tumor grading.

<p>Gleason grading score of the tumors for the samples used in Experiment 1 and Experiment 2. The sample on array 5 was used repeatedly on three arrays in Experiment 3.</p

Regions selected in first two experiments.

<p>The loci of the 20 regions selected in first and second experiments, according to hg18 and hg19 and the genes reported at these loci.</p

The proportion of regions that were selected in both Experiment 1 and Experiment 2.

<p>The underlying region was split up into equally sized regions and a fixed number of regions with the highest ratio of probes, within the region, expressed above the median, was selected. The proportion of regions that were selected in both Experiment 1 and Experiment 2 was calculated for varying length of each underlying region (y-axis) and the total number of regions to be selected (x-axis). The numbers within each cell show the exact proportions for the corresponding criteria.</p

The number of Monte Carlo simulations for which each region is chosen by the selection method using arrays with the same sample.

<p>The genomic location of the regions on 8q24 is on the x-axis. The proportion of Monte Carlo simulations for which the region was chosen is on the y-axis. The graph is shown with two different colourings, representing whether the region was among the previously experiment-wise selected regions (cyan) or not (pink). Those who were selected previously in Experiment 1 are shown at the top graph, Experiment 2 in the middle and Experiment 3 at the bottom. The simulations are done on the ten repeated spots for each probe for the three arrays in Experiment 3 that contained the same sample.</p

The number of Monte Carlo simulations for which each region is chosen by the selection method using arrays with different samples.

<p>The genomic location of the regions on 8q24 is on the x-axis. The proportion of Monte Carlo simulations for which the region was chosen is on the y-axis. The graph is shown with two different colourings, representing whether the region was among the previously experiment-wise selected regions (cyan) or not (pink). Those who were selected previously in Experiment 1 are shown at the top graph, Experiment 2 in the middle and Experiment 3 at the bottom. The simulations are done on the ten repeated spots for each probe for all nine arrays in Experiment 3.</p

Overview of non-HDL-C associations in the region around <i>LDLR</i>.

<p>Plot <b>A</b> is a 0.8Mb overview centered on <i>LDLR</i> and plot <b>B</b> is a 70kb overview around the <i>LDLR</i> gene. Black circles show-log₁₀<i>P</i> as a function of build 36 coordinates for associations with non-HDL-C and red crosses correspond to non-HDL-C associations after adjusting for the four variants rs17248720, rs72658867, rs200238879 and rs17248748 that are indicated by vertical broken lines in plot b. Genes are shown in blue and recombination rates are reported in cM/Mb.</p

RNA sequencing data from blood demonstrates increased expression and abnormal splicing characterized by intron 14 retention in carriers of the splice region variant rs72658867-A.

<p><b>A.</b> Normalized average <i>LDLR</i> exon coverage for non-carriers (<i>N</i> = 238, in blue) and heterozygotes (<i>N</i> = 15, in red) of rs72658867-A demonstrates increased expression of <i>LDLR</i> transcripts in heterozygotes by ~22%, <i>P</i> = 0.0075. The X-axis is the exon number corresponding to RefSeq transcript NM_000527 for <i>LDLR</i>. The Y-axis shows the median normalized coverage (normalized for each individual to the total number of aligned reads). The error bars are based on the median absolute deviation within each group and is calculated separately for each exon. <b>B.</b> Using the same samples as in a) preferential intron 14 retention is observed in heterozygous carriers of rs72658867-A (shown in red). The X-axis is the genomic position in Mb (hg18/Build36). The Y-axis is the median count of normalized reads as in a). The structure of all <i>LDLR</i> RefSeq transcript variants is shown. The upper panel shows the full length gene whereas the lower panel shows the exons 13, 14 and 15 and the intron retention in intron 14. <b>C.</b> Quantitation of the proportion of transcripts with intron 14 retention in heterozygotes. The Y-axis corresponds to the proportion of RNA sequencing reads that are spliced from exon 14 to exon 15 (correctly spliced) out of the total number of reads that cover the last base of exon 14 (individuals that do not have coverage at this position are omitted). Median proportion: 1.00 (non-carriers); 0.70 (heterozygotes). Mean proportion: 0.95 (non-carriers); 0.71 (heterozygotes). Mann-Whitney test for location shift gives <i>P</i> = 6.0×10⁻⁹.</p

Association of <i>LDLR</i> sequence variants with CAD and age at diagnosis of CAD in Iceland.

<p>Association results for rs17248720, rs17248748, rs200238879 and rs72658867 with CAD (coronary artery disease) and age at diagnosis of CAD. Association results for each variant is presented with and without adjusting for the other three variants in the table.</p><p>^aFreq A1 = allellic frequency of A1.</p><p>^bOR is given with respect to allele A1.</p><p>^cEffect (β) is given in years with respect to allele A1.</p><p>Association of <i>LDLR</i> sequence variants with CAD and age at diagnosis of CAD in Iceland.</p

Association of <i>LDLR</i> splice region variant rs72658867-A and intronic variant rs17248748-T with non-HDL-C in Denmark, Netherlands and Iran.

<p>Shown are association results for rs72658867-A and rs17248748-T with non-HDL-C, TG and HDL-C in replication samples from Denmark, Netherlands and Iran.</p><p>^aAssociation results are adjusted for the variants rs17248748-T and rs6511720-T (r² = 0.96 with rs17248720-T in Europeans in the 1000G Phase 3 data).</p><p>^bAssociation results are adjusted for the variants rs72658867-A and rs6511720-T (r² = 0.96 with rs17248720-T in Europeans in the 1000G Phase 3 data).</p><p>^cAll replication samples combined for each trait.</p><p>^dReplication samples combined with Icelandic samples, # non-HDL-C = 139,385, # TG = 100,350, # HDL = 139,753.</p><p>^eEffect (β) in mmol/l given with respect to allele A for rs72658867 and allele T for rs17248748.</p><p>^fEffect (β) in % change is given with respect to the allele A for rs72658867 and allele T for rs17248748.</p><p>^g<i>P</i>_<i>het</i> = <i>P</i>-value for a test of heterogeneity in the combined effect estimate.</p><p>Association of <i>LDLR</i> splice region variant rs72658867-A and intronic variant rs17248748-T with non-HDL-C in Denmark, Netherlands and Iran.</p

Characteristics of datasets included in the collaborative meta-analysis.

<p>Unless otherwise indicated all data is from direct genotyping. *ARCTIC (Assessment of Risk for Colorectal Tumors in Canada), AMFS (Australian Melanoma Family Study), CGEMS (Cancer Genetics Markers of Susceptibility), CAPS (Cancer of the Prostate in Sweden), CORGI (Colorectal Tumour Gene Identification), FHS (Framingham Heart Study), IARC (International Agency for Research on Cancer), JHH (Johns Hopkins Hospital), MDACC (M.D. Anderson Cancer Center, Texas), PANSCAN (Pancreatic Cancer Cohort Consortium), Q-MEGA (Queensland study of Melanoma: Environment and Genetic Associations), UKGPCS (UK Genetic Prostate Cancer Study). n/a: no available data; <i>i</i>: imputed; <i>p</i>: pooled.</p