List of the 49 validated <i>de novo</i> variants.

<p>List of the 49 validated <i>de novo</i> variants.</p

Regions identified in the Ashkenazi Jewish CD GWAS, replication, and combined association analyses.

a<p>Physical position in megabases; Genome build NCBI36/hg18.</p>b<p>Genes highlighted by genetic location of the top SNP ±250 kb, ordered by proximity to the top SNP. If the top SNP is intragenic, the gene is indicated in bold font. Additionally, if there is evidence of eQTL effect of LOD≥5 this is indicated with a <i>♦</i> symbol and the LOD is given in brackets.</p>c<p>The risk allele in the AJ cohort with its frequency in healthy controls given in parenthesis.</p>d<p>The odds ratio for the risk allele in the replication cohort, with ±95% confidence intervals given in parenthesis.</p>e,f,g<p>p-values for the initial discovery GWAS for Crohn's disease in Ashkenazi Jews (Discovery p-value), replication cohort (Replication p-value) and a combined score of both p-values (Combined p-value) are given. Association significance thresholds are 5×10⁻⁸, 0.05, and 5×10⁻⁸ for discovery, replication and combined p-values, respectively. The significance thresholds of gene regions previously associated in other cohorts are 5×10⁻⁶, 0.05 and 5×10⁻⁶ for discovery, replication and combined p-values, respectively.</p

Study cohort description.

<p>For each screen, the total number of individuals examined is shown (N_total), in addition to any Crohn's disease cases (NC_{D_cases}), non-Crohn's disease cases, which are a mix of individuals with Parkinson's disease, Schizophrenia, Type-2 Diabetes and Dystonia, (N_{non-CD_cases}), and non-diseased controls (N_controls).</p>b<p>Genotypes available for only a subset of 31 replication markers.</p

Regional plots of five novel associations to Crohn's disease in Ashkenazi Jews.

<p>Regional plots of the SNP p-values obtained in the discovery GWAS for a ±250 kb window around each of the 5 novel SNPs. The X-axis shows the chromosome and physical distance (kb), the left Y-axis shows the negative base ten logarithm of the p-value and the right y-axis shows recombination activity (cM/Mb) as a blue line. The chromosomal band is given above each plot. The replication SNP is indicated as a large red diamond, and linkage disequilibrium of surrounding SNPs with the replication SNP is indicated by a scale of intensity of red color filling as shown in the legend at the upper right hand corner of each plot. The combined discovery and replication p-value for the replication SNP is shown in blue, and is annotated with the SNP identifier and combined p-values. The position and location of any copy number variation in the mapping intervals are shown as a black rectangle. Positions, recombination rates and gene annotations are according the NCBI's build 36 (hg 18).</p

Association mapping of Crohn's disease in Ashkenazi Jews.

<p>(A) QQ-plots of the 100%, 75% and 50% AJ ancestry groups (Groups 1, 2 and 3, respectively). The inflation factors for the p-value distributions are given. For group 3, the p-values were genomic control-adjusted for over-inflation. (B) A Manhattan plot and QQ-plot (inset – in black) of the combined association scores from all three groups. The genome-wide threshold is shown in red and the replication threshold is shown in blue. The QQ-plot also shows association scores from all three groups but with 298 markers around the region of the <i>NOD2</i> signal on chromosome 16 removed before association mapping (in grey).</p

PCA analysis of the study participants.

<p>(A) PCA showing the first (X-axis) and second (Y-axis) eigenvectors plotting all 3,252 study participants (907 CD cases and 2,345 controls) across ∼22 K unlinked SNPs indicated by light blue open circles. Also included and color-coded in the graph are the four HapMap (<a href="http://www.hapmap.org" target="_blank">www.hapmap.org</a>) reference samples as solid triangles; CEPH-Utah (CEU; green), Yoruban-Nigeria (YRI; red), Han Chinese (CHB; orange) and Japanese (JPT; dark grey); and seven Jewish samples from the Jewish Hapmap project <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002559#pgen.1002559-Atzmon1" target="_blank">[2]</a> as solid circles, consisting of Ashkenazi Jews (AJ; blue), one European (Italian; purple), three Middle Eastern (Syrian; fuchsia, Iraqi; teal and Iranian; turquoise) and two Sephardic Jewish cohorts (Turkey; brown and Greek; orange). (B) The same analysis excluding the YRI and CHB+JPT reference panels. (C) A histogram of PC1 values for study participants (light blue) near the AJ cluster and intermediate between the AJ and CEU clusters. The histogram of PC1 values for the included samples show three distinct modes (Groups 1–3), with AJ reference (blue) and CEU (green) indicated.</p

Enrichment of alleles discovered in AJ exome sequencing project.

<p><b>A)</b> Histogram of estimated log enrichment statistic, defined as the log of the bias corrected odds ratio comparing the allele frequency in AJ population to the maximum allele frequency estimated from NFE, AFR, and AMR populations in ExAC. For each histogram bin we show a bar plot of the expected number of alleles belonging to the two groups we analyzed: 1) enriched (green) and 2) not enriched (white). <b>B)</b> Bar plots of estimated percentage of alleles belonging to the two groups we analyzed for all protein-coding (ALL), synonymous (SYN), protein-altering (PRA), and protein-truncating variants (PTV). An estimate of 34% of protein-coding alleles observed in AJ have a mean shift of 15-fold increased odds of the alternate allele compared to other reference populations. This observation is supported by the property that compared to intergenic variants, coding variants tend to be younger for a given frequency and the more pathogenic a variant, the younger it is, therefore tending to be population specific[<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1007329#pgen.1007329.ref013" target="_blank">13</a>].</p