Number of coding, rare and LoF variants across 24 candidate genes selected from exome sequencing of 75 individuals from multiply affected families.

<p>* MAF as defined in controls.</p><p>Number of coding, rare and LoF variants across 24 candidate genes selected from exome sequencing of 75 individuals from multiply affected families.</p

Summary of non-parametric linkage results in twelve multiply affected disease pedigrees.

<p>Summary of linkage data for the twelve families included in the NPL analysis. The linkage <i>p</i>-values were computed using Merlin [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0116845#pone.0116845.ref033" target="_blank">33</a>]. The power was assessed using simulations (see Methods).</p><p>Summary of non-parametric linkage results in twelve multiply affected disease pedigrees.</p

Top three most significant genes for the aggregate test for rare LoF variants only between cases (one per multiply affected family) and controls (with MAF <0.5% in 1000G).

<p>Top three most significant genes for the aggregate test for rare LoF variants only between cases (one per multiply affected family) and controls (with MAF <0.5% in 1000G).</p

Segregation result for a novel c.70G>A (p.V24I) SNV in <i>IL21R</i> in the entire Neu4801 family.

<p>All other individuals carry homozygous GG wild type alleles (genotypes not shown on figure).</p

Analytical design of our study of rare variation in CeD.

<p>Only post quality filtered SNVs and indels were included in each analytical test. A, Not in dbSNP132, <5% MAF in 1000G, <10% MAF in coeliac exomes, not in 101 control exomes (54 ultra rare diseases from Kings College London and 47 Environmental Genome Project samples from University of Washington). B, Rare allele defined as MAF <0.5% in 1000G (n = 1092) for 220 controls and 41 unrelated coeliac exomes. C, MAF <0.5%, only variants predicted to be damaging and regions without duplications.</p

Nonsynonymous missense SNVs located in linkage regions (<i>p</i> < 0.01).

<p>* Candidate genes selected for deep amplicon resequencing</p><p>Nonsynonymous missense SNVs located in linkage regions (<i>p</i> < 0.01).</p

Top 15 most significant genes for the aggregate test for rare LoF variants in immune genes between cases (one per multiply affected family) and controls (with MAF <0.5% in 1000G).

<p>* Candidate genes selected for deep amplicon resequencing.</p><p>Top 15 most significant genes for the aggregate test for rare LoF variants in immune genes between cases (one per multiply affected family) and controls (with MAF <0.5% in 1000G).</p

Top five <i>p</i>-values for multiple rare variant gene-based tests across all protein-coding variants (novel and known) in 24 candidate genes (case control analysis in 2,248 cases and 2,230 controls).

<p>Top five <i>p</i>-values for multiple rare variant gene-based tests across all protein-coding variants (novel and known) in 24 candidate genes (case control analysis in 2,248 cases and 2,230 controls).</p

Manhattan plot of single-SNP tests comparing case data (n = 41, one case per multiply affected family) with 220 control samples.

<p>Manhattan plot of single-SNP tests comparing case data (n = 41, one case per multiply affected family) with 220 control samples.</p

Minor allele frequencies WTCCC vs pooled NGS (24 pools combined).

<p>MAFs for 153 SNPs were compared between allele frequency estimates based on pooled NGS and genotyping data from the WTCCC [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004955#pgen.1004955.ref047" target="_blank">47</a>] for 634 individuals. MAFs are strongly correlated between both datasets (Spearman rank correlation coefficient R = 0.976), with only two SNPs showing substantial differences.</p