Results of gene-level rare variant association tests using various variant filters (MAF ≤ 1%).

<p>Results of gene-level rare variant association tests using various variant filters (MAF ≤ 1%).</p

Results of gene-level low frequency variant association tests using various variant filters (MAF ≤ 5%).

<p>Results of gene-level low frequency variant association tests using various variant filters (MAF ≤ 5%).</p

Hexbin plots representing gene-based SKAT analyses for all genes across the genome using a MAF cutoff of 5% with 4 lipid traits.

<p>The x-axis represents the–log10 transformed p-value from the analysis after filtering according to CADD annotations. The y-axis represents the–log10 transformed p-value from the analysis after filtering according to ‘nonsynonymous’ annotations. Only gene regions which had at least 2 variants in them after filtering by both methods were plotted.</p

Quantile-Quantile plots to compare distributions of p-values identified using individual domain and gene-based approaches to rare variant analysis.

<p>These Q-Q plots represent the distribution of p-values from an analysis where rare variants have been collapsed together using protein domain coordinates and analysed with lipid traits. The reference distribution for these plots are distributions of p-values from an identical analysis except collapsing rare variants using conventional gene-based coordinates.</p

Evaluation of the predicted pathogenicity of R125W according to a range of prediction tools.

<p>Evaluation of the predicted pathogenicity of R125W according to a range of prediction tools.</p

Comparison of homology models generated by Robetta, HHpred/MODELLER and I-TASSER servers.

*<p>Manually determined C alphas of secondary structure correspond to human TBC1D1 residues 18–56, 61–79, 92–120, 128–136 and 142–162.</p

Location of R125 in the homology model of human TBC1D1 PTB1.

<p>(A) Homology based model of TBC1D1 PTB domain (residues 13–161) predicted by Robetta server (<a href="http://robetta.bakerlab.org/" target="_blank">http://robetta.bakerlab.org/</a>). The R125 residue (red) is orientated towards the cleft formed between β5 and α2 (purple). (B) Solved structure of IRS-1 PTB domain (PDB ID: 1IRS, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0063897#pone.0063897-Zhou1" target="_blank">[47]</a>). The IL-4 phosphopeptide (red) lies within the cleft formed between the β5 and α2 (purple), a type I β turn redirects the peptide such that the phosphorylated Tyr (shown) is orientated towards the β6/β7 loop.</p