MHC-wide association results (uveitis-JIA vs non-uveitis JIA) conditioned on aspartic acid position 11 in HLA-DRB1

<p>Association results across the major histocompatibility complex (MHC) on chromosome 6, conditioned on aspartic acid (D) at position 11 in <em>HLA-DRB1</em>. Note that coordinates are on build hg18. Columns are:</p> <ol> <li>CHR: chromosome</li> <li>SNP: SNP identifier</li> <li>BP: basepair position (hg18)</li> <li>A1: minor allele/tested allele</li> <li>A2: other allele (major allele)</li> <li>FRQ: frequency of the A1 allele</li> <li>INFO: imputation quality info score</li> <li>OR: odds ratio</li> <li>SE: standard error of the t-statistic (note that the t-statistic is not provided in the file)</li> <li>P: p-value of the SNP</li> </ol

Discrimination of derived missense alleles by the NC statistic.

<p>Missense alleles are sub-classified info categories based on <i>PolyPhen-2</i> predictions. Effect sizes were calculated as standard deviations from the mean of the NC statistic for synonymous variants at the same minor allele count (MAC). Within each MAC class, P-values were calculated by 1-sided Mann-Whitney test. Combined P-values for MAC 2–6 were computed by meta-analysis (Methods).</p

Bootstrap distribution of normalized difference between NC statistic on missense and synonymous variants for derived allele count 2 and 3.

<p>Vertical red bars indicate 95% confidence intervals. For presentation, panels have been aligned along the X axis.</p

Empirical Cumulative Distribution Function of the NC statistic for alleles at minor allele count 3 in GoNL data.

<p>Synonymous derived variants serve as the baseline distribution. The distribution of NC for probably damaging derived missense variants is notably shifted towards higher values, consistent with their younger age. The NC-statistic distribution for ancestral alleles are at minor allele count 3 is strongly shifted towards lower values, consistent with much older age of those alleles.</p

Simulation and theoretical results for allelic age and sojourn times.

<p>a. Example trajectories for a neutral and deleterious allele with current population frequencies 3% (indicated by the arrow). The shaded areas indicate sojourn times at frequencies above 5%. b. Mean ages for neutral and deleterious alleles at a given population frequency (lines show theoretical predictions, dots show simulation results with standard error bars). Simulation results are averages of alleles in a frequency range, while theoretical prediction are for alleles at a fixed frequency. The graph shows that deleterious alleles at a given frequency are younger than neutral alleles, and that the effect is greater for more strongly selected alleles. c. Mean sojourn times for neutral and deleterious alleles. Vertical line denotes the current population frequency of the variant (3%). Mean sojourn times have been computed in bins of 1%. Line connects theoretical predictions for each frequency bin. Dots show simulation results. The graph illustrates that deleterious alleles spend much less time than neutral alleles at higher population frequencies in the past even if they have the same current frequency.</p

Correlation between the NC statistic and PolyPhen2 predictions.

<p>Within each minor allele count, derived missense alleles are positively correlated (Spearman's ) with PolyPhen2 predictions (pph2_prob), while no such correlation exists for ancestral missense alleles. P-values are 1-sided (alternative hypothesis ).</p

Cartoon presentation of the NC statistic.

<p>The NC statistic aims to capture the length of the haplotype carrying a variant. For a given variant (called the index variant, shown in the middle of the figure), the value of the NC statistic is the base-10 logarithm of the sum of physical distances measured up-stream (5′ direction) and down-stream (3′ direction) from the index variant to the closest variant that is either beyond a recombination spot (example shown on the left) or is linked to the index variant but is rarer than the index variant (example shown on the right). The red arrow in the figure illustrates that sum of the two distances.</p

Age distributions for neutral and deleterious alleles from simulations.

<p>(A) Constant-size, (B) recently rapidly expanding population, and (C) bottleneck followed by rapid expansion. For presentation, distributions are trimmed. Deleterious alleles in all cases are younger than neutral alleles at the same frequency, though the effect is weaker in rapidly expanding populations.</p

Allele frequency spectra in GoNL data, for synonymous alleles and non-synonymous alleles stratified by PolyPhen-2 functional predictions.

<p>For better presentation, the graphs have been cropped at minor allele count 10.</p

Allele frequency spectra and population-private coding alleles.

<p>The graphs show the proportion of population-private synonymous alleles and non-synonymous alleles stratified by PolyPhen-2 functional predictions.</p