The 20 functional (non-synonymous, nonsense and frameshift) variants in <i>ANGPTL4</i>, with PolyPhen-2 and GERP_RS scores included in the hierarchical model.

<p>The variants are sorted according to the log odds ratio estimates () from the hierarchical model. () is the minor allele count in cases (controls); RC is the return count from the backward elimination procedure; log odds ratios and their standard errors are estimated from the hierarchical model; PolyPhen-2 score, GERP_RS score, and SnpEff <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004729#pgen.1004729-Cingolani1" target="_blank">[69]</a> predicted effects are also reported.</p><p>The 20 functional (non-synonymous, nonsense and frameshift) variants in <i>ANGPTL4</i>, with PolyPhen-2 and GERP_RS scores included in the hierarchical model.</p

Top 20 functional (non-synonymous, nonsense and splice site) variants in <i>VPS13B</i> (among those selected by the backward elimination procedure), with PolyPhen-2 and GERP_RS scores included in the hierarchical model.

<p>The variants are sorted according to the log odds ratios estimates () from the hierarchical model. () is the minor allele count in cases (controls); hom_A (hom_U) is the number of homozygous genotypes in cases (controls); RC is the return count from the backward elimination procedure; log odds ratios and their standard errors are estimated from the hierarchical model; PolyPhen-2 score, GERP_RS score, and SnpEff <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004729#pgen.1004729-Cingolani1" target="_blank">[69]</a> predicted effects are also reported.</p><p>Top 20 functional (non-synonymous, nonsense and splice site) variants in <i>VPS13B</i> (among those selected by the backward elimination procedure), with PolyPhen-2 and GERP_RS scores included in the hierarchical model.</p

Predicted deleteriousness scores are shown for 71 rare functional variants (non-synonymous, nonsense and splice-sites).

<p>From the top, the first plot depicts the PolyPhen-2 score for each variant, the second depicts the GERP_RS score, and the third depicts variant counts for cases (up) and controls (down). Green tick marks indicate a variant contained in an exon, and red ticks indicate that a variant is selected by the backward elimination procedure. LoF variants are marked by a black asterisk; the homozygous probably damaging variant is marked by a red asterisk. The location of five protein domains (ChoreinN, TM2, TM4, DUF1162, Golgi targeting element, and ATG C) are depicted by boxes at the top of the plot (see <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004729#pgen.1004729.s010" target="_blank">Figure S10</a> for a complete view of VPS13B protein domains). Variants are plotted equidistantly on the x-axis.</p

Results from the backward elimination procedure for non-synonymous and splice site variants in <i>VPS13B</i>.

<p>(a) The change in p value is shown as variants are being removed one by one (when the backward elimination procedure is run once on all non-synonymous variants). (b) Distribution of return counts for non-synonymous and splice site variants in <i>VPS13B</i>; overlaid is a fitted mixture with two components.</p

The effect of multiple bioinformatic predictors for non-synonymous variants.

<p>Ranking is done only within the set of variants selected by the backward elimination procedure. (a) Median rank of causal variants for two disease models (M1 and M2) and three values for the NS:S ratio (R = {0.6, 1.0, 1.4}). The proportion of causal variants in the region is 20%. HM_S refers to the hierarchical model with ranking of the causal variants among the selected non-synonymous variants, based on their estimated effects, B₁ refers to the hierarchical model with one bioinformatic predictor (B₁, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004729#pgen-1004729-t002" target="_blank">Table 2</a>), B₂ refers to the hierarchical model with one bioinformatic predictor (B₂), mB₁ refers to the hierarchical model with three bioinformatic predictors (B₁, B₁, and B₂), and mB₂ refers to the hierarchical model with four bioinformatic predictors (four B₁s). (b) The number of causal variants in Top 10 for non-synonymous variants.</p

Two disease models M1 and M2.

<p>The odds ratio (OR) is a decreasing function of the minor allele frequency (MAF) at the causal variants.</p><p>Two disease models M1 and M2.</p

Normal learning and memory in Morris Water Maze and in fear conditioning but enhanced extinction of inhibitory avoidance in <i>Cyfip1</i> heterozygous mice.

<p>(<b>A</b>) Mice were tested using the Morris Water Maze. Time (s) to travel to the target platform was not significantly different between genotypes. (<b>B</b>) Mice were tested for fear conditioning, with mice receiving shocks at 120 and 180 seconds during training. Testing was performed 24 hours later, in the same test chamber, without footshock. (<b>C</b>) Inhibitory avoidance was measured by latency to enter the dark side of the box associated with prior shock. Extinction of inhibitory avoidance is enhanced in the heterozygotes. The lower panel shows the experimental design. WT, wildtype mice; Het, heterozygous mice; acq, acquisition; ext, extinction; IA, inhibitory avoidance. *, P = 0.027.</p

Basal synaptic properties and long-term potentiation are normal but long-term depression is enhanced in <i>Cyfip1</i> heterozygotes.

<p>(<b>A</b>) Hippocampal slices from 4–6 weeks old wildtype (WT) or Cyfip1 heterozygous (Het) mice were analyzed for baseline synaptic properties, determined by input/output function, representing the relationship between stimulus intensity and the size of the field EPSP slope. (<b>B</b>) Paired-pulse facilitation in the Schaffer collateral-commissural pathway is not different between genotypes over the test interpulse interval of 50 ms. (<b>C</b>) HFS-induced LTP was not significantly different between wildtype (WT) or <i>Cyfip1</i> heterozygous (Het) mice. (<b>D</b>) PP-LFS-induced LTD in <i>Cyfip1</i> heterozygous mice was significantly increased. Inset: Representative EPSP traces recorded before stimulation (arrow) or 60 min after stimulation in wildtype and heterozygous animals (scale: 10 ms and 0.5 mV).</p

Simulation scenarios.

<p>NS:S is the ratio of non-synonymous to synonymous variants; is the percentage of causal variants among the rare variants in a region, with being the percentage of causal variants among the non-synonymous ones, and being the proportion of causal variants among the synonymous ones; is the proportion of non-synonymous variants among the causal ones; is the proportion of non-synonymous variants among the non-causal ones (these values are calculated based on the NS:S ratio, , ). For non-synonymous variants only, we simulate two additional bioinformatic predictors (B₁ and B₂), meant to resemble the ‘damaging’ (including possibly and probably) and ‘probably damaging’ annotations from PolyPhen-2. is the proportion of causal variants that are labeled as ‘damaging’ and is the proportion of non-causal variants that are labeled as ‘damaging’. Similar notations for ‘probably damaging.’</p><p>Simulation scenarios.</p

(a) Median rank of causal variants among the non-synonymous variants for two disease models (M1 and M2) and three values for the NS:S ratio (R = {0.6, 1.0, 1.4}).

<p>The proportion of causal variants in the region is 20%. HM refers to the original hierarchical model with ranking of the causal variants among the non-synonymous variants, based on their estimated effects; BE refers to the backward elimination procedure for non-synonymous variants; and HM_S refers to the ranking of causal variants only among those non-synonymous variants selected by the backward elimination procedure, with ranks based on the estimated effects from the hierarchical model. (b) The number of causal variants in Top 10 for non-synonymous variants.</p