Independent study replication confirms enrichment in Crohn's disease.

<p>(A). Stratified True Discovery Rate (TDR) plots illustrating the increase in TDR associated with increased enrichment. (B) Cumulative replication plot showing the average rate of replication (p<.05) within sub-studies for a given p-value threshold shows enriched categories replicate at a higher rate in independent samples. The vertical intercept is the overall replication rate per category.</p

Enrichment improves discovery using established methods.

<p>Among three phenotypes, (A) Height, (B) Crohn's Disease, (C) and Schizophrenia, we demonstrate an increased discovery of SNPs at a given FDR when incorporating the enriched genic annotation information into an established stratified false discovery rate (sFDR; red) framework. SNPs declared significant by sFDR also replicate at a higher rate (<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003449#pgen.1003449.s012" target="_blank">Figure S12</a>).</p

Stratified Q-Q plots and true discovery rates show consistency of enrichment.

<p><i>Upper panel:</i> Stratified Q-Q plots illustrating consistent enrichment of genic annotation categories across diverse phenotypes: (A) Height, (B) Schizophrenia (SCZ), and (C) Cigarettes per Day (CPD). All figures are corrected for inflation using intergenic inflation control. Only nominal p-values below the standard genome-wide significance threshold (p<5×10⁻⁸) are shown. <i>Lower panel:</i> Stratified True Discovery Rate (TDR) plots illustrating the increase in TDR associated with increased enrichment in (D) Height, (E) SCZ and (F) CPD. Genic annotation categories were: 5′ untranslated region (5′UTR), Exon, Intron, 3′ untranslated region (3′UTR), All SNPs, in addition to Intergenic.</p

Power as a multiple of current effective sample size for Crohn’s disease and schizophrenia.

<p>Black line displays estimated proportion of additive genetic variance due to large effects for CD data, using a GWAS significance threshold of 5 × 10⁻⁸, current sample size (log₂ 32 = 0) to 64 times current sample size (log₂ 32 = 5). Red line displays same quantities for schizophrenia data.</p

Empirical and model-based replication rates for schizophrenia.

<p>Empirical (black lines) and model-based (red lines) finite sample replication estimates. Left panel displays the average replication proportion conditional on discovery sample <i>z</i>-scores, for 30% of the overall sample apportioned to discovery sample, with the remainder apportioned to the replication sample. Red lines are computed from best fitting scale mixture of two normals. The middle panel displays the same for 50%, and the right panel for 70% of the overall sample apportioned to the training sample.</p

Empirical and model-based posterior expectations and variances for schizophrenia and Crohn’s disease.

<p><i>Upper left panel</i>: Schizophrenia empirical conditional mean of split-half replication <i>z</i>-scores (purple line) and fitted effect sizes from scale mixture of normals model (yellow line). <i>Lower left panel</i>: Schizophrenia empirical conditional variance of split-half replication <i>z</i>-scores (purple line) and fitted variances from scale mixture of normals model (yellow line). <i>Upper right panel</i>: Crohn’s disease empirical conditional mean of split-half replication <i>z</i>-scores (purple line) and fitted effect sizes from scale mixture of normals model (yellow line). <i>Lower right panel</i>: Crohn’s disease empirical conditional variance of split-half replication <i>z</i>-scores (purple line) and fitted variances from scale mixture of normals model (yellow line).</p

Replication proportions and predicted replication probabilities.

<p>Local fdr estimate are shown on the x-axis (binned from 0 to 1 in increments of 0.10), with discovery fdr computed on 26 randomly selected sub-studies in the PGC schizophrenia data consisting of 17,691 cases and 24,683 controls on <i>N</i> = 129,973 SNPs pruned to pairwise LD ≤ 0:20. For the independent replication sample we computed the meta-analysis <i>z</i>-scores using the remaining 26 studies, with 17,785 cases and 22,156 controls. Replication was defined as: (i) discovery and replication <i>z</i>-scores have same sign, and (ii) replication <i>z</i>-score associated with one-tailed <i>p</i>-value ≤ 0:05. Black squares show actual replication proportions for each bin, whereas red squares show mean predicted replication probabilities given in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005717#pgen.1005717.e087" target="_blank">Eq (15)</a>.</p

Ohnologs (Ohno): Partial least square regression (PLSR) coefficients with multiple covariates.

<p>Ohnologs (Ohno): Partial least square regression (PLSR) coefficients with multiple covariates.</p

Probing the Association between Early Evolutionary Markers and Schizophrenia

<div><p>Schizophrenia is suggested to be a by-product of the evolution in humans, a compromise for our language, creative thinking and cognitive abilities, and thus, essentially, a human disorder. The time of its origin during the course of human evolution remains unclear. Here we investigate several markers of early human evolution and their relationship to the genetic risk of schizophrenia. We tested the schizophrenia evolutionary hypothesis by analyzing genome-wide association studies of schizophrenia and other human phenotypes in a statistical framework suited for polygenic architectures. We analyzed evolutionary proxy measures: human accelerated regions, segmental duplications, and ohnologs, representing various time periods of human evolution for overlap with the human genomic loci associated with schizophrenia. Polygenic enrichment plots suggest a higher prevalence of schizophrenia associations in human accelerated regions, segmental duplications and ohnologs. However, the enrichment is mostly accounted for by linkage disequilibrium, especially with functional elements like introns and untranslated regions. Our results did not provide clear evidence that markers of early human evolution are more likely associated with schizophrenia. While SNPs associated with schizophrenia are enriched in HAR, Ohno and SD regions, the enrichment seems to be mediated by affiliation to known genomic enrichment categories. Taken together with previous results, these findings suggest that schizophrenia risk may have mainly developed more recently in human evolution.</p></div

ABC: Enrichment plots showing schizophrenia association enrichment of brain genes with various regional affiliation scores.

<p>Enrichment plots for A) human accelerated regions (HAR), B) segmental duplications (SD) and C) ohnologs are shown for: SNPs annotated to genes with some relation to the brain, as established by an NCBI site search (“Brain”); SNPs affiliated to these regions of interest (HAR, SD or Ohno) and also annotated to genes with some relation to the brain (HAR Brain, SD Brain or Ohno Brain). In case of segmental duplications, the brain genes in the regions of interest (SD Brain) look more enriched (i.e. present a higher incidence of associations [lower p-values] with schizophrenia) compared to SD or just any Brain genes. In Ohnologs, the enrichment is way lower than in SD but Ohno Brain looks more enriched than other categories. HAR Brain and HAR show similar enrichment. All annotations are LD-weighted.</p