Representation of StMA gene occurrence (per 1000 CNV mapped genes) in autism CNV datasets (blue), schizophrenia (purple) and control datasets (green).

<p>The “dbVAR controls” represents a reference dataset created from the merger of all CNV loci derived from a series of control population datasets (shown in light green). </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

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

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

Segmental duplication (SD): Partial least square regression (PLSR) coefficients with multiple covariates.

<p>Segmental duplication (SD): Partial least square regression (PLSR) coefficients with multiple covariates.</p

Human accelerated regions (HAR): Partial least square regression (PLSR) coefficients with multiple covariates.

<p>Human accelerated regions (HAR): Partial least square regression (PLSR) coefficients with multiple covariates.</p

Demographic information on the Han Chinese sample used in the study.

<p>Demographic information on the Han Chinese sample used in the study.</p

Quantile-quantile plot for test statistic inflation, lambda median = 1.026.

<p>Quantile-quantile plot for test statistic inflation, lambda median = 1.026.</p

Top 25 results from the pre-imputation analysis of case-control association with heroin dependence, after implementation of clumping in PLINK to identify relatively independent signals.

<p>Genes are mapped based on chromosome and base pair position, using the program SeattleSeq.</p

ABC: Enrichment plots for schizophrenia, stratifying SNPs according to their affiliation to human accelerated regions segmental duplications and ohnologs.

<p>Plot A shows all SNPs stratified by affiliation to human accelerated regions (HAR) and non (NonHAR). Plot B shows all SNPs stratified by affiliation to segmental duplications (SD) and non (NonSD). Plot C shows all SNPs stratified by affiliation to ohnologs (Ohno) and non (NonOhno). Some enrichment could be present in HAR but the drop at the leftmost end of the plot suggests low SNP count and consequent high error rate. A clearer enrichment is present in segmental duplications and a similar but weaker one in ohnologs. All annotations are LD-weighted.</p

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