Probing the Association between Early Evolutionary Markers and Schizophrenia

Abstract

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.

Analysis of differentially methylated regions in primates and non-primates provides support for the evolutionary hypothesis of schizophrenia

“…Our results are also in line with the findings of Srinivasan et al (2017), who failed to find evidence of enrichment of schizophrenia using genomic markers of evolution dating back to 200 MYA. The same authors also reported enrichment of association for regions of more recent evolution in modern humans (Srinivasan et al, 2015).…”

“…Other regions known as human accelerated regions (HARs) (Gittelman et al, 2015; Pollard et al, 2006; Xu et al, 2015), first described by Pollard et al (2006), show accelerated evolution in humans compared to primates or mammals. HARs have also provided some evidence of enrichment of association with schizophrenia (Xu et al, 2015), but these findings may have been driven by a few genes since they were not replicated using a polygenic approach (Srinivasan et al, 2017, 2015).…”

Functional analysis of evolutionary human methylated regions in schizophrenia patients

“…Other genetic studies have also suggested that genomic markers of recent evolution are enriched for schizophrenia associated single nucleotide polymorphisms (SNPs ) [28][29][30]. Thus together with our results this has narrowed the evolutionary hypothesis of the schizophrenia proposed by TJ Crow and others [26,27] to a possible effect of recent evolution in the maintenance of schizophrenia in humans.…”

Schizophrenia and Human Self-Domestication: An Evolutionary Linguistics Approach

“…Likewise, genomic regions that have undergone positive selection in anatomically modern humans (AMH) are enriched in gene loci associated with SZ [Srinivasan et al, 2016]. This enrichment has been recently linked to changes in regulatory elements of the genome, like introns and untranslated regions [Srinivasan et al, 2017]. This raises the intriguing possibility that most SZ risk alleles have appeared more recently in human evolution.…”