Probing the Association between Early Evolutionary Markers and Schizophrenia

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.

现有研究提示，精神分裂症（Schizophrenia）是人类演化过程中的一项副产物，是我们为语言、创造性思维与认知能力所做出的演化权衡，因此本质上属于人类特有的精神障碍。其在人类演化历程中的起源时间至今尚不明确。本研究针对若干早期人类演化标记物及其与精神分裂症遗传风险的关联展开探究。我们采用适配多基因架构的统计框架，通过分析精神分裂症及其他人类表型的全基因组关联研究数据，对精神分裂症演化假说进行了检验。我们分析了三类演化替代指标：人类加速区域（human accelerated regions）、片段重复以及ohnolog基因（ohnologs），这些指标覆盖了人类演化的不同时段，用于与精神分裂症关联的人类基因组位点进行重叠分析。多基因富集分析图显示，精神分裂症关联位点在人类加速区域、片段重复区域及ohnolog基因区域中的分布占比更高。不过，该富集现象主要可由连锁不平衡（linkage disequilibrium）解释，尤其是与内含子、非翻译区等功能元件的连锁不平衡。本研究结果并未提供明确证据，证明早期人类演化标记物更易与精神分裂症产生关联。尽管与精神分裂症相关的单核苷酸多态性（single nucleotide polymorphisms, SNPs）在人类加速区域、ohnolog基因区域及片段重复区域中存在富集，但该富集现象似乎是通过与已知基因组富集类别的关联所介导的。结合既往研究成果，本研究发现提示，精神分裂症的风险变异或许主要是在人类演化的较晚阶段才逐渐形成的。