Dynamic expression of genes associated with schizophrenia and bipolar disorder across development
Dynamic expression of genes associated with schizophrenia and bipolar disorder across development
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DOI：
10.1038/s41398-019-0405-x
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发表时间：
2019-02-04
影响因子：
6.8
通讯作者：
Hall, Jeremy
中科院分区：
文献类型：
--
作者：
Clifton, Nicholas E.;Hannon, Eilis;Hall, Jeremy
常见的遗传变异在精神分裂症和双相情感障碍的风险中占很大比例。此外，有证据表明，这两种疾病之间的遗传风险存在显著但不完全的重叠。据推测，遗传变异赋予这些疾病的风险，通过影响大脑发育，导致后来出现的症状。然而，精神分裂症和双相情感障碍在不同脑区发育过程中风险基因表达的比较概况仍不清楚。使用来自最大可用队列患者和对照受试者的全基因组关联研究的基因型，我们调查了精神分裂症和双相情感障碍关联的基因是否在前额叶皮质和皮质下脑区域的13个发育阶段中的任何一个中表现出表达偏倚。我们发现，与精神分裂症的遗传关联是正相关的表达在前额叶皮层在早期中期胎儿发育和婴儿早期，并在儿童后期，在青春期稳定的表达呈负相关。相反，双相情感障碍的风险相关基因在任何产前阶段都没有表现出对表达的偏好，尽管出生后的表达模式与精神分裂症相似。这些结果突出了在前额叶皮层发育过程中，精神分裂症和双相情感障碍风险基因的动态表达，并支持产前神经发育事件与精神分裂症比双相情感障碍更密切相关的假设。
Common genetic variation contributes a substantial proportion of risk for both schizophrenia and bipolar disorder. Furthermore, there is evidence of significant, but not complete, overlap in genetic risk between the two disorders. It has been hypothesised that genetic variants conferring risk for these disorders do so by influencing brain development, leading to the later emergence of symptoms. The comparative profile of risk gene expression for schizophrenia and bipolar disorder across development over different brain regions however remains unclear. Using genotypes derived from genome-wide associations studies of the largest available cohorts of patients and control subjects, we investigated whether genes enriched for schizophrenia and bipolar disorder association show a bias for expression across any of 13 developmental stages in prefrontal cortical and subcortical brain regions. We show that genetic association with schizophrenia is positively correlated with expression in the prefrontal cortex during early midfetal development and early infancy, and negatively correlated with expression during late childhood, which stabilises in adolescence. In contrast, risk-associated genes for bipolar disorder did not exhibit a bias towards expression at any prenatal stage, although the pattern of postnatal expression was similar to that of schizophrenia. These results highlight the dynamic expression of genes harbouring risk for schizophrenia and bipolar disorder across prefrontal cortex development and support the hypothesis that prenatal neurodevelopmental events are more strongly associated with schizophrenia than bipolar disorder.