Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom; MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom.
Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, Maryland; Centre for Computational Biology, Johns Hopkins University Medical Campus, Baltimore, Maryland.
Biol Psychiatry. 2021 Sep 15;90(6):399-408. doi: 10.1016/j.biopsych.2021.03.009. Epub 2021 Mar 13.
Recent breakthroughs in psychiatric genetics have implicated biological pathways onto which genetic risk for psychiatric disorders converges. However, these studies do not reveal the developmental time point(s) at which these pathways are relevant.
We aimed to determine the relationship between psychiatric risk and developmental gene expression relating to discrete biological pathways. We used postmortem RNA sequencing data (BrainSeq and BrainSpan) from brain tissue at multiple prenatal and postnatal time points, with summary statistics from recent genome-wide association studies of schizophrenia, bipolar disorder, and major depressive disorder. We prioritized gene sets for overall enrichment of association with each disorder and then tested the relationship between the association of their constituent genes with their relative expression at each developmental stage.
We observed relationships between the expression of genes involved in voltage-gated cation channel activity during early midfetal, adolescence, and early adulthood time points and association with schizophrenia and bipolar disorder, such that genes more strongly associated with these disorders had relatively low expression during early midfetal development and higher expression during adolescence and early adulthood. The relationship with schizophrenia was strongest for the subset of genes related to calcium channel activity, while for bipolar disorder, the relationship was distributed between calcium and potassium channel activity genes.
Our results indicate periods during development when biological pathways related to the activity of calcium and potassium channels may be most vulnerable to the effects of genetic variants conferring risk for psychiatric disorders. Furthermore, they indicate key time points and potential targets for disorder-specific therapeutic interventions.
最近精神疾病遗传学的突破表明，精神疾病的遗传风险汇聚到了生物途径上。然而，这些研究并没有揭示这些途径相关的发展时间点。
我们旨在确定精神疾病风险与离散生物途径相关的发育基因表达之间的关系。我们使用了来自多个产前和产后时间点脑组织的精神病学全基因组关联研究的 RNA 测序数据（BrainSeq 和 BrainSpan），以及精神分裂症、双相情感障碍和重度抑郁症的汇总统计数据。我们优先考虑与每种疾病总体关联富集的基因集，然后测试其组成基因与每个发育阶段相对表达之间的关联。
我们观察到参与早期中期胎儿、青春期和成年早期电压门控阳离子通道活性的基因表达与精神分裂症和双相情感障碍的关联之间存在关系，即与这些疾病关联更强的基因在早期中期胎儿发育期间相对表达较低，而在青春期和成年早期表达较高。与精神分裂症关系最强的是与钙通道活性相关的基因子集，而对于双相情感障碍，这种关系分布在钙和钾通道活性基因之间。
我们的研究结果表明，在发育过程中与钙和钾通道活性相关的生物途径可能在遗传变异赋予精神疾病风险的影响下最脆弱的时期。此外，它们还指出了特定于疾病的治疗干预的关键时间点和潜在目标。
