Genetic variants in miRNAs differentially expressed during brain development and their relevance to psychiatric disorders susceptibility

MicroRNAs (miRNAs) play an important regulatory role in the expression of genes involved in brain functions during development. Genetic variants in miRNA genes may impact their regulatory function and lead to psychiatric disorders. To evaluate the role of genetic variants in genes of miRNAs differentially expressed during neurodevelopment on autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), schizophrenia (SCZ), and major depressive disorder (MDD). The miRNAs were identified in the literature. Summary statistics from the most recent genome-wide association studies to date were used to evaluate the association between the selected polymorphisms and each disorder in a look-up approach. In a global analysis, we compared the standardised risk effect of variants in neurodevelopment-related miRNAs with those in the remaining miRNAs from miRBase. The global analysis showed that variants in neurodevelopment-related miRNAs had higher risk effects compared to the other miRNAs for SCZ (<i>p</i> = 0.010) and ADHD (<i>p</i> = 0.001). <i>MIR33B, MIR29B2</i>, <i>MIR29C, MIR137</i>, and <i>MIR135A1</i> were significantly associated with SCZ, while 55.9% of the miRNAs were at least nominally associated with one or more psychiatric disorders (<i>p</i> Genetic variants in neurodevelopment-related miRNAs play an important role in the genetic susceptibility of psychiatric disorders, mainly SCZ and ADHD.

微小核糖核酸（microRNA，miRNA）在机体发育过程中，参与脑功能相关基因的表达调控，发挥关键作用。miRNA基因的遗传变异可影响其调控功能，进而诱发精神类疾病。为探究神经发育阶段差异表达的miRNA基因中的遗传变异，与自闭症谱系障碍（autism spectrum disorder，ASD）、注意缺陷多动障碍（attention deficit/hyperactivity disorder，ADHD）、精神分裂症（schizophrenia，SCZ）及重度抑郁症（major depressive disorder，MDD）的关联，本研究通过文献检索确定目标miRNA，并采用查询关联分析策略，利用截至目前最新的全基因组关联研究（genome-wide association study，GWAS）汇总统计数据，评估筛选出的多态性位点与上述各精神疾病的相关性。在全局分析中，我们将神经发育相关miRNA的变异所对应的标准化风险效应，与miRBase数据库中其余miRNA的变异风险效应进行了对比。全局分析结果显示，相较于miRBase中的其余miRNA，神经发育相关miRNA的变异对精神分裂症（SCZ，p=0.010）与注意缺陷多动障碍（ADHD，p=0.001）具有更高的风险效应。MIR33B、MIR29B2、MIR29C、MIR137及MIR135A1与精神分裂症（SCZ）存在显著关联；同时，55.9%的miRNA至少在名义统计水平上与一种或多种精神类疾病存在关联（p值）。神经发育相关miRNA中的遗传变异，对精神类疾病的遗传易感性具有重要作用，尤其体现在精神分裂症（SCZ）与注意缺陷多动障碍（ADHD）中。