Stella Carol, Díaz-Caneja Covadonga M, Penzol Maria Jose, García-Alcón Alicia, Solís Andrea, Andreu-Bernabeu Álvaro, Gurriarán Xaquín, Arango Celso, Parellada Mara, González-Peñas Javier
Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.
Front Genet. 2023 Mar 9;14:1072563. doi: 10.3389/fgene.2023.1072563. eCollection 2023.
Genetic overlap involving rare disrupting mutations may contribute to high comorbidity rates between autism spectrum disorders and epilepsy. Despite their polygenic nature, genome-wide association studies have not reported a significant contribution of common genetic variation to comorbidity between both conditions. Analysis of common genetic variation affecting specific shared pathways such as miRNA dysregulation could help to elucidate the polygenic mechanisms underlying comorbidity between autism spectrum disorders and epilepsy. We evaluated here the role of common predisposing variation to autism spectrum disorders and epilepsy across target genes of 14 miRNAs selected through bibliographic research as being dysregulated in both disorders. We considered 4,581 target genes from various sources. We described negative genetic correlation between autism spectrum disorders and epilepsy across variants located within target genes of the 14 miRNAs selected ( = 0.0228). Moreover, polygenic transmission disequilibrium test on an independent cohort of autism spectrum disorders trios (N = 233) revealed an under-transmission of autism spectrum disorders predisposing alleles within miRNAs' target genes across autism spectrum disorders trios without comorbid epilepsy, thus reinforcing the negative relationship at the common genetic variation between both traits. Our study provides evidence of a negative relationship between autism spectrum disorders and epilepsy at the common genetic variation level that becomes more evident when focusing on the miRNA regulatory networks, which contrasts with observed clinical comorbidity and results from rare variation studies. Our findings may help to conceptualize the genetic heterogeneity and the comorbidity with epilepsy in autism spectrum disorders.
涉及罕见破坏性突变的基因重叠可能导致自闭症谱系障碍和癫痫之间的高共病率。尽管它们具有多基因性质，但全基因组关联研究尚未报告常见基因变异对这两种疾病共病的显著贡献。分析影响特定共享途径（如miRNA失调）的常见基因变异，可能有助于阐明自闭症谱系障碍和癫痫共病背后的多基因机制。我们在此评估了通过文献研究选择的14种miRNA的靶基因中，常见的自闭症谱系障碍和癫痫易感变异的作用，这些miRNA在这两种疾病中均失调。我们考虑了来自各种来源的4581个靶基因。我们描述了在所选14种miRNA的靶基因内的变异中，自闭症谱系障碍和癫痫之间的负遗传相关性（ = 0.0228）。此外，对一个独立的自闭症谱系障碍三联体队列（N = 233）进行的多基因传递不平衡测试显示，在没有合并癫痫的自闭症谱系障碍三联体中，miRNA靶基因内的自闭症谱系障碍易感等位基因传递不足，从而加强了这两种性状在常见基因变异上的负相关关系。我们的研究提供了证据，表明在常见基因变异水平上，自闭症谱系障碍和癫痫之间存在负相关关系，当关注miRNA调控网络时，这种关系变得更加明显，这与观察到的临床共病情况以及罕见变异研究的结果形成对比。我们的发现可能有助于理解自闭症谱系障碍中的基因异质性以及与癫痫的共病情况。
