AUTHOR=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 

TITLE=Analysis of common genetic variation across targets of microRNAs dysregulated both in ASD and epilepsy reveals negative correlation

JOURNAL=Frontiers in Genetics

VOLUME=Volume 14 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2023.1072563

DOI=10.3389/fgene.2023.1072563

ISSN=1664-8021

ABSTRACT=Genetic overlap involving rare disrupting mutations may contribute to high comorbidity rates between autism spectrum disorders (ASD) and epilepsy. Despite their polygenic nature, genome-wide association studies (GWAS) 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 ASD and epilepsy. 
We evaluated here the role of common predisposing variation to ASD 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 in silico sources. We described negative genetic correlation between ASD and epilepsy across variants located within target genes of the 14 miRNAs selected (p=0.0228). Moreover, polygenic transmission disequilibrium test (pTDT) on an independent cohort of ASD trios (N = 233) revealed an under-transmission of ASD predisposing alleles within miRNAs’ target genes across ASD 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 ASD 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 ASD.