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

Front Genet. 2023 Mar 9:14:1072563. doi: 10.3389/fgene.2023.1072563. eCollection 2023.

Abstract

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 in silico sources. We described negative genetic correlation between autism spectrum disorders and epilepsy across variants located within target genes of the 14 miRNAs selected (p = 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.

Keywords: autism; comorbidity; epilepsy; genetic correlation; genetic heterogeneity; microRNA.

Grants and funding

CS was supported by Inphinit Grant from Fundación La Caixa. JGP was supported by a Sara Borrell contract from the ISCIII. This work was supported by the Spanish Ministry of Science and Innovation. Instituto de Salud Carlos III, CIBER—Consorcio Centro de Investigación Biomédica en Red- (CB/07/09/0023), co-financed by ERDF Funds from the European Commission, “A way of making Europe” (SAM16PE07CP1, PI17/00481, PI19/01024, PI20/00721, PI20/01382), financed by the European Union—NextGenerationEU (PMP21/00051), Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds, European Union Seventh Framework Program, European Union H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking: Project PRISM-2 (Grant agreement No. 101034377), Project AIMS-2-TRIALS (Grant agreement No. 777394), Horizon Europe, the National Institute of Mental Health of the National Institutes of Health under Award Number 1U01MH124639-01 (Project ProNET) and Award Number 5P50MH115846-03 (project FEP-CAUSAL), Fundación Familia Alonso, and Fundación Alicia Koplowitz. J González-Peñas holds a Sara Borrell grant from Instituto de Salud Carlos III (CD20/00118). C. M. Díaz-Caneja holds a Juan Rodés Grant from Instituto de Salud Carlos III (JR19/00024). ÁA-B holds a Hortega Grant from Instituto de Salud Carlos III (CM20/00114). CS has held an INPhINIT GRANT from the European Union’s Horizon 2020 Research and Innovation programme (Marie Skłodowska-Curie grant agreement No. 713673), co-founded by “la Caixa” Foundation. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results