Common and rare variants of microRNA genes in autism spectrum disorders

Abstract

Objectives. MicroRNAs (miRNAs) are post-transcriptional regulators that have been shown to be involved in disease susceptibility. Here we explore the possible contribution of common and rare variants in miRNA genes in autism spectrum disorders (ASD). Methods. A total of 350 tag SNPs from 163 miRNA genes were genotyped in 636 ASD cases and 673 controls. A replication study was performed in a sample of 449 ASD cases and 415 controls. Additionally, rare variants in 701 miRNA genes of 41 ASD patients were examined using whole-exome sequencing. Results. The most significant association in the discovery sample was obtained for the miR-133b/miR-206 cluster (rs16882131, P = 0.00037). The replication study did not reach significance. However, the pooled analysis (1,085 cases and 1,088 controls) showed association with two miRNA clusters: miR-133b/miR-206 (rs16882131, permP = 0.037) and miR-17/miR-18a/miR-19a/miR-20a/miR-19b-1/miR92a-1 (rs6492538, permP = 0.019). Both miR-133b and miR-206 regulate the MET gene, previously associated with ASD. Rare variant analysis identified mutations in several miRNA genes, among them miR-541, a brain-specific miRNA that regulates SYN1, found mutated in ASD. Conclusions. Although our results do not establish a clear role for miRNAs in ASD, we pinpointed a few candidate genes. Further exome and GWAS studies are warranted to get more insight into their potential contribution to the disorder.

Key words::

• autistic disorder
• genetic association studies
• biological psychiatry
• MicroRNAs
• exome

Acknowledgments

We are grateful to all the patients and their families for their kind participation. We thank all the clinical collaborators that contributed to the diagnosis of the probands. We would like to thank M. Monfort and M. Torres for technical support at the Spanish National Genotyping Center (CeGen) in Barcelona and in Santiago de Compostela, respectively and M. Bayés from the National Center for Genomic Analysis (CNAG), Barcelona. Financial support was received from “Fundació La Marató de TV3” (092010), “Fundación Alicia Koplowitz”, AGAUR (2014SGR932, 2014SGR1468), the Spanish “Ministerio de Economía y Competitividad” (SAF2012-33484, SAF2010-21165), the Spanish “Fondo de Investigación Sanitaria” (FIS PI-1002512 and PI-1302841), the University of Bologna (RFO), Saarland University (grant #T2042103-01 to C. Freitag), the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement numbers 278948 (TACTICS) and 602805 (AGGRESSOTYPE), the European Community's H2020 Research and Innovation Program under the Marie Sklodowska-Curie grant agreement number 643051 (MiND), and the Innovative Medicines Initiative Joint Undertaking under grant agreement number 115300. Collecting the Dutch samples was supported by grants from Karakter Child and Adolescent Psychiatry (to J. Buitelaar) and a grant by the Netherlands Organisation for Scientific Research (NWO grant #91610024 to N. Rommelse). CT was supported by the European Union (Marie Curie, PIEF-GA-2009-254930) and BT by AGAUR (Generalitat de Catalunya).

Statement of Interest

None to declare.

Supplementary material available online

Supplementary Tables 1 to 11 and Figures 1, 2.