Common microRNAs Target Established ASD Genes

COMPLEX GENETIC ARCHITECTURE IN AUTISM Autism spectrum disorder (ASD) encompasses a range of early-onset neurodevelopmental disorders characterized by impaired social interactions and communications, together with repetitive stereotypic behaviors (MIM20895; DSM5). Individuals with ASD can display a broad clinical profile ranging in symptom severity and comorbidities. A strong genetic component underlying ASD has been firmly established; hundreds of genes and chromosomal loci are known to be associated with the disorder and have been cataloged in ASD-specific genetic databases such as AutDB (1). The potential genetic risk factors range from candidate genes reported from genetic association studies to rare, recurrent gene-disruptive mutations identified in ASD individuals using high-throughput technologies such as whole exome sequencing (2). A number of recurrent copy number variants (CNVs) that overlap with related neurodevelopmental and neuropsychiatric disorders such as intellectual disability and schizophrenia have been implicated in ASD as well. Two recent studies, in particular, provide a deeper understanding of the complex genetic architecture of ASD. First, a genome-wide analysis revealed shared risk loci between five major psychiatric disorders including ASD, attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder, and schizophrenia (3). The second study examined the detailed structure of the type of genetic liability in ASD and showed that inherited common variants contributed to 49.4% heritability, whereas rare de novo variants accounted for only 2.6% (4). Despite this progress in ASD genetics, the underlying perturbations in brain development that contributes to the emergence of specific symptoms along developmental time points, whether in the first years of life in ASD or during adolescence in the case of schizophrenia, remains largely unresolved. The regulatory mechanisms that orchestrate the precise temporal and spatial patterns of gene expression in the brain are at the forefront of research for brain-based disorders. The importance of various types of non-coding RNAs is being increasingly recognized in this regulatory process, with microRNAs (miRNAs) emerging as a leading candidate. miRNAs are highly conserved small non-coding RNAs approximately 22 nucleotides in length that regulate gene expression mostly by binding to the 3 UTR of target messenger RNAs (mRNAs). miRNAs recognize their targets primarily through complementarity with the seed sequence at nucleotides 2–8 of the 5 end of the miRNA. A distinguishing feature of miRNAs lies in the ability of a single miRNA molecule to bind to the recognition site on many mRNAs and subsequently regulate their expression (5). By this mechanism, miRNA–mRNA interactions can potentially modulate expression of hundreds of target genes and influence the corresponding cellular networks. Any disturbances of such a system within a neuronal context could lead to altered brain circuits and synaptic function – processes implicated in disorders such as autism or schizophrenia.