Next-gen sequencing identifies non-coding variation disrupting miRNA-binding sites in neurological disorders

Abstract

Understanding the genetic factors underlying neurodevelopmental and neuropsychiatric disorders is a major challenge given their prevalence and potential severity for quality of life. While large scale genomic screens have made major advances in this area, for many disorders the genetic underpinnings are complex and poorly understood. To date the field has focused predominantly on protein coding variation, but given the importance of tightly controlled gene expression for normal brain development and disorder, variation that affects non-coding regulatory regions of the genome are likely to play an important role in these phenotypes. Herein we show the importance of 3’UTR non-coding regulatory variants across neurodevelopmental and neuropsychiatric disorders. We devised a pipeline for identifying and functionally validating putatively pathogenic variants from NGS data. We applied this pipeline to a cohort of children with severe specific language impairment (SLI) and identified a functional, SLI-associated variant affecting gene regulation in cells and post-mortem human brain. This variant, and the affected gene (ARHGEF39), represent new putative risk factors for SLI. Furthermore, we identified 3’UTR regulatory variants across autism, schizophrenia and bipolar disorder NGS cohorts demonstrating their impact on neurodevelopmental and neuropsychiatric disorders. Our findings show the importance of investigating non-coding regulatory variants when determining risk factors contributing to neurodevelopmental and neuropsychiatric disorders. In the future, integration of such regulatory variation with protein coding changes will be essential for uncovering the genetic causes of complex neurological disorders and the fundamental mechanisms underlying health and disease.

Multivariate genome-wide association study of rapid automatized naming and rapid alternating stimulus in Hispanic and African American youth

“…However, further functional assays must be conducted to shed mechanistic light on the pathways involved. There is growing evidence that noncoding regions of the genome have an impact on reading-related traits, and the identification of a lncRNA associated with a reading endophenotype lends additional support (59). Implication of RNLS also reinforces the hypothesis that alterations in neurochemical modulation in the brain could contribute to impairments in reading performance.…”

An integrative analysis of non-coding regulatory DNA variations associated with autism spectrum disorder

“…Recent genome sequencing studies have identified many risk genes from the loss-of-function protein-coding variants, which has driven a move toward analysis of convergent risk pathways [1][2][3][4]. However, less is known about the contribution to risk by the variants in non-coding regulatory regions, which hold the potential to disrupt the finely tuned biological pathways involved in brain development, as demonstrated by a recent study in the influence of the 3′ untranslated regions (3′UTR)-regulatory variants in language impairment [5]. Nevertheless, progress is being made by using whole-genome sequencing of the ASD families.…”

“…Moreover, these novel approaches involve predicting whether a variant has the potential to change the dynamics of gene networks by disrupting the interactions between key regulatory molecules, such as miRNAs and transcription factors, and their target functional pathways [8,15,16]. There is now an increased focus on ASD-associated mutations within the regulatory regions, particularly near-known ASD-risk genes [17,18], with studies examining the enhancer regions [19] and microRNA targeting [5]. Together these data provide a vision of how we might assess the potential impact of non-coding regulatory DNA variations associated with ASD.…”

Six new reference-quality bat genomes illuminate the molecular basis and evolution of bat adaptations

“…To test this hypothesis, we used reporter assays 104,105 to determine if the bat and human versions of miR-337-3p were functionally active and if they showed species-specific regulation of an “ideal” predicted target sequence (Table S20). While bat miR-337-3p strongly repressed the expression of its cognate bat target sequence, it had no effect on the human site, and vice versa (Fig.…”