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

Abstract

A number of genetic studies have identified rare protein-coding DNA variations associated with autism spectrum disorder (ASD), a neurodevelopmental disorder with significant genetic etiology and heterogeneity. In contrast, the contributions of functional, regulatory genetic variations that occur in the extensive non-protein-coding regions of the genome remain poorly understood. Here we developed a genome-wide analysis to identify the rare single nucleotide variants (SNVs) that occur in non-coding regions and determined the regulatory function and evolutionary conservation of these variants. Using publicly available datasets and computational predictions, we identified SNVs within putative regulatory regions in promoters, transcription factor binding sites, and microRNA genes and their target sites. Overall, we found that the regulatory variants in ASD cases were enriched in ASD-risk genes and genes involved in fetal neurodevelopment. As with previously reported coding mutations, we found an enrichment of the regulatory variants associated with dysregulation of neurodevelopmental and synaptic signaling pathways. Among these were several rare inherited SNVs found in the mature sequence of microRNAs predicted to affect the regulation of ASD-risk genes. We show a paternally inherited miR-873-5p variant with altered binding affinity for several risk-genes including NRXN2 and CNTNAP2 putatively overlay maternally inherited lossof-function coding variations in NRXN1 and CNTNAP2 to likely increase the genetic liability in an idiopathic ASD case. Our analysis pipeline provides a new resource for identifying loss-of-function regulatory DNA variations that may contribute to the genetic etiology of complex disorders.

The Landscape of Mutational Mosaicism in Autistic and Normal Human Cerebral Cortex

“…Although statistical analysis of WGS studies is challenged by thousands of simultaneous hypotheses that can be tested, the higher rate of mutation in open chromatin that we described above suggested a specific comparison of somatic mutations to a previous study that showed a role of de novo germline mutations in neural enhancer sequences in neurodevelopmental disorders 38 . We did not observe enrichment of overall sSNVs and validated mosaic indels in brain-active enhancers in ASD cases compared to controls; however, we did observe significant enrichment when assessing only sequences bearing active enhancer marks in a majority of brain epigenomes available for analysis (from Roadmap Epigenomics 39 ), reflecting those regions that are most likely to represent critical enhancers shared across individuals. When restricted to candidates that are recurrent in more than 50% (≥5/8) of available brain epigenomes, the odds ratio of having a mosaic mutation in an enhancer in ASD compared to that in control was 11.9 (95% CI: 1.97-487, p=8*10 −4 , two-tailed Fisher’s Exact test; Fig.…”

Adverse drug event‐related hospitalisation in persons with neurodevelopmental disorders: a state‐wide retrospective cohort study

“…; Williams et al . ), previous evidence has been established in separate categories, even in policy informative studies that grouped other major categories such as mood disorders, addiction or psychotic disorders (Gustavsson et al . ).…”

“…Despite high co-occurrence and co-causality of ID, ASD and ADHD (Guennewig et al 2018;Williams et al 2018), previous evidence has been established in separate categories, even in policy informative studies that grouped other major categories such as mood disorders, addiction or psychotic disorders (Gustavsson et al 2011). Understanding health disparities in relation to these NDD conditions as a group is essential to inform healthcare policy and planning as well as improve outcomes in this vulnerable population.…”

MicroRNA-210 Knockout Alters Dendritic Density and Behavioural Flexibility

“…MicroRNAs (miRNAs) represent an important class of small regulatory RNA that are enriched within the nervous system and are capable of regulating a large number of target, messenger RNAs (mRNAs) primarily through translational repression in association with the RNA induced silencing complex (RISC; Lewis et al, 2005). In recent years, increasing evidence has established miRNAs as critical regulators of neuronal development and synaptic plasticity, with new roles for neuronal miRNAs continually emerging (Guven-Ozkan et al, 2016;Williams et al, 2018;Zampa et al, 2018).…”