Individuals with intellectual disability have an increased burden of de novo variants in cis-regulatory elements of glutamatergic neurons.
Sosa, E. A.; O'Shea, D.; Rosean, S.; Yoon, C.; Stauber, J.; Castillo, P. E.; Seoighe, C.; Fazzari, M. J.; Greally, J. M.
Show abstract
To understand the role of non-coding sequence variation in neurodevelopmental disorders, we studied 709,222 de novo variants (DNVs) using the genomes of 20,366 individuals. We found enrichment of DNVs at cis-regulatory elements (CREs) of all somatic cell types, attributable to the deamination of 5-methylcytosine at CG dinucleotide-dense CREs. In neurodivergent individuals with or without intellectual disability (ID), the DNVs were enriched at genes implicated in autism/ID at promoter-proximal CREs of brain cell types specifically. As the properties of the DNVs were not sufficiently distinctive to explain the phenotypic associations, we performed a multivariate category-wide association study (CWAS) that revealed enrichment of DNVs in CREs of glutamatergic neurons in individuals with ID, with a random forest analysis demonstrating an increased burden of these events in these individuals with ID. Our findings are consistent with a model of non-coding variants contributing to the oligogenic heritability of neurodevelopmental disorders.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
- Genetic correlates of phenotypic heterogeneity in autism 97%
- Decomposition of phenotypic heterogeneity in autism reveals distinct and coherent genetic programs 97%
- Identification of shared and differentiating genetic risk for autism spectrum disorder, attention deficit hyperactivity disorder and case subgroups 96%
Similar papers in this journal
- Association between genes regulating neural pathways for quantitative traits of speech and language disorders 95%
- Exome sequencing of 457 autism families recruited online provides evidence for novel ASD genes 93%
- Discordance between a deep learning model and clinical-grade variant pathogenicity classification in a rare disease cohort 91%
Similar papers in this journal
- Whole genome sequence-based association analysis of African American individuals with bipolar disorder and schizophrenia 94%
- Long-read genome sequencing for the diagnosis of neurodevelopmental disorders 93%
- Challenges in screening for de novo noncoding variants contributing to genetically complex phenotypes 93%
Similar papers in this journal
- Effects of gene dosage on cognitive ability: A function-based association study across brain and non-brain processes 95%
- The genetic and phenotypic correlates of neonatal Complement Component 3 and 4 protein concentrations with a focus on psychiatric and autoimmune disorders 94%
- Interaction studies of risk proteins in human induced neurons reveal convergent biology and novel mechanisms underlying autism spectrum disorders 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.