Autism-Associated Genes and Neighboring LncRNAs Converge on Key Gene Regulatory Networks

Overview

Journal bioRxiv

Date 2025 Feb 3

PMID 39896631

Authors

Rebecca E Andersen

Maya Talukdar

Tyler Sakamoto

Janet H T Song

Xuyu Qian

Seungil Lee

Ryan N Delgado

Sijing Zhao

Gwenyth Eichfeld

Julia Harms

Christopher A Walsh

Affiliations

Soon will be listed here.

Abstract

The diversity of genes implicated in autism spectrum disorder (ASD) creates challenges for identifying core pathophysiological mechanisms. Aggregation of seven different classes of genetic variants implicated in ASD, in a database we call , reveals shared features across distinct types of ASD variants. Functional interrogation of 19 ASD genes and 9 neighboring long non-coding RNAs (lncRNAs) using CRISPR-Cas13 strikingly revealed differential gene expression profiles that were significantly enriched for other ASD genes. Furthermore, construction of a gene regulatory network (GRN) enabled the identification of central regulators that exhibit convergently altered activity upon ASD gene disruption. Thus, this study reveals how perturbing distinct ASD-associated genes can lead to shared, broad dysregulation of GRNs with critical relevance to ASD. This provides a crucial framework for understanding how diverse genes, including lncRNAs, can play convergent roles in key neurodevelopmental processes and ultimately contribute to ASD.

References

Gandal M, Haney J, Wamsley B, Yap C, Parhami S, Emani P . Broad transcriptomic dysregulation occurs across the cerebral cortex in ASD. Nature. 2022; 611(7936):532-539. PMC: 9668748. DOI: 10.1038/s41586-022-05377-7. View

Li C, Fleck J, Martins-Costa C, Burkard T, Themann J, Stuempflen M . Single-cell brain organoid screening identifies developmental defects in autism. Nature. 2023; 621(7978):373-380. PMC: 10499611. DOI: 10.1038/s41586-023-06473-y. View

Shepherdson J, Hutchison K, Wellalage Don D, McGillivray G, Choi T, Allan C . Variants in ZFX are associated with an X-linked neurodevelopmental disorder with recurrent facial gestalt. Am J Hum Genet. 2024; 111(3):487-508. PMC: 10940019. DOI: 10.1016/j.ajhg.2024.01.007. View

Szklarczyk D, Kirsch R, Koutrouli M, Nastou K, Mehryary F, Hachilif R . The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res. 2022; 51(D1):D638-D646. PMC: 9825434. DOI: 10.1093/nar/gkac1000. View

Liberzon A, Birger C, Thorvaldsdottir H, Ghandi M, Mesirov J, Tamayo P . The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 2016; 1(6):417-425. PMC: 4707969. DOI: 10.1016/j.cels.2015.12.004. View

Paulsen B, Velasco S, Kedaigle A, Pigoni M, Quadrato G, Deo A . Autism genes converge on asynchronous development of shared neuron classes. Nature. 2022; 602(7896):268-273. PMC: 8852827. DOI: 10.1038/s41586-021-04358-6. View

Bai D, Yip B, Windham G, Sourander A, Francis R, Yoffe R . Association of Genetic and Environmental Factors With Autism in a 5-Country Cohort. JAMA Psychiatry. 2019; 76(10):1035-1043. PMC: 6646998. DOI: 10.1001/jamapsychiatry.2019.1411. View

Rockowitz S, Zheng D . Significant expansion of the REST/NRSF cistrome in human versus mouse embryonic stem cells: potential implications for neural development. Nucleic Acids Res. 2015; 43(12):5730-43. PMC: 4499139. DOI: 10.1093/nar/gkv514. View

Mattick J, Amaral P, Carninci P, Carpenter S, Chang H, Chen L . Long non-coding RNAs: definitions, functions, challenges and recommendations. Nat Rev Mol Cell Biol. 2023; 24(6):430-447. PMC: 10213152. DOI: 10.1038/s41580-022-00566-8. View

10.

Wei J, Lotfy P, Faizi K, Baungaard S, Gibson E, Wang E . Deep learning and CRISPR-Cas13d ortholog discovery for optimized RNA targeting. Cell Syst. 2023; 14(12):1087-1102.e13. DOI: 10.1016/j.cels.2023.11.006. View

11.

Noor A, Whibley A, Marshall C, Gianakopoulos P, Piton A, Carson A . Disruption at the PTCHD1 Locus on Xp22.11 in Autism spectrum disorder and intellectual disability. Sci Transl Med. 2010; 2(49):49ra68. PMC: 2987731. DOI: 10.1126/scitranslmed.3001267. View

12.

Ang C, Ma Q, Wapinski O, Fan S, Flynn R, Lee Q . The novel lncRNA is pro-neurogenic and mutated in human neurodevelopmental disorders. Elife. 2019; 8. PMC: 6380841. DOI: 10.7554/eLife.41770. View

13.

Wang Y, Chen S, Li W, Jiang R, Wang Y . Associating divergent lncRNAs with target genes by integrating genome sequence, gene expression and chromatin accessibility data. NAR Genom Bioinform. 2021; 2(2):lqaa019. PMC: 7671357. DOI: 10.1093/nargab/lqaa019. View

14.

Werling D, Parikshak N, Geschwind D . Gene expression in human brain implicates sexually dimorphic pathways in autism spectrum disorders. Nat Commun. 2016; 7:10717. PMC: 4762891. DOI: 10.1038/ncomms10717. View

15.

Katayama Y, Nishiyama M, Shoji H, Ohkawa Y, Kawamura A, Sato T . CHD8 haploinsufficiency results in autistic-like phenotypes in mice. Nature. 2016; 537(7622):675-679. DOI: 10.1038/nature19357. View

16.

Boukas L, Havrilla J, Hickey P, Quinlan A, Bjornsson H, Hansen K . Coexpression patterns define epigenetic regulators associated with neurological dysfunction. Genome Res. 2019; 29(4):532-542. PMC: 6442390. DOI: 10.1101/gr.239442.118. View

17.

Zhang P, Omanska A, Ander B, Gandal M, Stamova B, Schumann C . Neuron-specific transcriptomic signatures indicate neuroinflammation and altered neuronal activity in ASD temporal cortex. Proc Natl Acad Sci U S A. 2023; 120(10):e2206758120. PMC: 10013873. DOI: 10.1073/pnas.2206758120. View

18.

Grove J, Ripke S, Als T, Mattheisen M, Walters R, Won H . Identification of common genetic risk variants for autism spectrum disorder. Nat Genet. 2019; 51(3):431-444. PMC: 6454898. DOI: 10.1038/s41588-019-0344-8. View

19.

Weinschutz Mendes H, Neelakantan U, Liu Y, Fitzpatrick S, Chen T, Wu W . High-throughput functional analysis of autism genes in zebrafish identifies convergence in dopaminergic and neuroimmune pathways. Cell Rep. 2023; 42(3):112243. PMC: 10277173. DOI: 10.1016/j.celrep.2023.112243. View

20.

Kalkman H . A review of the evidence for the canonical Wnt pathway in autism spectrum disorders. Mol Autism. 2012; 3(1):10. PMC: 3492093. DOI: 10.1186/2040-2392-3-10. View