Integrated gene analyses of de novo variants from 46,612 trios with autism and developmental disorders DOI Creative Commons
Tianyun Wang, Chang N. Kim, Trygve E. Bakken

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(46)

Published: Nov. 9, 2022

Most genetic studies consider autism spectrum disorder (ASD) and developmental (DD) separately despite overwhelming comorbidity shared etiology. Here, we analyzed de novo variants (DNVs) from 15,560 ASD (6,557 SPARK) 31,052 DD trios independently also combined as broader neurodevelopmental disorders (NDDs) using three models. We identify 615 NDD candidate genes (false discovery rate [FDR] < 0.05) supported by ≥1 models, including 138 reaching Bonferroni exome-wide significance (P 3.64e-7) in all The group into five functional networks associating with different brain lineages based on single-cell nuclei transcriptomic data. find no evidence for ASD-specific contrast to 18 significantly enriched DD. There are 53 that show mutational bias, enrichments missense (n = 41) or truncating 12) DNVs. 10 of male- female-bias enrichment, 4 X chromosome significant female burden (DDX3X, MECP2, WDR45, HDAC8). This large-scale integrative analysis identifies candidates subsets genes.

Language: Английский

Genomic architecture of autism from comprehensive whole-genome sequence annotation DOI Creative Commons
Brett Trost, Bhooma Thiruvahindrapuram,

Ada J. S. Chan

et al.

Cell, Journal Year: 2022, Volume and Issue: 185(23), P. 4409 - 4427.e18

Published: Nov. 1, 2022

Language: Английский

Citations

157
Polygenic architecture of rare coding variation across 394,783 exomes DOI
Daniel J. Weiner, Ajay Nadig, Karthik A. Jagadeesh

et al.

Nature, Journal Year: 2023, Volume and Issue: 614(7948), P. 492 - 499

Published: Feb. 8, 2023

Language: Английский

Citations

112
Molecular and network-level mechanisms explaining individual differences in autism spectrum disorder DOI
A. Buch, Petra E. Vértes, Jakob Seidlitz

et al.

Nature Neuroscience, Journal Year: 2023, Volume and Issue: 26(4), P. 650 - 663

Published: March 9, 2023

Language: Английский

Citations

84
Multi-omic profiling of the developing human cerebral cortex at the single-cell level DOI Creative Commons
Kaiyi Zhu, Jaroslav Bendl, Samir Rahman

et al.

Science Advances, Journal Year: 2023, Volume and Issue: 9(41)

Published: Oct. 12, 2023

The cellular complexity of the human brain is established via dynamic changes in gene expression throughout development that mediated, part, by spatiotemporal activity cis-regulatory elements (CREs). We simultaneously profiled and chromatin accessibility 45,549 cortical nuclei across six broad developmental time points from fetus to adult. identified cell type-specific domains which highly correlated with expression. Differentiation pseudotime trajectory analysis indicates at CREs precedes transcription structure play a critical role neuronal lineage commitment. In addition, we mapped temporally specific genetic loci implicated neuropsychiatric traits, including schizophrenia bipolar disorder. Together, our results describe complex regulation composition stages determination shed light on impact alterations disease.

Language: Английский

Citations

58
The contributions of rare inherited and polygenic risk to ASD in multiplex families DOI Creative Commons
Matilde Cirnigliaro, Timothy S. Chang, Stephanie A. Arteaga

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(31)

Published: July 28, 2023

Autism spectrum disorder (ASD) has a complex genetic architecture involving contributions from both de novo and inherited variation. Few studies have been designed to address the role of rare variation or its interaction with common polygenic risk in ASD. Here, we performed whole-genome sequencing largest cohort multiplex families date, consisting 4,551 individuals 1,004 having two more autistic children. Using this study design, identify seven previously unrecognized ASD genes supported by majority variants, finding support for total 74 our 152 after combined analysis other studies. Autistic children demonstrate an increased burden protein-truncating variants known genes. We also find that score (PGS) is overtransmitted nonautistic parents who harbor consistent combinatorial effects offspring, which may explain reduced penetrance these parents. observe addition social dysfunction, language delay associated PGS overtransmission. These results are additive further suggest core biological feature

Language: Английский

Citations

53
GATK-gCNV enables the discovery of rare copy number variants from exome sequencing data DOI
Mehrtash Babadi, Jack Fu, Samuel K. Lee

et al.

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(9), P. 1589 - 1597

Published: Aug. 21, 2023

Language: Английский

Citations

51
Phenotypic effects of genetic variants associated with autism DOI Creative Commons
Thomas Rolland, Freddy Cliquet, Richard Anney

et al.

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(7), P. 1671 - 1680

Published: June 26, 2023

Abstract While over 100 genes have been associated with autism, little is known about the prevalence of variants affecting them in individuals without a diagnosis autism. Nor do we fully appreciate phenotypic diversity beyond formal autism diagnosis. Based on data from more than 13,000 and 210,000 undiagnosed individuals, estimated odds ratios for to rare loss-of-function (LoF) 185 alongside 2,492 displaying intolerance LoF variants. In contrast autism-centric approaches, investigated correlates these We show that are small but significant decrease fluid intelligence, qualification level income an increase metrics related material deprivation. These effects were larger autism-associated other LoF-intolerant genes. Using brain imaging 21,040 UK Biobank, could not detect differences overall anatomy between carriers non-carriers. Our results highlight importance studying effect genetic categorical need research understand association sociodemographic factors, best support carrying

Language: Английский

Citations

49
Genetic insights into human cortical organization and development through genome-wide analyses of 2,347 neuroimaging phenotypes DOI
Varun Warrier, Eva-Maria Stauffer, Qin Qin Huang

et al.

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(9), P. 1483 - 1493

Published: Aug. 17, 2023

Language: Английский

Citations

47
Single-cell multi-cohort dissection of the schizophrenia transcriptome DOI
W. Brad Ruzicka, Shahin Mohammadi, John F. Fullard

et al.

Science, Journal Year: 2024, Volume and Issue: 384(6698)

Published: May 23, 2024

The complexity and heterogeneity of schizophrenia have hindered mechanistic elucidation the development more effective therapies. Here, we performed single-cell dissection schizophrenia-associated transcriptomic changes in human prefrontal cortex across 140 individuals two independent cohorts. Excitatory neurons were most affected cell group, with transcriptional converging on neurodevelopment synapse-related molecular pathways. Transcriptional alterations included known genetic risk factors, suggesting convergence rare common genomic variants neuronal population-specific schizophrenia. Based magnitude change, identified populations marked by expression specific excitatory inhibitory states. This atlas links to etiological contextualizing established knowledge within cortical cytoarchitecture facilitating understanding pathophysiology heterogeneity.

Language: Английский

Citations

38
De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome DOI Creative Commons
Yuyang Chen, Ruebena Dawes, Hyung Chul Kim

et al.

Nature, Journal Year: 2024, Volume and Issue: 632(8026), P. 832 - 840

Published: July 11, 2024

Abstract Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily protein-coding genes 1 . Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here we identify RNA RNU4-2 as a syndromic NDD gene. encodes U4 small nuclear (snRNA), which is critical component U4/U6.U5 tri-snRNP complex major spliceosome 2 We an 18 base pair region mapping two structural elements U4/U6 snRNA duplex (the T-loop and stem III) that severely depleted variation general population, but heterozygous variants 115 NDD. Most (77.4%) have same highly recurrent single insertion (n.64_65insT). In 54 whom it could be determined, de novo were all on maternal allele. demonstrate expressed developing human brain, contrast RNU4-1 other homologues. Using sequencing, show how 5′ splice-site use systematically disrupted variants, consistent known role this during activation. Finally, estimate explain 0.4% This work underscores importance rare will provide diagnosis thousands worldwide.

Language: Английский

Citations

31