Some individuals with autism spectrum disorder (ASD) carry functional mutations rarely observed in the general population. We explored the genes disrupted by these variants from joint analysis of protein-truncating (PTV), missense, and copy number variants (CNVs) in a cohort of 63,237 individuals. We discovered 72 ASD risk genes at false discovery rate (FDR)≤0.001 (185 at FDR≤0.05). De novo PTVs, damaging missense variants, and CNVs represented 57.5%, 21.1%, and 8.44% of association evidence, while CNVs conferred greatest relative risk. Meta-analysis with cohorts ascertained for developmental delay (DD, N=91,605) yielded 373 ASD/DD risk genes at FDR≤0.001 (664 at FDR≤0.05), some of which differed in relative frequency of mutation between ASD and DD. The DD-associated genes were enriched in transcriptomes of progenitor and immature neuronal cells whereas genes displaying stronger evidence in ASD were more enriched in maturing neurons and overlapped with schizophreniaassociated genes, emphasizing that these neuropsychiatric disorders share common pathways to risk.
Individuals with autism spectrum disorder (ASD) or related neurodevelopmental disorders (NDDs) often carry disruptive mutations in genes that are depleted of functional variation in the broader population. We build upon this observation and exome sequencing from 154,842 individuals to explore the allelic diversity of rare protein-coding variation contributing risk for ASD and related NDDs. Using an integrative statistical model, we jointly analyzed rare protein-truncating variants (PTVs), damaging missense variants, and copy number variants (CNVs) derived from exome sequencing of 63,237 individuals from ASD cohorts. We discovered 71 genes associated with ASD at a false discovery rate (FDR) ≤ 0.001, a threshold approximately equivalent to exome-wide significance, and 183 genes at FDR ≤ 0.05. Associations were predominantly driven by de novo PTVs, damaging missense variants, and CNVs: 57.4%, 21.2%, and 8.32% of evidence, respectively. Though fewer in number, CNVs conferred greater relative risk than PTVs, and repeat-mediated de novo CNVs exhibited strong maternal bias in parent-of-origin (e.g., 92.3% of 16p11.2 CNVs), whereas all other CNVs showed a paternal bias. To explore how genes associated with ASD and NDD overlap or differ, we analyzed our ASD cohort alongside a developmental delay (DD) cohort from the deciphering developmental disorders study (DDD; n=91,605 samples). We first reanalyzed the DDD dataset using the same models as the ASD cohorts, then performed joint analyses of both cohorts and identified 373 genes contributing to NDD risk at FDR ≤ 0.001 and 662 NDD risk genes at FDR ≤ 0.05. Of these NDD risk genes, 54 genes (125 genes at FDR ≤ 0.05) were unique to the joint analyses and not significant in either cohort alone. Our results confirm overlap of most ASD and DD risk genes, although many differ significantly in frequency of mutation. Analyses of single-cell transcriptome datasets showed that genes associated predominantly with DD were strongly enriched for earlier neurodevelopmental cell types, whereas genes displaying stronger evidence for association in ASD cohorts were more enriched for maturing neurons. The ASD risk genes were also enriched for genes associated with schizophrenia from a separate rare coding variant analysis of 121,570 individuals, emphasizing that these neuropsychiatric disorders share common pathways to risk.
<b><i>Background:</i></b> Both depression and use of antidepressants have been reported to be risk factors for stroke, but results from the literature are still not conclusive regarding the risk attributable to antidepressants rather than to the underlying disease. <b><i>Objective:</i></b> To estimate the risk of incident stroke associated with use of antidepressants, a meta-analysis was performed. <b><i>Methods:</i></b> PubMed, Medline, Cochrane, ProQuest, Scopus, and bibliographies of articles were searched up to September 2018. The final meta-analysis included 31 observational studies. STROBE statement-checklist and GRADE guidelines were used for quality assessment. <b><i>Results:</i></b> The random-effects meta-analysis on the association between use of any antidepressant and risk of any stroke resulted in meta-risk ratio (RR) of 1.41 (95% CI 1.13–1.69, <i>I</i><sup>2</sup> = 93, 7%). The pooled estimate for selective serotonin reuptake inhibitors (SSRIs) resulted in a meta-RR of 1.41 (95% CI 1.13–1.69, <i>I</i><sup>2</sup> = 94, 5%) and for tricyclic antidepressants (TCAs) of 1.08 (95% CI 0.93–1.22, <i>I</i><sup>2</sup> = 0%). SSRI users displayed a higher risk of ischemic (1.57, 95% CI 1.06–2.09, <i>I</i><sup>2</sup> = 96.4%) than hemorrhagic stroke (1.34, 95% CI 1.15–1.53, <i>I</i><sup>2</sup> = 72.9%). Meta-RRs were lower for TCA, although with smaller heterogeneity (ischemic 1.22, 95% CI 0.97–1.46; <i>I</i><sup>2</sup> = 0%; hemorrhagic: 1.00, 95% CI 0.83–1.18, <i>I</i><sup>2</sup> = 0%). Restricting to studies on depressed individuals, both SSRI and TCA remained associated with an increased risk of any stroke type (meta-RR for SSRI: 1.27, 95% CI 1.11–1.43, <i>I</i><sup>2</sup> = 76.6%; meta-RR for TCA: 1.21 (95% CI 1.02–1.40, <i>I</i><sup>2</sup> = 47, 3%). <b><i>Conclusions:</i></b> Despite the high heterogeneity, these results demonstrate that even after adjusting for depression, use of antidepressants retains an independent increased risk of stroke.
USP9X is an X-chromosome gene that escapes X-inactivation. Loss or compromised function of USP9X leads to neurodevelopmental disorders in males and females. While males are impacted primarily by hemizygous partial loss-of-function missense variants, in females de novo heterozygous complete loss-of-function mutations predominate, and give rise to the clinically recognisable USP9X-female syndrome. Here we provide evidence of the contribution of USP9X missense and small in-frame deletion variants in USP9X-female syndrome also. We scrutinise the pathogenicity of eleven such variants, ten of which were novel. Combined application of variant prediction algorithms, protein structure modelling, and assessment under clinically relevant guidelines universally support their pathogenicity. The core phenotype of this cohort overlapped with previous descriptions of USP9X-female syndrome, but exposed heightened variability. Aggregate phenotypic information of 35 currently known females with predicted pathogenic variation in USP9X reaffirms the clinically recognisable USP9X-female syndrome, and highlights major differences when compared to USP9X-male associated neurodevelopmental disorders.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.