scholarly journals Environmental carcinogens disproportionally mutate genes implicated in neurodevelopmental disorders

2021 ◽  
Author(s):  
Brennan H Baker ◽  
Shaoyi Zhang ◽  
Jeremy M Simon ◽  
Sarah M McLarnan ◽  
Wendy K Chung ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Developmental Disorders ◽  
De Novo ◽  
Autism Spectrum ◽  
Disease Genes ◽  
Environmental Carcinogens ◽  
De Novo Mutations ◽  
New Paradigm ◽  
Disease Etiology ◽  
Neurodevelopmental Disease

De novo mutations contribute to a large proportion of sporadic psychiatric and developmental disorders, yet the potential role of environmental carcinogens as drivers of causal de novo mutations in neurodevelopmental disorders is poorly studied. We demonstrate that several mutagens, including polycyclic aromatic hydrocarbons (PAHs), disproportionately mutate genes related to neurodevelopmental disorders including autism spectrum disorders (ASD), schizophrenia, and attention deficit hyperactivity disorder (ADHD). Other disease genes including amyotrophic lateral sclerosis (ALS), Alzheimers disease, congenital heart disease, orofacial clefts, and coronary artery disease were generally not mutated more than expected. Our findings support a new paradigm of neurodevelopmental disease etiology driven by a contribution of environmentally induced rather than random mutations.

scholarly journals A new paradigm emerges from the study of de novo mutations in the context of neurodevelopmental disease

2012 ◽  
Vol 18 (2) ◽  
pp. 141-153 ◽  
Author(s):  
C S Ku ◽  
C Polychronakos ◽  
E K Tan ◽  
N Naidoo ◽  
Y Pawitan ◽  
...  
Keyword(s):  
De Novo ◽  
De Novo Mutations ◽  
New Paradigm ◽  
Neurodevelopmental Disease

scholarly journals Schizophrenia, autism spectrum disorders and developmental disorders share specific disruptive coding mutations

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Elliott Rees ◽  
Hugo D. J. Creeth ◽  
Hai-Gwo Hwu ◽  
Wei J. Chen ◽  
Ming Tsuang ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Neurodevelopmental Disorders ◽  
Developmental Disorders ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Increase Risk ◽  
Spectrum Disorders ◽  
Using Data ◽  
Shared Risk

AbstractPeople with schizophrenia are enriched for rare coding variants in genes associated with neurodevelopmental disorders, particularly autism spectrum disorders and intellectual disability. However, it is unclear if the same changes to gene function that increase risk to neurodevelopmental disorders also do so for schizophrenia. Using data from 3444 schizophrenia trios and 37,488 neurodevelopmental disorder trios, we show that within shared risk genes, de novo variants in schizophrenia and neurodevelopmental disorders are generally of the same functional category, and that specific de novo variants observed in neurodevelopmental disorders are enriched in schizophrenia (P = 5.0 × 10−6). The latter includes variants known to be pathogenic for syndromic disorders, suggesting that schizophrenia be included as a characteristic of those syndromes. Our findings imply that, in part, neurodevelopmental disorders and schizophrenia have shared molecular aetiology, and therefore likely overlapping pathophysiology, and support the hypothesis that at least some forms of schizophrenia lie on a continuum of neurodevelopmental disorders.

scholarly journals Schizophrenia, autism spectrum disorders and developmental disorders share specific disruptive coding mutations

2020 ◽  
Author(s):  
Elliott Rees ◽  
Hugo Creeth ◽  
Hai-Gwo Hwu ◽  
Wei Chen ◽  
Ming Tsuang ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Intellectual Disability ◽  
Neurodevelopmental Disorders ◽  
Developmental Disorders ◽  
De Novo ◽  
Autism Spectrum ◽  
Risk Genes ◽  
Spectrum Disorders ◽  
Coding Variants ◽  
Shared Risk

Abstract Genes enriched for rare disruptive coding variants in schizophrenia overlap those in which disruptive mutations are associated with neurodevelopmental disorders (NDDs), particularly autism spectrum disorders and intellectual disability. However, it is unclear whether this implicates the same specific variants, or even variants with the same functional effects on shared risk genes. Here, we show that de novo mutations in schizophrenia are generally of the same functional category as those that confer risk for NDDs, and that the specific de novo mutations in NDDs are enriched in schizophrenia. These findings indicate that, in part, NDDs and schizophrenia have shared molecular aetiology, and therefore likely overlapping pathophysiology. We also observe pleiotropic effects for variants known to be pathogenic for several syndromic developmental disorders, suggesting that schizophrenia should be included among the phenotypes associated with these mutations. Collectively, our findings support the hypothesis that at least some forms of schizophrenia lie within a continuum of neurodevelopmental disorders.

scholarly journals Schizophrenia, autism spectrum disorders and developmental disorders share specific disruptive coding mutations

2020 ◽  
Author(s):  
Elliott Rees ◽  
Hugo D. J. Creeth ◽  
Hai-Gwo Hwu ◽  
Wei J. Chen ◽  
Ming Tsuang ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Intellectual Disability ◽  
Neurodevelopmental Disorders ◽  
Developmental Disorders ◽  
De Novo ◽  
Autism Spectrum ◽  
Risk Genes ◽  
Spectrum Disorders ◽  
Coding Variants ◽  
Shared Risk

AbstractGenes enriched for rare disruptive coding variants in schizophrenia overlap those in which disruptive mutations are associated with neurodevelopmental disorders (NDDs), particularly autism spectrum disorders and intellectual disability. However, it is unclear whether this implicates the same specific variants, or even variants with the same functional effects on shared risk genes. Here, we show that de novo mutations in schizophrenia are generally of the same functional category as those that confer risk for NDDs, and that the specific de novo mutations in NDDs are enriched in schizophrenia. These findings indicate that, in part, NDDs and schizophrenia have shared molecular aetiology, and therefore likely overlapping pathophysiology. We also observe pleiotropic effects for variants known to be pathogenic for several syndromic developmental disorders, suggesting that schizophrenia should be included among the phenotypes associated with these mutations. Collectively, our findings support the hypothesis that at least some forms of schizophrenia lie within a continuum of neurodevelopmental disorders.

scholarly journals Paternal-age-related de novo mutations and risk for five disorders

2017 ◽  
Author(s):  
Jacob L. Taylor ◽  
Jean-Christophe P.G. Debost ◽  
Sarah U. Morton ◽  
Emilie M. Wigdor ◽  
Henrike O. Heyne ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
De Novo ◽  
Autism Spectrum ◽  
National Registry ◽  
Paternal Age ◽  
De Novo Mutations ◽  
Single Nucleotide Variants ◽  
Advanced Paternal Age ◽  
Age Related ◽  
Rate Ratios

AbstractBackgroundThere are well-established epidemiologic associations between advanced paternal age and increased offspring risk for several psychiatric and developmental disorders. These associations are commonly attributed to age-related de novo mutations. However, the actual magnitude of risk conferred by age-related de novo mutations in the male germline is unknown. Quantifying this risk would clarify the clinical and public health significance of delayed paternity.MethodsUsing results from large, parent-child trio whole-exome-sequencing studies, we estimated the relationship between paternal-age-related de novo single nucleotide variants (dnSNVs) and offspring risk for five disorders: autism spectrum disorders (ASD), congenital heart disease (CHD), neurodevelopmental disorders with epilepsy (EPI), intellectual disability (ID), and schizophrenia (SCZ). Using Danish national registry data, we then investigated the degree to which the epidemiologic association between each disorder and advanced paternal age was consistent with the estimated role of de novo mutations.ResultsIncidence rate ratios comparing dnSNV-based risk to offspring of 45 versus 25-year-old fathers ranged from 1.05 (95% confidence interval 1.01–1.13) for SCZ to 1.29 (95% CI 1.13-1.68) for ID. Epidemiologic estimates of paternal age risk for CHD, ID and EPI were consistent with the dnSNV effect. However, epidemiologic effects for ASDs and SCZ significantly exceeded the risk that could be explained by dnSNVs alone (p<2e-4 for both comparisons).ConclusionIncreasing dnSNVs due to advanced paternal age confer a small amount of offspring risk for psychiatric and developmental disorders. For ASD and SCZ, epidemiologic associations with delayed paternity largely reflect factors that cannot be assumed to increase with age.

scholarly journals Rare schizophrenia risk variants are enriched in genes shared with neurodevelopmental disorders

2016 ◽  
Author(s):  
Tarjinder Singh ◽  
James T. R. Walters ◽  
Mandy Johnstone ◽  
David Curtis ◽  
Jaana Suvisaari ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Developmental Disorders ◽  
De Novo ◽  
Copy Number Variant ◽  
Autism Spectrum ◽  
Risk Genes ◽  
Mrna Targets ◽  
Risk Variants ◽  
Autism Spectrum Disorder Risk ◽  
Significant Enrichment

AbstractBy meta-analyzing rare coding variants in whole-exome sequences of 4,264 schizophrenia cases and 9,343 controls, de novo mutations in 1,077 trios, and array-based copy number variant calls from 6,882 cases and 11,255 controls, we show that individuals with schizophrenia carry a significant burden of rare damaging variants in a subset of 3,230 “highly constrained” genes previously identified as having near-complete depletion of protein truncating variants. Furthermore, rare variant enrichment analyses demonstrate that this burden is concentrated in known autism spectrum disorder risk genes, genes diagnostic of severe developmental disorders, and the autism-implicated sets of promoter targets of CHD8, and mRNA targets of FMRP. We further show that schizophrenia patients with intellectual disability have a greater enrichment of rare damaging variants in highly constrained genes and developmental disorder genes, but that a weaker but significant enrichment exists throughout the larger schizophrenia population. Combined, our results demonstrate that schizophrenia risk loci of large effect across a range of variant types implicate a common set of genes shared with broader neurodevelopmental disorders, suggesting a path forward in identifying additional risk genes in psychiatric disorders and further supporting a neurodevelopmental etiology to the pathogenesis of schizophrenia.

scholarly journals Transcript expression-aware annotation improves rare variant discovery and interpretation

2019 ◽  
Author(s):  
Beryl B. Cummings ◽  
Konrad J. Karczewski ◽  
Jack A. Kosmicki ◽  
Eleanor G. Seaby ◽  
Nicholas A. Watts ◽  
...  
Keyword(s):  
Rare Variant ◽  
Developmental Disorders ◽  
De Novo ◽  
Disease Diagnosis ◽  
Autism Spectrum ◽  
Disease Genes ◽  
Loss Of Function ◽  
Tissue Samples ◽  
Complex Disorders ◽  
Alternative Mrna Splicing

AbstractThe acceleration of DNA sequencing in patients and population samples has resulted in unprecedented catalogues of human genetic variation, but the interpretation of rare genetic variants discovered using such technologies remains extremely challenging. A striking example of this challenge is the existence of disruptive variants in dosage-sensitive disease genes, even in apparently healthy individuals. Through manual curation of putative loss of function (pLoF) variants in haploinsufficient disease genes in the Genome Aggregation Database (gnomAD)(1), we show that one explanation for this paradox involves alternative mRNA splicing, which allows exons of a gene to be expressed at varying levels across cell types. Currently, no existing annotation tool systematically incorporates this exon expression information into variant interpretation. Here, we develop a transcript-level annotation metric, the proportion expressed across transcripts (pext), which summarizes isoform quantifications for variants. We calculate this metric using 11,706 tissue samples from the Genotype Tissue Expression project(2) (GTEx) and show that it clearly differentiates between weakly and highly evolutionarily conserved exons, a proxy for functional importance. We demonstrate that expression-based annotation selectively filters 22.8% of falsely annotated pLoF variants found in haploinsufficient disease genes in gnomAD, while removing less than 4% of high-confidence pathogenic variants in the same genes. Finally, we apply our expression filter to the analysis of de novo variants in patients with autism spectrum disorder (ASD) and developmental disorders and intellectual disability (DD/ID) to show that pLoF variants in weakly expressed regions have effect sizes similar to those of synonymous variants, while pLoF variants in highly expressed exons are most strongly enriched among cases versus controls. Our annotation is fast, flexible, and generalizable, making it possible for any variant file to be annotated with any isoform expression dataset, and will be valuable for rare disease diagnosis, rare variant burden analyses in complex disorders, and curation and prioritization of variants in recall-by-genotype studies.

scholarly journals Integrated gene analyses of de novo mutations from 46,612 trios with autism and developmental disorders

2021 ◽  
Author(s):  
Tianyun Wang ◽  
Chang Kim ◽  
Trygve E. Bakken ◽  
Madelyn A. Gillentine ◽  
Barbara Henning ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
De Novo ◽  
Autism Spectrum ◽  
Mutational Bias ◽  
De Novo Mutations ◽  
Cell Nuclei ◽  
Genetic Studies ◽  
Risk Genes ◽  
Functional Studies ◽  
Disease Subtypes

ABSTRACTMost genetic studies consider autism spectrum disorder (ASD) and developmental disorder (DD) separately despite overwhelming comorbidity and shared genetic etiology. Here we analyzed de novo mutations (DNMs) from 15,560 ASD (6,557 are new) and 31,052 DD trios independently and combined as broader neurodevelopmental disorders (NDD) using three models. We identify 615 candidate genes (FDR 5%, 189 potentially novel) by one or more models, including 138 reaching exome-wide significance (p < 3.64e-07) in all models. We find no evidence for ASD-specific genes in contrast to 18 genes significantly enriched for DD. There are 53 genes show particular mutational-bias including enrichments for missense (n=41) or truncating DNM (n=12). We find 22 genes with evidence of sex-bias including five X chromosome genes also with significant female burden (DDX3X, MECP2, SMC1A, WDR45, and HDAC8). NDD risk genes group into five functional networks associating with different brain developmental lineages based on single-cell nuclei transcriptomic data, which provides important insights into disease subtypes and future functional studies.

scholarly journals De novo mutations in regulatory elements cause neurodevelopmental disorders

2017 ◽  
Author(s):  
Patrick J. Short ◽  
Jeremy F. McRae ◽  
Giuseppe Gallone ◽  
Alejandro Sifrim ◽  
Hyejung Won ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Developmental Disorders ◽  
De Novo ◽  
Genetic Disorders ◽  
Fetal Brain ◽  
Regulatory Elements ◽  
De Novo Mutations ◽  
Active Elements ◽  
Diagnostic Coding ◽  
Genome Wide

SummaryDe novo mutations in hundreds of different genes collectively cause 25-42% of severe developmental disorders (DD). The cause in the remaining cases is largely unknown. The role of de novo mutations in regulatory elements affecting known DD associated genes or other genes is essentially unexplored. We identified de novo mutations in three classes of putative regulatory elements in almost 8,000 DD patients. Here we show that de novo mutations in highly conserved fetal-brain active elements are significantly and specifically enriched in neurodevelopmental disorders. We identified a significant two-fold enrichment of recurrently mutated elements. We estimate that, genome-wide, de novo mutations in fetaLbrain active elements are likely to be causal for 1-3% of patients without a diagnostic coding variant and that only a small fraction (<2%) of de novo mutations in these elements are pathogenic. Our findings represent a robust estimate of the contribution of de novo mutations in regulatory elements to this genetically heterogeneous set of disorders, and emphasise the importance of combining functional and evolutionary evidence to delineate regulatory causes of genetic disorders.

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