Genes4Epilepsy: An epilepsy gene resource

Epilepsia, Journal Year: 2023, Volume and Issue: 64(5), P. 1368 - 1375

Published: Feb. 21, 2023

Abstract Objective “How many epilepsy genes are there?” is a frequently asked question. We sought to (1) provide curated list of that cause monogenic epilepsies, and (2) compare contrast gene panels from multiple sources. Methods compared included on the (as July 29, 2022) four clinical diagnostic providers: Invitae, GeneDx, Fulgent Genetics, Blueprint Genetics; two research resources: PanelApp Australia ClinGen. A master all unique was supplemented by additional identified via PubMed searches up until August 15, 2022, using search terms “genetics” AND/OR “epilepsy” “seizures”. Evidence supporting role for manually reviewed; those with limited or disputed evidence were excluded. All annotated according inheritance pattern broad phenotype. Results The comparison revealed high heterogeneity in both number (range: 144–511) content. Just 111 (15.5%) panels. Subsequent manual curation “epilepsy genes” >900 etiologies. Almost 90% associated developmental epileptic encephalopathies. By only 5% causes “common epilepsies” (i.e., generalized focal syndromes). Autosomal recessive most frequent (56% genes); however, this varied phenotype(s). Genes common syndromes more likely be dominantly inherited types. Significance Our publicly available: github.com/bahlolab/genes4epilepsy will regularly updated. This resource can utilized target beyond panels, enrichment methods candidate prioritization. invite ongoing feedback contributions scientific community [email protected] .

Language: Английский

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A concerted neuron–astrocyte program declines in ageing and schizophrenia

Nature, Journal Year: 2024, Volume and Issue: 627(8004), P. 604 - 611

Published: March 6, 2024

Abstract Human brains vary across people and over time; such variation is not yet understood in cellular terms. Here we describe a relationship between people’s cortical neurons astrocytes. We used single-nucleus RNA sequencing to analyse the prefrontal cortex of 191 human donors aged 22–97 years, including healthy individuals with schizophrenia. Latent-factor analysis these data revealed that, whose more strongly expressed genes encoding synaptic components, astrocytes distinct functions for synthesizing cholesterol, an astrocyte-supplied component membranes. call this neuron astrocyte program (SNAP). In schizophrenia ageing—two conditions that involve declines cognitive flexibility plasticity 1,2 —cells divested from SNAP: astrocytes, glutamatergic (excitatory) GABAergic (inhibitory) all showed reduced SNAP expression corresponding degrees. The astrocytic neuronal components both involved which genetic risk factors were concentrated. SNAP, varies quantitatively even among similar age, may underlie many aspects normal interindividual differences be important point convergence multiple kinds pathophysiology.

Language: Английский

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Rare copy-number variants as modulators of common disease susceptibility

Genome Medicine, Journal Year: 2024, Volume and Issue: 16(1)

Published: Jan. 8, 2024

Copy-number variations (CNVs) have been associated with rare and debilitating genomic disorders (GDs) but their impact on health later in life the general population remains poorly described.

Language: Английский

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Identification of novel genomic risk loci shared between common epilepsies and psychiatric disorders

Brain, Journal Year: 2023, Volume and Issue: 146(8), P. 3392 - 3403

Published: Feb. 9, 2023

Psychiatric disorders and common epilepsies are heritable with a high comorbidity overlapping symptoms. However, the causative mechanisms underlying this relationship poorly understood. Here we aimed to identify genetic loci between epilepsy psychiatric gain better understanding of their shared clinical features. We analysed genome-wide association study data for all (n = 44 889), generalized 33 446), focal 39 348), schizophrenia 77 096), bipolar disorder 406 405), depression 500 199), attention deficit hyperactivity 53 293) autism spectrum 46 350). First, applied MiXeR tool estimate total number causal variants influencing disorders. Next, used conjunctional false discovery rate statistical framework improve power discover genomic loci. Additionally, assessed validity findings in independent cohorts, functionally characterized identified The phenotypes were considerably less polygenic (1.0 K 3.4 variants) than (5.6 13.9 variants), being least having highest polygenicity (13.9 variants). observed cross-trait enrichment depression. Using analysis, 40 distinct jointly associated at <0.05, four which epilepsy. Most risk 31). Among loci, 32 novel epilepsy, two epilepsies. There was mixture concordant discordant allelic effects sign concordance highly consistent datasets disorders, supporting findings. Gene-set analysis implicated biological processes related cell cycle regulation, protein phosphatase activity, membrane vesicle function; gene-set analyses other underpowered. extensive overlap mixed effect directions demonstrates complex these line bi-directional relationship, indicates that may contribute pathophysiological features

Language: Английский

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Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: July 20, 2023

Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure share genetic factors, we pooled CNV data from 10,590 individuals disorders, 16,109 clinically validated epilepsy, and 492,324 population controls identified 25 genome-wide significant loci, 22 of which novel such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, reciprocal CNVs 16p11.2, 22q11.21. Using additional 248,751 23 neuropsychiatric phenotypes, explored pleiotropy these loci. Finally, in a subset epilepsy detailed clinical available, performed phenome-wide association analyses between individual annotations categorized through Human Phenotype Ontology (HPO). For six CNVs, 19 associations specific HPO terms generated, all phenotype signatures across 17 categories relevant epileptologists. This is most comprehensive investigation related potential implications practice.

Language: Английский

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An integrated single-nucleus and spatial transcriptomics atlas reveals the molecular landscape of the human hippocampus

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 28, 2024

Abstract The hippocampus contains many unique cell types, which serve the structure’s specialized functions, including learning, memory and cognition. These cells have distinct spatial topography, morphology, physiology, connectivity, highlighting need for transcriptome-wide profiling strategies that retain cytoarchitectural organization. Here, we generated spatially-resolved transcriptomics (SRT) single-nucleus RNA-sequencing (snRNA-seq) data from adjacent tissue sections of anterior human across ten adult neurotypical donors. We defined molecular profiles hippocampal types domains. Using non-negative matrix factorization transfer integrated these to define gene expression patterns within snRNA-seq infer in SRT data. With this approach, leveraged existing rodent datasets feature information on circuit connectivity neural activity induction make predictions about axonal projection targets likelihood ensemble recruitment spatially-defined cellular populations hippocampus. Finally, genome-wide association studies with transcriptomic identify enrichment genetic components neurodevelopmental, neuropsychiatric, neurodegenerative disorders domains, To comprehensive atlas accessible scientific community, both raw processed are freely available, through interactive web applications.

Language: Английский

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Deep learning predicts DNA methylation regulatory variants in specific brain cell types and enhances fine mapping for brain disorders

Science Advances, Journal Year: 2025, Volume and Issue: 11(1)

Published: Jan. 1, 2025

DNA methylation (DNAm) is essential for brain development and function potentially mediates the effects of genetic risk variants underlying disorders. We present INTERACT, a transformer-based deep learning model to predict regulatory affecting DNAm levels in specific cell types, leveraging existing single-nucleus data from human brain. show that INTERACT accurately predicts type–specific profiles, achieving an average area under receiver operating characteristic curve 0.99 across types. Furthermore, variants, which reflect cellular context enrich heritability brain-related traits relevant demonstrate incorporating predicted variant CpG sites enhances fine mapping three disorders—schizophrenia, depression, Alzheimer’s disease—and facilitates causal genes particular Our study highlights power identifying will enhance our understanding genetics complex traits.

Language: Английский

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Shared and distinct ultra-rare genetic risk for diverse epilepsies: A whole-exome sequencing study of 54,423 individuals across multiple genetic ancestries

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Feb. 24, 2023

Identifying genetic risk factors for highly heterogeneous disorders like epilepsy remains challenging. Here, we present the largest whole-exome sequencing study of to date, with >54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple ancestry groups diverse subtypes and 33,444 controls, investigate rare variants that confer disease risk. These analyses implicate seven individual genes, three gene sets, four copy number at exome-wide significance. Genes encoding ion channels show strong association subtypes, including epileptic encephalopathies, generalized focal epilepsies, while most other discoveries are subtype-specific, highlighting distinct contributions different epilepsies. Combining results single nucleotide/short indel-, number-, common variants, offer an expanded view architecture epilepsy, growing evidence convergence among loci on same genes. Top candidate genes enriched roles in synaptic transmission neuronal excitability, particularly postnatally neocortex. We also identify shared variant between neurodevelopmental disorders. Our data can be accessed via interactive browser, hopefully facilitating diagnostic efforts accelerating development follow-up studies.

Language: Английский

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Breaking down causes, consequences, and mediating effects of telomere length variation on human health

Genome biology, Journal Year: 2024, Volume and Issue: 25(1)

Published: May 17, 2024

Abstract Background Telomeres form repeated DNA sequences at the ends of chromosomes, which shorten with each cell division. Yet, factors modulating telomere attrition and health consequences thereof are not fully understood. To address this, we leveraged data from 326,363 unrelated UK Biobank participants European ancestry. Results Using linear regression bidirectional univariable multivariable Mendelian randomization (MR), elucidate relationships between leukocyte length (LTL) 142 complex traits, including diseases, biomarkers, lifestyle factors. We confirm that telomeres age show a stronger decline in males than females, these contributing to majority 5.4% LTL variance explained by phenome. MR reveals 23 traits LTL. Smoking cessation high educational attainment associate longer LTL, while weekly alcohol intake, body mass index, urate levels, female reproductive events, such as childbirth, shorter also identify 24 affected risk for cardiovascular, pulmonary, some autoimmune diseases being increased short other conditions cancers. Through MR, may partially mediate impact attainment, childbirth on proxied lifespan. Conclusions Our study sheds light modulators, consequences, mediatory role telomeres, portraying an intricate relationship lifestyle, socio-economic

Language: Английский

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Haploinsufficiency underlies the neurodevelopmental consequences of SLC6A1 variants

The American Journal of Human Genetics, Journal Year: 2024, Volume and Issue: 111(6), P. 1222 - 1238

Published: May 22, 2024

Heterozygous variants in SLC6A1, encoding the GAT-1 GABA transporter, are associated with seizures, developmental delay, and autism. The majority of affected individuals carry missense variants, many which recurrent germline de novo mutations, raising possibility gain-of-function or dominant-negative effects. To understand functional consequences, we performed an vitro uptake assay for 213 unique including 24 control variants. De consistently resulted a decrease uptake, keeping haploinsufficiency underlying all neurodevelopmental phenotypes. Where present, ClinVar pathogenicity reports correlated well data; data can inform future remaining 72% unscored Surface localization was assessed 86 variants; two-thirds loss-of-function prevented from being present on membrane while surface but reduced activity third. Surprisingly, showed moderate effects that no evidence Using linear regression across multiple severity scores to extrapolate potential SLC6A1 observe abundance residues sensitive substitution. extent this vulnerability accounts clinically observed enrichment; overlap hypermutable CpG sites Strategies increase expression wild-type allele likely be beneficial disorders, though stage required rescue remain unknown.

Language: Английский

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