Genome-wide analysis reveals extensive genetic overlap between childhood phenotypes and later-life type 2 diabetes

Computers in Biology and Medicine, Journal Year: 2024, Volume and Issue: 171, P. 108065 - 108065

Published: Jan. 29, 2024

Language: Английский

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Unraveling the shared genetics of common epilepsies and general cognitive ability.

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

Published: March 26, 2024

Objective: Cognitive impairment is prevalent among individuals with epilepsy, and it possible that genetic factors can underlie this relationship. Here, we investigated the potential shared basis of common epilepsies general cognitive ability (COG). Methods: We applied linkage disequilibrium score (LDSC) regression, MiXeR conjunctional false discovery rate (conjFDR) to analyze different aspects overlap between COG epilepsies. used largest available genome–wide association study data on ( n = 269,867) 27,559 cases, 42,436 controls), including broad phenotypes ′all epilepsy ′, focal generalized (GGE), as well specific subtypes. functionally annotated identified loci using a variety biological resources validated results in independent samples. Results: Using MiXeR, (11.2k variants) was estimated be almost four times more polygenic than epilepsy′, GGE, juvenile myoclonic (JME), childhood absence (CAE) (2.5k — 2.9k variants). The other were insufficiently powered for analysis. show extensive significant negative correlations (-0.23 -0.04). share variants both GGE 2.3k JME CAE. conjFDR, 66 distinct epilepsies, novel associations (27), epilepsy′ (5), (5) CAE (5). implicated genes significantly expressed multiple brain regions. samples (COG: p 1.0 × 10 -14 ; epilepsy′: 5.6 -3 ). Significance: Our demonstrates substantial identifies overlapping genomic loci. Enhancing our understanding relationship may lead development comorbidity–targeted treatments.

Language: Английский

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Dissecting the Shared Genetic Architecture of Common Epilepsies With Cortical Brain Morphology

Neurology Genetics, Journal Year: 2024, Volume and Issue: 10(3)

Published: May 29, 2024

Epilepsies are associated with differences in cortical thickness (TH) and surface area (SA). However, the mechanisms underlying these relationships remain elusive. We investigated extent to which phenotypes share genetic influences.

Language: Английский

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Translational study on the role of genetic and prenatal risk factors in neurodevelopmental psychiatric disorders

Published: Jan. 1, 2024

Neurodevelopmental psychiatric disorders (NPDs) like attention deficit hyperactivity disorder (ADHD), autism spectrum (ASD), and schizophrenia, affect millions of people worldwide. Despite recent progress in NPD research, much remains to be discovered about their underpinnings, therapeutic targets, effects biological sex age. Risk factors influencing brain development signalling include prenatal inflammation genetic variation. This dissertation aimed build upon these findings by combining behavioural, molecular, neuromorphological investigations mouse models such risk factors, i.e. maternal immune activation (MIA), neuron-specific overexpression (OE) the cytoplasmatic isoforms RNA-binding protein RBFOX1, neuronal deletion small Ras GTPase DIRAS2. Maternal infections during pregnancy pose an increased for NPDs offspring. While viral-like MIA has been previously established elsewhere, this study was first our institution implement model. I validated NPD-relevant deficits anxiety- depression-like behaviours, as well dose- sex-specific social offspring following early gestation. Proteomic analyses embryonic adult hippocampal (HPC) synaptoneurosomes highlighted novel known targets affected MIA. Analysis dataset implicated neurodevelopmental disruptions lipid, polysaccharide, glycoprotein metabolism, important proper membrane function, signalling, myelination, NPD-pertinent sequelae. In adulthood, observed changes encompassed transmembrane trafficking intracellular apoptosis, cytoskeletal organisation pathways. Importantly, 50 proteins altered HPC were enriched synaptic vesicle cycle. A persistently upregulated cluster formed a functional network involved presynaptic downregulated embryos but adults correlated with deficits. 49/50 genes encoding significantly associated NPD- comorbidity-relevant traits human phenome-wise association data phenotypes. These highlight future intervention at-risk individuals. MIA-evoked neuroarchitecture prefrontal cortex (PFC) male female mice sex- region-specific alterations dendritic spine morphology, possibly underlining behavioural To further investigate NPDs, performed based on implications RBFOX1’s pleiotropic role neuropsychiatric previous preclinical findings. Cytoplasmatic OE which affects stability translation thousands used disseminate its morphology behaviour. RBFOX1 length branching PFC led both HPC. Due ASD-like endophenotypes Rbfox1 KO importance gene × environment susceptibility, probed interaction low-dose Both alone loss perinatal period. Preliminary suggested that might increase anhedonia-like behaviours. Morphological density reduced complexity. post-mortem dorsolateral older did not reveal significant common variant abundance. expand risks, evaluated homo- (KO) or heterozygous (HET) Diras2 novel, DIRAS2’s function is largely unknown, it ADHD humans neurodevelopment vitro. mice, there subtle behaviour, more pronounced males, keeping data. had subtly improved cognitive performance, while HET exhibited behaviours line core symptoms, e.g. earning difficulties (females), response inhibition (males), suggesting dose-sensitivity sex-specificity. The morphological revealed multiple aberrations PFC, HPC, amygdala males. KOs exclusively opposite those HETs NPD-like Region- genotype-specific expression Diras1 six relevant regions females, also revealing differences survival regulator mTOR, underlie differences. conclusion, partial knockdown resembled each other core, NPD-associated phenotypes, full differed from those. My suggest complex sex-dependent relationships between interventions, whose influences converge onto molecular An assessment putative overlap, available proteomic three linked via downstream interactions, upstream regulators. Future studies should distinct shared aspects MIA, DIRAS2

Language: Английский

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Exome Sequencing of 963 Chinese Families Identifies Novel Epilepsy Candidate Genes

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

Published: June 11, 2024

Abstract Epilepsy, a prevalent neurodevelopmental disorder in children, is often accompanied by detrimental psychological consequences and other comorbidities. We performed exome sequencing on 963 patient-parent trios, revealing differences genetic epidemiology between Chinese European epilepsy cohorts. The diagnostic yield for known genes was 40%. Pathogenic variants were most commonly found SCN1A, KCNQ2, DEPDC5. Additionally, we identified 15 novel monogenic candidates at least two patients diagnosed with developmental epileptic encephalopathy, non-acquired focal epilepsy, or generalized including ADCY2, BCAR3, CDC45, CHRNG, CRTC2, CSMD1, CSMD2, KDM6B, KIF1B, PLEKHM3, PPP4R1, RASGRP2, SGSM2, SYNE1 , ZFHX3 . Aside from ADCY2 which implicated the GABAergic synapse pathway based KEGG analysis, these do not belong to pathways. Local field potential recordings zebrafish calcium imaging experiments validated associations 11 of genes, excluding those unsuitable functional analyses. Furthermore, that CRTC2 overexpression leads hippocampal neuronal hyperactivity using multi-electrode arrays electrophysiology. have documented first-line medications prescribed harboring candidate genes. This study expands our understanding underpinnings provides opportunities early diagnosis personalized medicine approaches.

Language: Английский

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