Genetic architectures of cerebral ventricles and their overlap with neuropsychiatric traits

Nature Human Behaviour, Год журнала: 2023, Номер 8(1), С. 164 - 180

Опубликована: Окт. 19, 2023

The cerebral ventricles are recognized as windows into brain development and disease, yet their genetic architectures, underlying neural mechanisms utility in maintaining health remain elusive. Here we aggregated neuroimaging data from 61,974 participants (age range, 9 to 98 years) five cohorts elucidate the basis of ventricular morphology examined overlap with neuropsychiatric traits. Genome-wide association analysis a discovery sample 31,880 individuals identified 62 unique loci 785 candidate genes associated morphology. We replicated over 80% well-matched cohort lateral volume. Gene set revealed enrichment ventricular-trait-associated biological processes disease pathogenesis during both early degeneration. explored age-dependent associations different age groups investigate possible roles neurodevelopmental neurodegenerative processes. describe between traits through comprehensive integrative approaches under correlative causal assumptions. propose volume inferior heritable endophenotype predict risk Alzheimer's which might be consequence prodromal disease. Our study provides an advance understanding genetics demonstrates potential measurements tracking disorders across lifespan. A genome-wide ventricle phenotypes finds reveals

Язык: Английский

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The genetic architecture of fornix white matter microstructure and their involvement in neuropsychiatric disorders

Translational Psychiatry, Год журнала: 2023, Номер 13(1)

Опубликована: Май 26, 2023

Abstract The fornix is a white matter bundle located in the center of hippocampaldiencephalic limbic circuit that controls memory and executive functions, yet its genetic architectures involvement brain disorders remain largely unknown. We carried out genome-wide association analysis 30,832 UK Biobank individuals six diffusion magnetic resonance imaging (dMRI) traits. post-GWAS allowed us to identify causal variants phenotypes at single nucleotide polymorphisms (SNP), locus, gene levels, as well overlap with health-related further generalized our GWAS adolescent cognitive development (ABCD) cohort. identified 63 independent significant within 20 genomic loci associated ( P < 8.33 × 10 −9 ) dMRI Geminin coiled-coil domain containing GMNC NUAK family SNF1-like kinase 1 NUAK1 were highlighted, which found UKB replicated ABCD. heritability traits ranged from 10% 27%. Gene mapping strategies 213 genes, where 11 supported by all four methods. Gene-based analyses revealed pathways relating cell differentiation, astrocytes be significantly enriched. Pleiotropy eight neurological psychiatric shared variants, especially schizophrenia under conjFDR threshold 0.05. These findings advance understanding complex their relevance disorders.

Язык: Английский

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Genetic architecture of plasma Alzheimer disease biomarkers

Human Molecular Genetics, Год журнала: 2023, Номер 32(15), С. 2532 - 2543

Опубликована: Май 19, 2023

Abstract Genome-wide association studies (GWAS) of cerebrospinal fluid (CSF) Alzheimer’s Disease (AD) biomarker levels have identified novel genes implicated in disease risk, onset and progression. However, lumbar punctures limited availability may be perceived as invasive. Blood collection is readily available well accepted, but it not clear whether plasma biomarkers will informative for genetic studies. Here we perform analyses on concentrations amyloid-β peptides Aβ40 (n = 1,467) Aβ42 1,484), Aβ42/40 1467) total tau 504), phosphorylated (p-tau181; n 1079) neurofilament light (NfL; 2,058). GWAS gene-based analysis was used to identify single variant associated with levels. Finally, polygenic risk score summary statistics were investigate overlapping architecture between biomarkers, CSF AD risk. We found a six genome-wide significant signals. APOE Aβ42, Aβ42/40, tau, p-tau181 NfL. proposed 10 candidate functional the basis 12 nucleotide polymorphism-biomarker pairs brain differential gene expression analysis. overlap biomarkers. also demonstrate that possible improve specificity sensitivity these when variants regulating protein are included model. This current study using quantitative traits can critical identification impact more accurate interpretation

Язык: Английский

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Genome-wide association study unravels mechanisms of brain glymphatic activity

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 13, 2025

Язык: Английский

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Lipoic acid scaffold applications in the design of multitarget-directed ligands against Alzheimer’s disease

Bioorganic Chemistry, Год журнала: 2025, Номер 157, С. 108241 - 108241

Опубликована: Фев. 3, 2025

Язык: Английский

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