The shared genetic risk architecture of neurological and psychiatric disorders: a genome-wide analysis

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Июль 23, 2023

While neurological and psychiatric disorders have historically been considered to reflect distinct pathogenic entities, recent findings suggest shared pathobiological mechanisms. However, the extent which these heritable share genetic influences remains unclear. Here, we performed a comprehensive analysis of GWAS data, involving nearly 1 million cases across ten diseases disorders, compare their common risk biological underpinnings. Using complementary statistical tools, demonstrate widespread overlap even in absence correlations. This indicates that large set variants impact multiple but with divergent effect sizes. Furthermore, interrogation revealed range processes associated diseases, while consistently implicated neuronal biology. Altogether, study key etiological aspects, has important implications for disease classification, precision medicine, clinical practice.

Язык: Английский

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Association of caffeine consumption with cerebrospinal fluid biomarkers in mild cognitive impairment and Alzheimer's disease: A BALTAZAR cohort study

Alzheimer s & Dementia, Год журнала: 2024, Номер unknown

Опубликована: Авг. 4, 2024

Abstract INTRODUCTION We investigated the link between habitual caffeine intake with memory impairments and cerebrospinal fluid (CSF) biomarkers in mild cognitive impairment (MCI) Alzheimer's disease (AD) patients. METHODS MCI ( N = 147) AD 116) patients of Biomarker AmyLoid pepTide AlZheimer's diseAse Risk (BALTAZAR) cohort reported their at inclusion using a dedicated survey. Associations consumption CSF (tau, p‐tau181, amyloid beta 1‐42 [Aβ ], Aβ 1‐40 ) were analyzed logistic analysis covariance models. RESULTS Adjusted on Apolipoprotein E APOE ε4), age, sex, education level, tobacco, lower was associated higher risk to be amnestic (OR: 2.49 [95% CI: 1.13 5.46]; p 0.023) 0.047), /Aβ 0.040), /p‐tau181 0.020) whole cohort. DISCUSSION Data support beneficial effect markers Highlights studied impact BALTAZAR Low is being MCI/AD Caffeine

Язык: Английский

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LD‐informed deep learning for Alzheimer's gene loci detection using WGS data

Alzheimer s & Dementia Translational Research & Clinical Interventions, Год журнала: 2025, Номер 11(1)

Опубликована: Янв. 1, 2025

Язык: Английский

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Polygenic risk discriminates Lewy body dementia from Alzheimer's disease

Alzheimer s & Dementia, Год журнала: 2025, Номер unknown

Опубликована: Янв. 24, 2025

Lewy body dementia (LBD) shares genetic risk factors with Alzheimer's disease (AD), including apolipoprotein E (APOE), but is distinguishable at the genome-wide level. Polygenic scores (PRS) may therefore improve diagnostic classification. We assessed classification using AD-PRS excluding APOE (AD-PRSno APOE), score (APOE-RS), and plasma phosphorylated tau 181 (p-tau181), in 83 participants LBD, 27 positron emission tomography amyloid beta (Aβ)positive mild cognitive impairment or AD (MCI+/AD), 57 controls. Together AD-PRSno APOE-RS performed similarly to p-tau181 discriminating MCI+/AD from controls (area under curve 76% vs. 79%) LBD (71% 72%). In Aβ positivity was significantly associated APOE-RS, not APOE, p-tau181. Combining improved discrimination of (81%) (75%), detection (82%). deposition while also beyond APOE. explains phenotypic variance captured by investigated (AD) polygenic (PRS), (p-tau181) classify (LBD). achieved similar accuracy without contributed LBD. Amyloid AD-PRS, accuracy.

Язык: Английский

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The genetics of neurodegenerative diseases is the genetics of age-related damage clearance failure

Molecular Psychiatry, Год журнала: 2025, Номер unknown

Опубликована: Янв. 29, 2025

Abstract In this perspective we draw together the data from genome wide association studies for Alzheimer’s disease, Parkinson’s disease and tauopathies reach conclusion that in each case, most of risk loci are involved clearance deposited proteins: microglial removal Aβ, synucleinopathies, lysosomal synuclein tauopathies, tau protein by ubiquitin proteasome. We make point identified through not strictly pathogenic but rather relate to failures remove age related damage. discuss these issues context copathologies elderly individuals prediction polygenic score analysis at different ages. Finally, what analytic approaches needed now have adequately sized case control analyses white populations.

Язык: Английский

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Genetic Markers of Postmortem Brain Iron

Journal of Neurochemistry, Год журнала: 2025, Номер 169(2)

Опубликована: Фев. 1, 2025

ABSTRACT Brain iron (Fe) dyshomeostasis is implicated in neurodegenerative diseases. Genome‐wide association studies (GWAS) have identified plausible loci correlated with peripheral levels of Fe. Systemic organs and the brain share several Fe regulatory proteins but there likely exist different homeostatic pathways. We performed first GWAS inductively coupled plasma mass spectrometry measures postmortem from 635 Rush Memory Aging Project (MAP) participants. Sixteen single nucleotide polymorphisms (SNPs) associated at least one four regions were measured ( p < 5 × 10 −8 ). Promising SNPs −6 ) followed up for replication published blood, spleen, imaging traits mapped to candidate genes targeted cortical transcriptomic epigenetic analysis MAP. Results previously other also examined. Ninety‐eight nominally 0.05) or more related traits. Most novel had no direct links pathways rather endoplasmic reticulum‐Golgi trafficking SORL1, SORCS2, MARCH1, CLTC ), heparan sulfate HS3ST4, HS3ST1 coenzyme A SLC5A6, PANK3 ); supported by nearest gene function omic analyses. replicated mapping cellular systemic regulation. Finally, BMAL, COQ5, SLC25A11 prior PINK1, PPIF, LONP1 lend support role circadian rhythms mitochondria regulation generally. In summary, we provide linked that may greater relevance accumulation; some which are neurodegeneration. However, a subset blood suggests genetic determinants biological underlying accumulation not completely distinct those circulating periphery. image

Язык: Английский

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Enhancing nonlinear transcriptome- and proteome-wide association studies via trait imputation with applications to Alzheimer’s disease

PLoS Genetics, Год журнала: 2025, Номер 21(4), С. e1011659 - e1011659

Опубликована: Апрель 10, 2025

Genome-wide association studies (GWAS) performed on large cohort and biobank datasets have identified many genetic loci associated with Alzheimer’s disease (AD). However, the younger demographic of participants relative to typical age late-onset AD has resulted in an insufficient number cases, limiting statistical power GWAS any downstream analyses. To mitigate this limitation, several trait imputation methods been proposed impute expected future status individuals who may not yet developed disease. This paper explores use imputed nonlinear transcriptome/proteome-wide (TWAS/PWAS) identify genes proteins whose genetically regulated expression is risk. In particular, we considered TWAS/PWAS method DeLIVR, which utilizes deep learning model effects We trained transcriptome proteome models for DeLIVR data from Genotype-Tissue Expression (GTEx) Project UK Biobank (UKB), respectively, UKB as outcome. Next, hypothesis testing using clinically diagnosed cases Disease Sequencing (ADSP). Our results demonstrate that outcomes successfully identifies known putative risk proteins. Notably, found training can increase without inflating false positives, enabling discovery molecular exposures potentially neurodegeneration.

Язык: Английский

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Mutual-assistance learning for trustworthy biomarker discovery and disease prediction

Briefings in Bioinformatics, Год журнала: 2025, Номер 26(2)

Опубликована: Март 1, 2025

Abstract Integrating and analyzing multiple omics datasets, such as genomics, environmental influences, imaging endophenotypes, has yielded an abundance of candidate biomarkers. However, translating findings into beneficial clinical knowledge for disease prediction remains challenging. This becomes even more challenging when studying interpretable high-order feature interactions gene-environment interaction (G$\times $E) to understand the etiology. To fill this gap, we draw on idea mutual-assistance (MA) learning accordingly propose a fresh powerful scheme, referred causal biomarker discovery stable approach (MA-CBxDP). Specifically, design bi-directional mapping framework, integrated with module, extract co-expression patterns across different modalities identify trustworthy biomarkers including G$\times $E. A cooperative module is further incorporated ensure accurate diagnosis identification effects pathogenesis. Importantly, can mutually reinforce each other, helping provide novel insights chronic diseases. Furthermore, in light large computational burden incurred by high-dimensional interactions, devise rapid strategy extend it practical but chromosome-wide setting. We conduct extensive experiments two databases under three tasks, i.e. multimodal correlation, diagnosis, trait prediction. MA-CBxDP establishes new state-of-the-art results predicting scores status classification, while maintaining exceptional interpretability, verifying its flexibility versatility applications.

Язык: Английский

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BIN1 and Alzheimer’s disease: the tau connection

Trends in Neurosciences, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

Язык: Английский

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Adiponectin Gene Polymorphisms: A Case–Control Study on Their Role in Late-Onset Alzheimer’s Disease Risk

Life, Год журнала: 2024, Номер 14(3), С. 346 - 346

Опубликована: Март 7, 2024

Adiponectin, a hormone secreted by adipose tissue, plays complex role in regulating metabolic homeostasis and has also garnered attention for its potential involvement the pathogenesis of late-onset Alzheimer’s disease (LOAD). The objective this study was to investigate association ADIPOQ variants with plasma adiponectin levels LOAD risk subjects from Slovak Caucasian population. For purpose, 385 patients 533 controls without cognitive impairment were recruited genotyped total eighteen single nucleotide polymorphisms (SNPs). Both single-locus haplotype-based logistic regression analyses employed assess SNPs risk, while linear analysis used explore their influence on patients. rs822395 rs2036373 intron 1 found significantly elevate after accounting several confounders. Additional 5′ region exhibited non-significant trend adiponectin. However, none showed an neither whole-group nor subgroup stratification sex or APOE ε4 allele, well-established factor. In summary, emerged as contributor development LOAD, did not unveil any significant gene susceptibility disease.

Язык: Английский

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