Local genetic covariance analysis with lipid traits identifies novel loci for early-onset Alzheimer’s Disease

PLoS Genetics, Journal Year: 2025, Volume and Issue: 21(3), P. e1011631 - e1011631

Published: March 17, 2025

The genetic component of early-onset Alzheimer disease (EOAD), accounting for ~10% all Alzheimer’s (AD) cases, is largely unexplained. Recent studies suggest that EOAD may be enriched variants acting in the lipid pathway. current study examines shared heritability between and pathway using genome-wide multi-trait covariance analyses. Summary statistics were obtained from GWAS meta-analyses by Disease Genetics Consortium ( n =19,668) five blood traits Global Lipids =1,320,016). significant results compared lipids analyses performed via SUPERGNOVA. Genes linkage disequilibrium (LD) with top hits identified regions scored ranked causality combining evidence gene-based analysis, AD-risk scores incorporating transcriptomic proteomic evidence, eQTL data, colocalization analyses, DNA methylation single-cell RNA sequencing Direct comparison showed 5 loci overlapping at least one trait harboring APOE , TREM2 MS4A4E LILRA5 LRRC25 . Local 3 trait. Gene prioritization nominated likely causative genes these loci: ANKDD1B CUZD1 MS4A64 .The lipids, providing further architecture mechanistic pathways two traits.

Language: Английский

Local genetic covariance analysis with lipid traits identifies novel loci for early-onset Alzheimer’s Disease

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

Published: Aug. 20, 2024

ABSTRACT Background The genetic component of early-onset Alzheimer’s disease (EOAD), accounting for ∼10% all (AD) cases, is largely unexplained. Recent studies suggest that EOAD may be enriched variants acting in the lipid pathway. Objective To examine shared heritability between and pathway by genome-wide multi-trait covariance analyses. Methods Summary statistics were obtained from GWAS meta-analyses Disease Genetics Consortium ( n =19,668) five blood traits Global Lipids =1,320,016), analyses performed via SUPERGNOVA. Genes linkage disequilibrium (LD) with top hits identified regions scored ranked causality combining evidence gene-based analysis, AD-risk scores incorporating transcriptomic proteomic evidence, eQTL data, colocalization analyses, DNA methylation single-cell RNA sequencing Results Local 3 at least one trait. Gene prioritization nominated likely causative genes these loci: ANKDD1B , CUZD1 MS4A64 . Conclusion current study lipids, providing further architecture mechanistic pathways two traits.

Language: Английский

Inhibition of brain glutamate carboxypeptidase II (GCPII) to enhance cognitive function

Advances in pharmacology, Journal Year: 2024, Volume and Issue: unknown, P. 27 - 63

Published: Nov. 5, 2024

Language: Английский