ArticleGenome medicine2025
Structural variants linked to Alzheimer's disease and other common age-related clinical and neuropathologic traits.
Article in Genome medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed.
- TMEM106B is a selective modulator of TDP-43 pathology in Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Coordinated dysregulation of modular gene activity in human neuropathologies.bioRxiv : the preprint server for biology · 2026Article
- Intragenic deletions from whole genome sequencing of 1054 suicide deaths.Research square · 2026Article
- Dissecting Alzheimer's disease heterogeneity by cross-trait polygenic prediction.bioRxiv : the preprint server for biology · 2026Article
- Proteome-wide association study of cortical proteins that may provide resilience for late-life disability.The journals of gerontology. Series A, Biological sciences and medical sciences · 2026Article
- Integration of aged brain multi-omics reveals cross-system mechanisms underlying Alzheimer's disease heterogeneity.Cell reports · 2026Article
- Genetic analysis of neurodegenerative diseases.The Journal of clinical investigation · 2026Review
- Decoding Alzheimer's genetic risk through intercellular communication in the human brain: Lessons from Clusterin.Current opinion in neurobiology · 2026Review
- Balanced deep learning on multi-omics networks identifies molecular subgroups of pathological brain aging.medRxiv : the preprint server for health sciences · 2026Article
- The Impact of Structural Variation on Alzheimer's Disease in the Alzheimer's Disease Sequencing Project.Research square · 2026Article
- Alzheimer's disease: genetic background in the era of next-generation sequencing technologies.Brain communications · 2026Review
- Long-read genome sequencing and multi-omics in aging and neurodegeneration.medRxiv : the preprint server for health sciences · 2025Article
- Integration of aged brain multi-omics reveals cross-system mechanisms underlying Alzheimer's disease heterogeneity.bioRxiv : the preprint server for biology · 2025Article
- Article
- Brain Multi-Omic Subtypes of Neuroticism reveal molecular signatures linked to Alzheimer's Disease.bioRxiv : the preprint server for biology · 2025Article
- TDP-43 toxic gain of function links ALS, FTD and Alzheimer's Disease through splicing dysregulation.bioRxiv : the preprint server for biology · 2025Article
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Abstract
backgroundAlzheimer's disease (AD) is a complex neurodegenerative disorder with substantial genetic influence. While genome-wide association studies (GWAS) have identified numerous risk loci for late-onset AD (LOAD), the functional mechanisms underlying most of these associations remain unresolved. Large genomic rearrangements, known as structural variants (SVs), represent a promising avenue for elucidating such mechanisms within some of these loci.
methodsBy leveraging data from two ongoing cohort studies of aging and dementia, the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP), we performed genome-wide association analysis testing 20,205 common SVs from 1088 participants with whole genome sequencing (WGS) data. A range of Alzheimer's disease and other common age-related clinical and neuropathologic traits were examined.
resultsFirst, we mapped SVs across 81 AD risk loci and discovered 22 SVs in linkage disequilibrium (LD) with GWAS lead variants and directly associated with the phenotypes tested. The strongest association was a deletion of an Alu element in the 3'UTR of the TMEM106B gene, in high LD with the respective AD GWAS locus and associated with multiple AD and AD-related disorders (ADRD) phenotypes, including tangles density, TDP-43, and cognitive resilience. The deletion of this element was also linked to lower TMEM106B protein abundance. We also found a 22-kb deletion associated with depression in ROS/MAP and bearing similar association patterns as GWAS SNPs at the IQCK locus. In addition, we leveraged our catalog of SV-GWAS to replicate and characterize independent findings in SV-based GWAS for AD and five other neurodegenerative diseases. Among these findings, we highlight the replication of genome-wide significant SVs for progressive supranuclear palsy (PSP), including markers for the 17q21.31 MAPT locus inversion and a 1483-bp deletion at the CYP2A13 locus, along with other suggestive associations, such as a 994-bp duplication in the LMNTD1 locus, suggestively linked to AD and a 3958-bp deletion at the DOCK5 locus linked to Lewy body disease (LBD) (P = 3.36 × 10
conclusionsWhile still limited in sample size, this study highlights the utility of including analysis of SVs for elucidating mechanisms underlying GWAS loci and provides a valuable resource for the characterization of the effects of SVs in neurodegenerative disease pathogenesis.
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