Structural variants linked to Alzheimer's disease and other common age-related clinical and neuropathologic traits

Genome Med. 2025 Mar 4;17(1):20. doi: 10.1186/s13073-025-01444-6.

Abstract

Background: Alzheimer'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.

Methods: By 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.

Results: First, 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 × 10-4).

Conclusions: While 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.

Keywords: Alzheimer’s disease; Cognitive decline; GWAS; Structural variants; WGS.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Aged, 80 and over
  • Aging* / genetics
  • Alzheimer Disease* / genetics
  • Alzheimer Disease* / pathology
  • Female
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Genomic Structural Variation*
  • Humans
  • Linkage Disequilibrium
  • Male
  • Membrane Proteins / genetics
  • Nerve Tissue Proteins / genetics
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Whole Genome Sequencing

Substances

  • TMEM106B protein, human
  • Nerve Tissue Proteins
  • Membrane Proteins