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

Authors :
Vialle RA
de Paiva Lopes K
Li Y
Ng B
Schneider JA
Buchman AS
Wang Y
Farfel JM
Barnes LL
Wingo AP
Wingo TS
Seyfried NT
De Jager PL
Gaiteri C
Tasaki S
Bennett DA
Source :
MedRxiv : the preprint server for health sciences [medRxiv] 2024 Aug 13. Date of Electronic Publication: 2024 Aug 13.
Publication Year :
2024

Abstract

Advances have led to a greater understanding of the genetics of Alzheimer's Disease (AD). However, the gap between the predicted and observed genetic heritability estimates when using single nucleotide polymorphisms (SNPs) and small indel data remains. Large genomic rearrangements, known as structural variants (SVs), have the potential to account for this missing genetic heritability. 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 around 20,000 common SVs from 1,088 participants with whole genome sequencing (WGS) data. A range of Alzheimer's Disease and Related Disorders (AD/ADRD) clinical and pathologic traits were examined. Given the limited sample size, no genome-wide significant association was found, but we mapped SVs across 81 AD risk loci and discovered 22 SVs in linkage disequilibrium (LD) with GWAS lead variants and directly associated with AD/ADRD phenotypes (nominal P < 0.05). The strongest association was a deletion of an Alu element in the 3'UTR of the TMEM106B gene. This SV was in high LD with the respective AD GWAS locus and was associated with multiple AD/ADRD phenotypes, including tangle 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 ROSMAP and bearing similar association patterns as AD GWAS SNPs at the IQCK locus. In addition, genome-wide scans allowed the identification of 7 SVs, with no LD with SNPs and nominally associated with AD/ADRD traits. This result suggests potentially new ADRD risk loci not discoverable using SNP data. Among these findings, we highlight a 5.6 kb duplication of coding regions of the gene C1orf186 at chromosome 1 associated with indices of cognitive impairment, decline, and resilience. While further replication in independent datasets is needed to validate these findings, our results support the potential roles of common structural variations in the pathogenesis of AD/ADRD.

Details

Language :
English
Database :
MEDLINE
Journal :
MedRxiv : the preprint server for health sciences
Publication Type :
Academic Journal
Accession number :
39185527
Full Text :
https://doi.org/10.1101/2024.08.12.24311887