Investigating the role of structural variants in Alzheimer’s Disease and AD‐Related traits

Abstract

AbstractBackgroundAlthough recent advances have led to a greater understanding of the genetics of Alzheimer’s Disease (AD), there remains a discrepancy between the predicted and observed genetic heritability estimates when using single nucleotide polymorphisms (SNPs) and small indel data. Large genomic rearrangements, known as structural variants (SVs), have the potential to account for this missing genetic heritability.MethodHere, we investigate the role of SVs in AD and AD‐related dementias (ADRD) 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 analyzed over 25,000 SVs discovered using whole genome sequencing (WGS) data of 1,106 participants and tested for association with multiple indices for AD/ADRD, including measurements of cognitive decline, amyloid beta, neuronal neurofibrillary tangles, TDP‐43, cerebral amyloid angiopathy, and resilience.ResultOur findings revealed five associations reaching genome‐wide significance. These included a 106 bp insertion (chr21:17,134,448; MAF = 0.01), located in the intronic region of the gene USP25, associated with a higher TDP‐43 burden (P‐value = 1.83×10−6). An 82 bp insertion at chr19:45,444,699 (MAF = 0.25), previously mapped as eQTL for APOC1 and sQTL for APOC2 in brain tissues, was linked to greater cerebral amyloid angiopathy (P‐value = 1.02×10−6). An 820 bp deletion chr15:26,003,040 (MAF = 0.031) overlapping a CTCF site near ATP10A was associated with greater odds of Lewy Body disease (P‐value = 1.03×10−6). A 55 bp insertion (chr12:131,797,376; MAF = 0.21) in an intergenic region was found to be associated with reduced vascular disease burden (P‐value = 2.96×10−7); and a 53 bp insertion (chr4:99,901,557; MAF = 0.014) mapped as protein QTL for ADH5 was linked to lower cognitive resilience (P‐value = 8.51×10−7).ConclusionThese findings provide evidence that common genetic variation, particularly SVs, can play a significant role in AD/ADRD traits. We are now investigating the functional impact of these SVs by integrating multi‐omics assays available from brain tissues of the same individuals. Our goal is to connect genetics to phenotype and gain a deeper understanding of the role of SVs in AD/ADRD.