TIGP (BIO)—Unraveling the Genetic Landscape of Alzheimer's Disease Through Association Analysis on Large-Scale Whole Genome Sequence Data, Including Common and Rare Variants as well as Structural Variants

Abstract

Alzheimer's Disease (AD) is a prevalent disorder among the elderly, characterized by high heritability and genetic heterogeneity.  Our investigation explores the associations between AD and genetic factors, including common variants, as well as aggregated rare coding and noncoding variants. To broaden our perspective, we extended our study to include structural variants (SVs) and copy number variants (CNVs). The analysis is done on a diverse cohort of 16,905 individuals with whole-genome sequence (WGS) data from the Alzheimer's Disease Sequencing Project (ADSP), and our analyses involved both pooled-population and population-specific (African Americans, Hispanics, and Non-Hispanic Whites) approaches.
 
We first performed analyses on single nucleotide variants (SNVs) and short insertions deletions (indels). Pooled-population analyses identified genetic variants in or near APOE, BIN1, and LINC00320 significantly associated with AD (p < 5x10-8). Population-specific analyses identified a haplotype on chromosome 14 including PSEN1 associated with AD in Hispanics, further supported by aggregate testing of rare coding and noncoding variants in this region. Finally, we observed suggestive associations (p < 5x10-5) of aggregates of rare coding rare variants in ABCA7 among non-Hispanic Whites (p=5.4x10-6), and rare noncoding variants in the promoter of TOMM40 distinct of APOE in pooled-population analyses (p=7.2x10-8). Complementary pooled-population and population-specific analyses offered unique insights into the genetic architecture of AD.
 
Shifting focus to SVs, known contributors to the genetic landscape of human diseases, our study addressed the dearth of understanding regarding their role in AD. Analyzing WGS data from the ADSP, we identified a substantial number of SVs, totaling 400,234 (168,223 high-quality). Laboratory validation attested to a sensitivity of 82% (85% for high-quality). Notably, a significant burden of deletions and duplications surfaced in AD cases, particularly among singletons and homozygous events. Within AD-associated genes, we observed ultra-rare SVs, including protein-altering SVs in ABCA7, APP, PLCG2, and SORL1. Furthermore, 21 SVs were found in linkage disequilibrium (LD) with known AD-risk variants, exemplified by a 5k deletion in complete LD with rs143080277 in NCK2. Additionally, 16 SVs were associated with AD, and 13 SVs were linked to AD-related pathological/cognitive endophenotypes. This comprehensive study underscores the pivotal role of SVs in reshaping our understanding of AD genetics.

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