Association of Common and Rare Variants with Alzheimer’s Disease in over 13,000 Diverse Individuals with Whole-Genome Sequencing from the Alzheimer’s Disease Sequencing Project

Abstract

Abstract Alzheimer’s Disease (AD) is a common disorder of the elderly that is both highly heritable and genetically heterogeneous. Here, we investigated the association between AD and both common variants and aggregates of rare coding and noncoding variants in 13,371 individuals of diverse ancestry with whole genome sequence (WGS) data. Pooled-population analyses identified genetic variants in or near APOE, BIN1 , and LINC00320 significantly associated with AD (p < 5×10 -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 < 5×10 -5 ) of aggregates of rare coding rare variants in ABCA7 among non-Hispanic Whites (p=5.4×10 -6 ), and rare noncoding variants in the promoter of TOMM40 distinct of APOE in pooled-population analyses (p=7.2×10 -8 ). Complementary pooled-population and population-specific analyses offered unique insights into the genetic architecture of AD.