Genome-wide search for pleiotropy in ischemic stroke, normal pressure hydrocephalus, and neuropathology endophenotypes linked to Alzheimer’s disease

- Objectives of the proposed research: Accumulating evidence indicates that ischemic stroke (IS) and normal pressure hydrocephalus (NPH) share common risk factors and critical mechanisms with Alzheimer’s disease (AD). This study aims to identify pleiotropy between (1) IS and AD-associated neuropathology endophenotypes (NPEs) and (2) NPH and AD-associated NPEs. Based on the identified pleiotropic variants or loci, we will also investigate shared pathways underlying biological mechanisms of IS, NPH, and AD.

- Study design: We will conduct genome-wide pleiotropy analyses using summary statistics obtained from previous genome-wide association studies (GWAS) for IS, NPH, and AD-associated NPEs. Along with GWAS summary statistics for NPEs (Shade et al., 2024, Nat Genet), we will use GWAS summary statistics for IS (Malik et al., 2018, Nat Genet) and NPH (Rasanen et al., 2024, Neurology), generated in individuals of European ancestry.

- Analysis plan: Two separate genome-wide pleiotropy analyses will be conducted: (1) pleiotropy GWAS for IS and AD-associated NPEs and (2) pleiotropy GWAS for NPH and AD-associated NPEs. We will evaluate pleiotropy for variants with minor allele frequency (MAF) > 0.01 and Z-scores < 80 using the R package PLACO, which examines the composite null hypothesis that a given variant is associated with a maximum of one trait, such that rejecting this hypothesis implies that the variant influences both traits and is thus pleiotropic. For top-ranked loci containing genome-wide significant pleiotropic variants, we will differentiate horizontal pleiotropy from mediated pleiotropy by conducting Bayesian colocalization analysis using the R package COLOC. We also plan to conduct pathway enrichment analyses for top-ranked pleiotropic variants to identify pathways underlying biological mechanisms shared by IS, NPH, and AD.

- Planned collaboration: There are no planned collaborations with researchers at other institutions for this study.

Accumulating evidence indicates that ischemic stroke (IS) and normal pressure hydrocephalus (NPH) are known to share common risk factors and critical mechanisms with Alzheimer’s disease (AD). Although large-scale genome-wide association studies (GWAS) have identified many variants or loci associated solely with IS, NPH, and AD, only a few studies have investigated shared genetic factors or pathways underlying their biological mechanisms. This study aims to identify variants or loci that influence AD-associated neuropathology endophenotypes (NPEs) and IS or AD-associated NPEs and NPH simultaneously. Using GWAS summary statistics for each neurodegenerative disease, we will conduct genome-wide pleiotropy analyses, differentiate horizontal pleiotropy (direct genetic effect on AD or through mechanisms that bypass IS or NPH) from mediated pleiotropy (genetic effect on AD through IS or NPH), and investigate biological pathways implicated in shared mechanisms of IS, NPH, and AD. Our findings may provide insight into the genetic basis and underlying mechanisms shared by IS, NPH, and AD.