Identification of novel associations of candidate loci with Alzheimer's disease by leveraging the shared genetic basis with hippocampal volume

Abstract

ObjectiveAlzheimers disease (AD) is a complex neurodegenerative disorder with a considerable genetic contribution that remains not fully understood. The hippocampus plays a critical role in learning and memory, with its volume loss being a core hallmark of AD. Hippocampal volume also has a strong heritable component and its genetic underpinnings may help us to understand the complex biological mechanism underlying AD. MethodsWe performed cross-trait analysis of exisiting GWAS data on late-onset AD and Hippocampal volumes using the conjunctional false discovery rate (conjFDR) framework to identify the specific shared genetic basis.For identified SNPs, we performed functional annotation and phenome-wide association studies (PheWAS). ResultsOur cross-trait analyses identified 11 non-APOE lead genetic loci, of which 7 loci showed discordant directional effects (loci associated with decreased risk for AD and smaller hippocampal volumes, and vice versa). We found that SHARPIN and TNIP1 genes play a role in AD by affecting the hippocampal volumes. In addition, we observed 9 novel AD-hippocampus loci in genes previously implicated in AD (IGIP and ACE) and novel AD-genes (KCTD13, HINT1, SH3TC2, FAM53B, TPM1, IL34 and SSH2). Phenome-wide association study highlighted varying degrees of pleiotropy, including brain imaging measurements, white blood cell markers, red blood cell markers, and lipids in multiple shared loci. ConclusionsOur integrating GWAS study reveals a shared genetic basis between AD and hippocampal volumes. By integrating GWAS summary statistics for these two traits, we identified both novel and previously reported AD-hippocampus loci. Functional analysis highlights the roles of immune cells and lipid markers in the shared loci and traits, suggesting a shared neurobiological basis for both traits.