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

Abstract

Objective: Alzheimer's 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. Methods: We 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). Results: Our 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. Conclusions: Our 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.