Identification of novel candidate loci for Alzheimer’s disease and related dementias by leveraging the shared genetic basis with hippocampal volume

Alzheimer's disease and related dementias (ADRD) are complex neurodegenerative disorders of which the genetic basis remains incompletely understood. Hippocampal volume loss is 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 ADRD. To identify shared genetic risk loci across late-onset ADRD and bilateral hippocampal volumes, we conducted a cross-trait analysis of existing GWAS data on the two traits using the conjunctional false discovery rate (conjFDR) framework. Functional annotation and phenome-wide association studies (PheWAS) were performed on the identified shared loci to characterize their biological relevance. We identified 11 unique lead genetic loci, of which 7 loci showed discordant directional effects (loci associated with increased risk for ADRD and smaller hippocampal volumes). We found that <i>SHARPIN</i> and <i>TNIP1</i> genes play a role in ADRD by affecting hippocampal volumes. In addition, we observed 9 novel ADRD-hippocampus loci in genes previously implicated in AD (<i>IGIP</i> and <i>ACE</i>) and novel ADRD-genes (<i>KCTD13</i>, <i>HINT1</i>, <i>SH3TC2</i>, <i>FAM53B</i>, <i>TPM1</i>, <i>IL34</i> and <i>SSH2</i>). PheWAS results show that most shared loci associated with neuroimaging measurements, white blood cell markers, red blood cell markers, and lipids. This study shows a shared genetic basis between ADRD and bilateral hippocampal volumes. By integrating summary statistics for these two traits, we identified both novel and previously reported ADRD-hippocampus loci. Functional analysis highlights the role of immune cells and lipid markers in the shared loci, suggesting a shared neurobiological basis for ADRD and bilateral hippocampal volumes.