Multi-trait association studies discover pleiotropic loci between Alzheimer's disease and cardiometabolic traits [article]

William Paul Bone, Katherine M Siewert, Anupama Jha, Derek Klarin, Scott M Damrauer, Kyong-Mi Chang, Philip S Tsao, Themistocles L Assimes, Marylyn D Ritchie, Benjamin Franklin Voight, the VA Million Veteran Project
2020 medRxiv   pre-print
Identification of genetic risk factors that are shared between Alzheimer's disease (AD) and other traits, i.e., pleiotropy, can help improve our understanding of the etiology of AD and potentially detect new therapeutic targets. Motivated by previous epidemiological correlations observed between cardiometabolic traits and AD, we performed a set of bivariate genome-wide association studies coupled with colocalization analysis to identify loci that are shared between AD and eleven cardiometabolic
more » ... traits. We identified three previously unreported pleiotropic trait associations at known AD loci as well as four novel pleiotropic loci. One associated locus was tagged by a low-frequency coding variant in the gene DOCK4 and is potentially implicated in its alternative splicing. Statistical colocalization with expression quantitative trait loci identified by the Genotype-Tissue Expression (GTEx) project identified additional candidate genes, including ACE, the target of the hypertensive drug class of ACE-inhibitors. We found that the allele associated with decreased ACE expression in brain tissue was also associated with increased risk of AD, providing human genetic evidence of a potential increase in AD risk from use of an established anti-hypertensive therapeutic. Overall, our results support a complex genetic relationship between AD and these cardiometabolic traits, and the candidate causal genes identified suggest that blood pressure and immune response play a role in the pleiotropy between these traits.
doi:10.1101/2020.08.26.20179366 fatcat:uo4tfmls3rbvbpfo4anffaqnz4