Comprehensive analysis of genetic risk loci uncovers novel candidate genes and pathways in the comorbidity between depression and Alzheimer’s disease

Abstract As there is growing evidence of shared pathogenesis between Alzheimer’s disease and depression, we aimed to further investigate the shared disease mechanisms of these highly comorbid disorders using brain-specific eQTL data and gene co-expression networks of genetic loci significantly associated with Alzheimer’s disease and depression. We found no identical GWAS SNPs between Alzheimer’s disease and depression, but brain-specific eQTL data uncovered six shared genes: SRA1 , MICA , PCDHA-7, PCDHA-8, PCDHA-10 and PCDHA-13 . To identify genes related to the shared eQTL genes, we obtained genes in co-expression with the eQTL genes, specifically in the hippocampus. Next, we performed pathway analysis on these disease-specific gene sets. Clustering of these pathways uncovered key roles for synaptic signaling and organization, myelination, development and the immune system in the hippocampus as shared pathology between Alzheimer’s disease and depression. With this study we show that the genetic underpinnings in both diseases affect pathways in the hippocampus that could work in tandem for the development of both Alzheimer’s disease and depression.