Genetic correlation analysis identifies TMEM106B, ACE , and ERC2 as genetic loci shared between Alzheimer’s disease and primary psychiatric disorders

Background Neuropsychiatric symptoms (NPS) occur in up to 85% of Alzheimer’s disease (AD) cases. Current treatments—repurposed from psychiatric disorders despite limited understanding of etiologic overlap—are often ineffective. Methods To characterize the genetic overlap between AD and major psychiatric disorders and identify shared molecular pathways we conducted genetic correlation analyses between AD and depression, schizophrenia, bipolar disorder and anxiety using MiXeR and LAVA using GWAS summary statistics (AD: n=487,511; bipolar disorder: n=413,466; depression: n=1,154,267; schizophrenia: n=130,644; anxiety: n=1,096,458). Results Genetic correlation analyses followed by fine mapping and functional analyses identified a missense variant in TMEM106B (rs3173615) shared between AD and depression and anxiety, a regulatory region variant in ACE (rs4292) shared between AD/schizophrenia, and two NMD transcript variants in ERC2 (rs17288728; rs815460) shared between AD/anxiety. Conclusion The specific molecular pathways associated with these variants provide critical information on shared etiologic components underlying these traits, and inform development of improved therapeutic targets.