Abstract
INTRODUCTION: Neuropsychiatric symptoms (NPSs) 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 Local Analysis of [co]Variant Annotation with genome wide association studies (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: Local 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 nonsense-mediated mRNA decay transcript variants in ERC2 (rs17288728; rs815460) shared between AD/anxiety. DISCUSSION: 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.