Weijia Dang ¹ Tianqi Hao ¹ Ning Li ² Hualin Zhang ¹ Ziqi Li ¹ Hongmei Yu ^1,3 Yalu Wen ^4* Deqiang Zheng ^2* Liu Long ^1,3*

• ¹ Shanxi Medical University, Taiyuan, China
• ² Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing, Beijing, China
• ³ Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan, China
• ⁴ Department of Statistics, University of Auckland, Auckland, New Zealand

Introduction: Observational studies have reported that patients with Alzheimer's disease (AD) have a greater burden of comorbidities typically associated with stress-related psychiatric disorders. However, the contribution of hereditary factors to this comorbidity remains unclear. We evaluated phenotypic associations using observational data from the UK Biobank. Method: Our study focused on investigating the shared risk variants and genetic etiology underlying AD and three stress-related psychiatric disorders: post-traumatic stress disorder, anxiety disorder, and major depressive disorder. By leveraging summary statistics from genome-wide association studies, we investigated global genetic correlations using linkage disequilibrium score regression, genetic covariance analysis, and high-definition likelihood. Genome-wide cross-trait analysis with association analysis based on subsets and cross-phenotype association were performed to discover genome-wide significant risk variants shared between AD and the three stress-related psychiatric disorders. Results: A significant positive genetic correlation was observed between AD and major depressive disorder using linkage disequilibrium score regression (rg = 0.231; P = 0.018), genetic covariance analysis (rg = 0.138; P < 0.001), and high-definition likelihood (rg = 0.188; P < 0.001). Association analysis based on subsets and cross-phenotype association revealed thirteen risk variants in six genes shared between AD and post-traumatic stress disorder; seven risk variants in four genes shared between AD and anxiety disorder; and 23 risk variants in four genes shared between AD and major depressive disorder. Functional annotation and gene-set enrichment analysis indicated that 12 genes for comorbidity shared between patients with AD and all three stress-related psychiatric disorders were enriched in the spleen, pancreas, and whole blood. Conclusion: These results advance our knowledge of the shared genetic origins of comorbidities and pave the way for advancements in the diagnosis, management, and prevention of stress-related AD.