Investigating the common genetic architecture and causality of metabolic disorders with neurodegenerative diseases

作者：Hao Hong, Qi Fu, Pan Gu, Jingyi Zhao, Jinglan Dai, Kuanfeng Xu, Tao Yang, Hao Dai, Sipeng Shen · 发表于：Diabetes Obesity and Metabolism · 年份：2024 · DOI：10.1111/dom.16130 · 被引用次数：5 · 研究领域：Genetic Associations and Epidemiology、Genomics and Rare Diseases、Neurological diseases and metabolism

BACKGROUND: The co-occurrence of metabolic dysfunction and neurodegenerative diseases suggests a genetic link, yet the shared genetic architecture and causality remain unclear. We aimed to comprehensively characterise these genetic relationships. METHODS: We investigated genetic correlations among four neurodegenerative diseases and seven metabolic dysfunctions, followed by bidirectional Mendelian randomisation (MR) to assess potential causal relationships. Pleiotropy analysis (PLACO) was used to detect the pleiotropic effects of genetic variants. Significant pleiotropic loci were refined and annotated using functional mapping and annotation (FUMA) and Bayesian colocalisation analysis. We further explored mapped genes with tissue-specific expression and gene set enrichment analyses. RESULTS: We identified significant genetic correlations in nine out of 28 trait pairs. MR suggested causal relationships between specific trait pairs. Pleiotropy analysis revealed 25 931 significant single-nucleotide polymorphisms, with 246 pleiotropic loci identified via FUMA and 55 causal loci through Bayesian colocalisation. These loci are involved in neurotransmitter transport and immune response mechanisms, notably the missense variant rs41286192 in SLC18B1. The tissue-specific analysis highlighted the pancreas, left ventricle, amygdala, and liver as critical organs in disease progression. Drug target analysis linked 74 unique genes to existing therapeutic agents, while gene set enrichment id...