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

IF 5.4 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Diabetes, Obesity & Metabolism Pub Date : 2024-12-20 DOI:10.1111/dom.16130
Hao Hong, Qi Fu, Pan Gu, Jingyi Zhao, Jinglan Dai, Kuanfeng Xu, Tao Yang, Hao Dai, Sipeng Shen
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Abstract

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 identified 189 pathways related to lipid metabolism, cell differentiation and immune responses.

Conclusion: Our findings reveal a shared genetic basis, pleiotropic loci, and potential causal relationships between metabolic dysfunction and neurodegenerative diseases. These insights highlight the biological connections underlying their phenotypic association and offer implications for future research to reduce the risk of neurodegenerative diseases.

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研究代谢性疾病与神经退行性疾病的共同遗传结构和因果关系。
背景:代谢功能障碍和神经退行性疾病的共同发生提示了遗传联系,但共享的遗传结构和因果关系尚不清楚。我们的目标是全面描述这些遗传关系。方法:我们研究了4种神经退行性疾病和7种代谢功能障碍之间的遗传相关性,然后采用双向孟德尔随机化(MR)来评估潜在的因果关系。多效性分析(PLACO)用于检测遗传变异的多效性效应。使用功能映射和注释(fua)和贝叶斯共定位分析对显著多效位点进行了细化和注释。我们通过组织特异性表达和基因集富集分析进一步探索了定位基因。结果:我们在28对性状对中发现了9对显著的遗传相关性。MR显示了特定性状对之间的因果关系。多效性分析揭示了25931个显著的单核苷酸多态性,其中FUMA鉴定出246个多效性位点,贝叶斯共定位鉴定出55个因果位点。这些基因座参与神经递质转运和免疫反应机制,特别是SLC18B1中的错义变体rs41286192。组织特异性分析强调胰腺、左心室、杏仁核和肝脏是疾病进展的关键器官。药物靶标分析将74个独特的基因与现有的治疗药物联系起来,而基因集富集鉴定了189个与脂质代谢、细胞分化和免疫反应相关的途径。结论:我们的研究结果揭示了代谢功能障碍和神经退行性疾病之间具有共同的遗传基础、多效位点和潜在的因果关系。这些见解强调了其表型关联背后的生物学联系,并为未来降低神经退行性疾病风险的研究提供了启示。
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来源期刊
Diabetes, Obesity & Metabolism
Diabetes, Obesity & Metabolism 医学-内分泌学与代谢
CiteScore
10.90
自引率
6.90%
发文量
319
审稿时长
3-8 weeks
期刊介绍: Diabetes, Obesity and Metabolism is primarily a journal of clinical and experimental pharmacology and therapeutics covering the interrelated areas of diabetes, obesity and metabolism. The journal prioritises high-quality original research that reports on the effects of new or existing therapies, including dietary, exercise and lifestyle (non-pharmacological) interventions, in any aspect of metabolic and endocrine disease, either in humans or animal and cellular systems. ‘Metabolism’ may relate to lipids, bone and drug metabolism, or broader aspects of endocrine dysfunction. Preclinical pharmacology, pharmacokinetic studies, meta-analyses and those addressing drug safety and tolerability are also highly suitable for publication in this journal. Original research may be published as a main paper or as a research letter.
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