Genomic insights into the comorbidity between type 2 diabetes and schizophrenia
Genomic insights into the comorbidity between type 2 diabetes and schizophrenia
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DOI：
10.1038/s41537-024-00445-5
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发表时间：
2024-02-21
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影响因子：
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通讯作者：
Zeggini，Eleftheria
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文献类型：
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作者：
Arruda，Ana Luiza;Khandaker，Golam M.;Zeggini，Eleftheria
多发病是日益重要的公共卫生挑战，对卫生管理和政策具有深远影响。精神健康和代谢性疾病之间有着良好的流行病学联系。在这项研究中，我们调查了2型糖尿病和精神分裂症之间的遗传交集。我们使用孟德尔随机化方法来检验这两种疾病和相关内表型之间的潜在因果关系。我们没有报告令人信服的证据表明2型糖尿病的遗传责任潜在地影响精神分裂症的风险，反之亦然。我们的发现表明，增加的身体质量指数(BMI)对精神分裂症有保护作用，与众所周知的BMI对2型糖尿病风险增加的影响相反。我们在11个基因组基因座上发现了这两种疾病的关联信号共存的证据，其中6个基因座对2型糖尿病和精神分裂症的影响方向相反。为了阐明这些共定位信号，我们整合了来自批量和单细胞基因表达研究的多组学数据以及功能信息。我们确定了假定的效应基因，并发现它们富含动态平衡和脂质相关的途径。我们还强调了药物再利用的机会，包括N-甲基-D-天冬氨酸(NMDA)受体拮抗剂。我们的发现为2型糖尿病和精神分裂症的共同生物机制提供了见解，突出了在相反方向上影响这两种疾病风险的共同因素，并揭示了这种共病的复杂性质。
Multimorbidity represents an increasingly important public health challenge with far-reaching implications for health management and policy. Mental health and metabolic diseases have a well-established epidemiological association. In this study, we investigate the genetic intersection between type 2 diabetes and schizophrenia. We use Mendelian randomization to examine potential causal relationships between the two conditions and related endophenotypes. We report no compelling evidence that type 2 diabetes genetic liability potentially causally influences schizophrenia risk and vice versa. Our findings show that increased body mass index (BMI) has a protective effect against schizophrenia, in contrast to the well-known risk-increasing effect of BMI on type 2 diabetes risk. We identify evidence of colocalization of association signals for these two conditions at 11 genomic loci, six of which have opposing directions of effect for type 2 diabetes and schizophrenia. To elucidate these colocalizing signals, we integrate multi-omics data from bulk and single-cell gene expression studies, along with functional information. We identify putative effector genes and find that they are enriched for homeostasis and lipid-related pathways. We also highlight drug repurposing opportunities including N-methyl-D-aspartate (NMDA) receptor antagonists. Our findings provide insights into shared biological mechanisms for type 2 diabetes and schizophrenia, highlighting common factors that influence the risk of the two conditions in opposite directions and shedding light on the complex nature of this comorbidity.