Jared G Maina, Zhanna Balkhiyarova, Arie Nouwen, Igor Pupko, Anna Ulrich, Mathilde Boissel, Amélie Bonnefond, Philippe Froguel, Amna Khamis, Inga Prokopenko, Marika Kaakinen
{"title":"双向孟德尔随机化和多表型GWAS显示抑郁症和2型糖尿病之间的因果关系和共同的病理生理。","authors":"Jared G Maina, Zhanna Balkhiyarova, Arie Nouwen, Igor Pupko, Anna Ulrich, Mathilde Boissel, Amélie Bonnefond, Philippe Froguel, Amna Khamis, Inga Prokopenko, Marika Kaakinen","doi":"10.2337/dc22-2373","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>Depression is a common comorbidity of type 2 diabetes. We assessed the causal relationships and shared genetics between them.</p><p><strong>Research design and methods: </strong>We applied two-sample, bidirectional Mendelian randomization (MR) to assess causality between type 2 diabetes and depression. We investigated potential mediation using two-step MR. To identify shared genetics, we performed 1) genome-wide association studies (GWAS) separately and 2) multiphenotype GWAS (MP-GWAS) of type 2 diabetes (19,344 case subjects, 463,641 control subjects) and depression using major depressive disorder (MDD) (5,262 case subjects, 86,275 control subjects) and self-reported depressive symptoms (n = 153,079) in the UK Biobank. We analyzed expression quantitative trait locus (eQTL) data from public databases to identify target genes in relevant tissues.</p><p><strong>Results: </strong>MR demonstrated a significant causal effect of depression on type 2 diabetes (odds ratio 1.26 [95% CI 1.11-1.44], P = 5.46 × 10-4) but not in the reverse direction. Mediation analysis indicated that 36.5% (12.4-57.6%, P = 0.0499) of the effect from depression on type 2 diabetes was mediated by BMI. GWAS of type 2 diabetes and depressive symptoms did not identify shared loci. MP-GWAS identified seven shared loci mapped to TCF7L2, CDKAL1, IGF2BP2, SPRY2, CCND2-AS1, IRS1, CDKN2B-AS1. MDD has not brought any significant association in either GWAS or MP-GWAS. Most MP-GWAS loci had an eQTL, including single nucleotide polymorphisms implicating the cell cycle gene CCND2 in pancreatic islets and brain and the insulin signaling gene IRS1 in adipose tissue, suggesting a multitissue and pleiotropic underlying mechanism.</p><p><strong>Conclusions: </strong>Our results highlight the importance to prevent type 2 diabetes at the onset of depressive symptoms and the need to maintain a healthy weight in the context of its effect on depression and type 2 diabetes comorbidity.</p>","PeriodicalId":11140,"journal":{"name":"Diabetes Care","volume":null,"pages":null},"PeriodicalIF":14.8000,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10465984/pdf/","citationCount":"0","resultStr":"{\"title\":\"Bidirectional Mendelian Randomization and Multiphenotype GWAS Show Causality and Shared Pathophysiology Between Depression and Type 2 Diabetes.\",\"authors\":\"Jared G Maina, Zhanna Balkhiyarova, Arie Nouwen, Igor Pupko, Anna Ulrich, Mathilde Boissel, Amélie Bonnefond, Philippe Froguel, Amna Khamis, Inga Prokopenko, Marika Kaakinen\",\"doi\":\"10.2337/dc22-2373\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>Depression is a common comorbidity of type 2 diabetes. We assessed the causal relationships and shared genetics between them.</p><p><strong>Research design and methods: </strong>We applied two-sample, bidirectional Mendelian randomization (MR) to assess causality between type 2 diabetes and depression. We investigated potential mediation using two-step MR. To identify shared genetics, we performed 1) genome-wide association studies (GWAS) separately and 2) multiphenotype GWAS (MP-GWAS) of type 2 diabetes (19,344 case subjects, 463,641 control subjects) and depression using major depressive disorder (MDD) (5,262 case subjects, 86,275 control subjects) and self-reported depressive symptoms (n = 153,079) in the UK Biobank. We analyzed expression quantitative trait locus (eQTL) data from public databases to identify target genes in relevant tissues.</p><p><strong>Results: </strong>MR demonstrated a significant causal effect of depression on type 2 diabetes (odds ratio 1.26 [95% CI 1.11-1.44], P = 5.46 × 10-4) but not in the reverse direction. Mediation analysis indicated that 36.5% (12.4-57.6%, P = 0.0499) of the effect from depression on type 2 diabetes was mediated by BMI. GWAS of type 2 diabetes and depressive symptoms did not identify shared loci. MP-GWAS identified seven shared loci mapped to TCF7L2, CDKAL1, IGF2BP2, SPRY2, CCND2-AS1, IRS1, CDKN2B-AS1. MDD has not brought any significant association in either GWAS or MP-GWAS. Most MP-GWAS loci had an eQTL, including single nucleotide polymorphisms implicating the cell cycle gene CCND2 in pancreatic islets and brain and the insulin signaling gene IRS1 in adipose tissue, suggesting a multitissue and pleiotropic underlying mechanism.</p><p><strong>Conclusions: </strong>Our results highlight the importance to prevent type 2 diabetes at the onset of depressive symptoms and the need to maintain a healthy weight in the context of its effect on depression and type 2 diabetes comorbidity.</p>\",\"PeriodicalId\":11140,\"journal\":{\"name\":\"Diabetes Care\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":14.8000,\"publicationDate\":\"2023-09-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10465984/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Diabetes Care\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.2337/dc22-2373\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ENDOCRINOLOGY & METABOLISM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Diabetes Care","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2337/dc22-2373","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
引用次数: 0
摘要
目的:抑郁症是2型糖尿病的常见合并症。我们评估了它们之间的因果关系和共同基因。研究设计和方法:我们采用双样本、双向孟德尔随机化(MR)来评估2型糖尿病和抑郁症之间的因果关系。为了确定共同遗传学，我们分别进行了1)全基因组关联研究(GWAS)和2)多表型GWAS (MP-GWAS)，包括2型糖尿病(19,344例受试者，463,641例对照受试者)和抑郁症(5262例受试者，86,275例对照受试者)，以及英国生物银行中自我报告的抑郁症状(n = 153,079)。我们分析了来自公共数据库的表达数量性状位点(eQTL)数据，以确定相关组织中的靶基因。结果:MR显示抑郁对2型糖尿病有显著的因果关系(优势比1.26 [95% CI 1.11-1.44]， P = 5.46 × 10-4)，但相反方向无显著影响。中介分析显示，抑郁症对2型糖尿病的影响有36.5% (12.4 ~ 57.6%，P = 0.0499)是由BMI介导的。2型糖尿病和抑郁症状的GWAS未发现共享位点。MP-GWAS鉴定出7个共享基因座，分别与TCF7L2、CDKAL1、IGF2BP2、SPRY2、CCND2-AS1、IRS1、CDKN2B-AS1相关。MDD与GWAS或MP-GWAS均无显著相关性。大多数MP-GWAS位点具有eQTL，包括涉及胰岛和脑的细胞周期基因CCND2和脂肪组织的胰岛素信号基因IRS1的单核苷酸多态性，表明其多组织和多效性的潜在机制。结论:我们的研究结果强调了在抑郁症状开始时预防2型糖尿病的重要性，以及在抑郁和2型糖尿病合并症的影响下保持健康体重的必要性。
Bidirectional Mendelian Randomization and Multiphenotype GWAS Show Causality and Shared Pathophysiology Between Depression and Type 2 Diabetes.
Objective: Depression is a common comorbidity of type 2 diabetes. We assessed the causal relationships and shared genetics between them.
Research design and methods: We applied two-sample, bidirectional Mendelian randomization (MR) to assess causality between type 2 diabetes and depression. We investigated potential mediation using two-step MR. To identify shared genetics, we performed 1) genome-wide association studies (GWAS) separately and 2) multiphenotype GWAS (MP-GWAS) of type 2 diabetes (19,344 case subjects, 463,641 control subjects) and depression using major depressive disorder (MDD) (5,262 case subjects, 86,275 control subjects) and self-reported depressive symptoms (n = 153,079) in the UK Biobank. We analyzed expression quantitative trait locus (eQTL) data from public databases to identify target genes in relevant tissues.
Results: MR demonstrated a significant causal effect of depression on type 2 diabetes (odds ratio 1.26 [95% CI 1.11-1.44], P = 5.46 × 10-4) but not in the reverse direction. Mediation analysis indicated that 36.5% (12.4-57.6%, P = 0.0499) of the effect from depression on type 2 diabetes was mediated by BMI. GWAS of type 2 diabetes and depressive symptoms did not identify shared loci. MP-GWAS identified seven shared loci mapped to TCF7L2, CDKAL1, IGF2BP2, SPRY2, CCND2-AS1, IRS1, CDKN2B-AS1. MDD has not brought any significant association in either GWAS or MP-GWAS. Most MP-GWAS loci had an eQTL, including single nucleotide polymorphisms implicating the cell cycle gene CCND2 in pancreatic islets and brain and the insulin signaling gene IRS1 in adipose tissue, suggesting a multitissue and pleiotropic underlying mechanism.
Conclusions: Our results highlight the importance to prevent type 2 diabetes at the onset of depressive symptoms and the need to maintain a healthy weight in the context of its effect on depression and type 2 diabetes comorbidity.
期刊介绍：
The journal's overarching mission can be captured by the simple word "Care," reflecting its commitment to enhancing patient well-being. Diabetes Care aims to support better patient care by addressing the comprehensive needs of healthcare professionals dedicated to managing diabetes.
Diabetes Care serves as a valuable resource for healthcare practitioners, aiming to advance knowledge, foster research, and improve diabetes management. The journal publishes original research across various categories, including Clinical Care, Education, Nutrition, Psychosocial Research, Epidemiology, Health Services Research, Emerging Treatments and Technologies, Pathophysiology, Complications, and Cardiovascular and Metabolic Risk. Additionally, Diabetes Care features ADA statements, consensus reports, review articles, letters to the editor, and health/medical news, appealing to a diverse audience of physicians, researchers, psychologists, educators, and other healthcare professionals.
京公网安备 11010802042870号
京ICP备2023020795号-1
分享
求助内容：
应助结果提醒方式：
扫码关注我们
