双向全基因组关联研究抑郁症状与 2 型糖尿病及定量血糖特征的关系。
Bivariate Genome-Wide Association Study of Depressive Symptoms With Type 2 Diabetes and Quantitative Glycemic Traits.
机构信息
From the Departments of Psychology and Logopedics (Haljas, Räikkönen) and Psychology and Logopedics, Faculty of Medicine (Lahti), and Helsinki Collegium for Advanced Studies (Lahti), University of Helsinki, Helsinki, Finland; Department of Epidemiology (Amare, Alizadeh, Snieder), University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Harvard Medical School (Hsu), Boston, Massachusetts; Institute for Molecular Medicine Finland (FIMM) (Groop), Helsinki, Finland; Lund University Diabetes Centre (Groop), Lund University, Lund, Sweden; Department of General Practice and Primary Health Care (Eriksson), University of Helsinki and Helsinki University Hospital; Folkhälsan Research Center (Eriksson), Helsinki, Finland; Department of Medicine (Mosley), University of Mississippi Medical Center, Jackson, Mississippi; Department of Epidemiology, School of Public Health (Newman), University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Medicine, Section of General Internal Medicine (Murabito), Boston University School of Medicine, Boston; Boston University and National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts (Murabito); Departments of Epidemiology and Psychiatry (Tiemeier), Erasmus University Medical Center, Rotterdam, the Netherlands; Translational Gerontology Branch (Tanaka), National Institute on Aging, Baltimore, Maryland; Genetic Epidemiology Unit, Department of Epidemiology (van Duijn), Erasmus University Medical Center, Rotterdam; Centre for Medical Systems Biology (van Duijn), Leiden, the Netherlands; Department of Internal Medicine, Division of Geriatrics (Ding), Wake Forest University, Winston-Salem, North Carolina; University of Exeter Medical School (Llewellyn), Exeter, UK; Rush Alzheimer's Disease Center (Bennett), Chicago, Illinois; Florida State University, College of Medicine (Terracciano), Tallahassee, Florida; Laboratory of Epidemiology and Population Sciences (Launer), National Institute on Aging, Bethesda, Maryland; Department of Psychiatry and Psychotherapy (Grabe), Helios Hospital Stralsund; Department of Psychiatry and Psychotherapy (Grabe) and Institute for Community Medicine (Teumer), University Medicine Greifswald; German Center for Neurodegenerative Diseases (Grabe), Site Rostock/Greifswald, Greifswald, Germany; Institute of Epidemiology II, Mental Health Research Unit, Helmholtz Zentrum München (Ladwig), German Research Center for Environmental Health, Neuherberg, Germany; Psychosomatic Medicine and Psychotherapy (Ladwig), Universitäts-Klinikum Rechts der Isar, Technische Universität München, Munich, Germany & German Center for Diabetes Research (DZD), München-Neuherberg, Germany; Department of Preventive Medicine (Cornelis), Northwestern University Feinberg School of Medicine, Chicago, Illinois; and Department of Epidemiology, School of Public Health (Kardia, Ware, Smith), and Survey Research Center, Institute for Social Research (Ware, Smith), University of Michigan, Ann Arbor, Michigan.
出版信息
Psychosom Med. 2018 Apr;80(3):242-251. doi: 10.1097/PSY.0000000000000555.
OBJECTIVE
Shared genetic background may explain phenotypic associations between depression and Type 2 diabetes (T2D). We aimed to study, on a genome-wide level, if genetic correlation and pleiotropic loci exist between depressive symptoms and T2D or glycemic traits.
METHODS
We estimated single-nucleotide polymorphism (SNP)-based heritability and analyzed genetic correlation between depressive symptoms and T2D and glycemic traits with the linkage disequilibrium score regression by combining summary statistics of previously conducted meta-analyses for depressive symptoms by CHARGE consortium (N = 51,258), T2D by DIAGRAM consortium (N = 34,840 patients and 114,981 controls), fasting glucose, fasting insulin, and homeostatic model assessment of β-cell function and insulin resistance by MAGIC consortium (N = 58,074). Finally, we investigated pleiotropic loci using a bivariate genome-wide association study approach with summary statistics from genome-wide association study meta-analyses and reported loci with genome-wide significant bivariate association p value (p < 5 × 10). Biological annotation and function of significant pleiotropic SNPs were assessed in several databases.
RESULTS
The SNP-based heritability ranged from 0.04 to 0.10 in each individual trait. In the linkage disequilibrium score regression analyses, depressive symptoms showed no significant genetic correlation with T2D or glycemic traits (p > 0.37). However, we identified pleiotropic genetic variations for depressive symptoms and T2D (in the IGF2BP2, CDKAL1, CDKN2B-AS, and PLEKHA1 genes), and fasting glucose (in the MADD, CDKN2B-AS, PEX16, and MTNR1B genes).
CONCLUSIONS
We found no significant overall genetic correlations between depressive symptoms, T2D, or glycemic traits suggesting major differences in underlying biology of these traits. However, several potential pleiotropic loci were identified between depressive symptoms, T2D, and fasting glucose, suggesting that previously established phenotypic associations may be partly explained by genetic variation in these specific loci.
目的
共同的遗传背景可能可以解释抑郁和 2 型糖尿病（T2D）之间的表型关联。我们旨在在全基因组水平上研究抑郁症状与 T2D 或血糖特征之间是否存在遗传相关性和多效性位点。
方法
我们通过结合 CHARGE 联盟（N=51258）先前进行的抑郁症状元分析的汇总统计数据，使用连锁不平衡评分回归，估计基于单核苷酸多态性（SNP）的遗传率，并分析抑郁症状与 T2D 和血糖特征之间的遗传相关性。T2D 由 DIAGRAM 联盟（N=34840 例患者和 114981 例对照）、空腹血糖、空腹胰岛素和 MAGIC 联盟（N=58074）的稳态模型评估β细胞功能和胰岛素抵抗进行分析。最后，我们使用来自全基因组关联研究荟萃分析的汇总统计数据，使用双变量全基因组关联研究方法，研究多效性位点，并报告具有全基因组显著双变量关联 p 值（p < 5×10）的多效性位点。在几个数据库中评估了显著多效性 SNP 的生物学注释和功能。
结果
在每个个体特征中，SNP 基于的遗传率范围为 0.04 至 0.10。在连锁不平衡评分回归分析中，抑郁症状与 T2D 或血糖特征之间没有显著的遗传相关性（p>0.37）。然而，我们确定了抑郁症状和 T2D（在 IGF2BP2、CDKAL1、CDKN2B-AS 和 PLEKHA1 基因中）以及空腹血糖（在 MADD、CDKN2B-AS、PEX16 和 MTNR1B 基因中）的多效性遗传变异。
结论
我们没有发现抑郁症状、T2D 或血糖特征之间存在显著的总体遗传相关性，这表明这些特征的潜在生物学差异很大。然而，在抑郁症状、T2D 和空腹血糖之间确定了几个潜在的多效性位点，这表明先前建立的表型关联可能部分解释为这些特定位点的遗传变异。
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