Bivariate Genome-Wide Association Study of Depressive Symptoms With Type 2 Diabetes and Quantitative Glycemic Traits
Kadri Haljas1, Azmeraw T Amare, Behrooz Z Alizadeh
1From 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.
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.
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