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Bi-directional Mendelian randomization and multi-phenotype GWAS show causality and shared pathophysiology between depression and type 2 diabetes

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posted on 2023-07-26, 19:17 authored by Jared G Maina, Zhanna Balkhiyarova, Arie Nouwen, Igor Pupko, Anna Ulrich, Mathilde Boissel, Amélie Bonnefond, Philippe Froguel, Amna Khamis, Inga Prokopenko, Marika Kaakinen

OBJECTIVE. Depression is a common co-morbidity of type 2 diabetes. We assessed the causal relationships and shared genetics between them.

RESEARCH DESIGN AND METHODS. We applied two-sample bi-directional 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) GWAS, separately, and 2) multi-phenotype GWAS (MP-GWAS) of type 2 diabetes (cases=19,344, controls=463,641) and depression, using major depressive disorder (MDD, cases=5,262, controls=86,275) and self-reported depressive symptoms (n=153,079) in UK biobank. We analyzed expression quantitative trait loci (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 (OR=1.26[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 to 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 was insignificant in both GWAS and MP-GWAS. Most MP-GWAS loci had an eQTL, including SNPs implicating the cell cycle gene CCND2 in pancreatic islets and brain, and insulin signaling gene IRS1 in adipose tissue, suggesting a multi-tissue and pleiotropic underlying mechanism.

CONCLUSION. 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 co-morbidity.

Funding

This research was in part funded by the Diabetes UK (BDA number: 20/0006307), the European Union’s Horizon 2020 research and innovation programme (LONGITOOLS, H2020-SC1-2019-874739). Agence Nationale de la Recherche (PreciDIAB, ANR-18-IBHU-0001), by the European Union through the “Fonds européen de développement regional” (FEDER), by the “Conseil Régional des Hauts-de-France” (Hauts-de-France Regional Council) and by the “Métropole Européenne de Lille” (MEL, European Metropolis of Lille)

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