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. 2023 Sep 1;46(9):1707-1714.
doi: 10.2337/dc22-2373.

Bidirectional Mendelian Randomization and Multiphenotype GWAS Show Causality and Shared Pathophysiology Between Depression and Type 2 Diabetes

Jared G Maina  1   2 , Zhanna Balkhiyarova  3   4   5 , Arie Nouwen  6 , Igor Pupko  3   4 , Anna Ulrich  4 , Mathilde Boissel  1   2 , Amélie Bonnefond  1   2   4 , Philippe Froguel  1   2   4 , Amna Khamis  1   2   4 , Inga Prokopenko  1   2   3   5 , Marika Kaakinen  3   4   5
Affiliations

Bidirectional Mendelian Randomization and Multiphenotype GWAS Show Causality and Shared Pathophysiology Between Depression and Type 2 Diabetes

Jared G Maina et al. Diabetes Care. .

Abstract

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.

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Conflict of interest statement

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Figures

None
Graphical abstract
Figure 1
Figure 1
Forest plots showing the MR analysis results between type 2 diabetes (outcome) (A) and depression (exposure) (B). The ORs, 95% CIs, and P values are shown.
Figure 2
Figure 2
Manhattan plots of type 2 diabetes (A) and PHQ-9 (B) after MP-GWAS in the UKBB. The red horizontal lines show the genome-wide significance threshold (P < 5 × 10−8). The dashed horizontal lines show the suggestive genome-wide significance threshold (P < 1 × 10−5). The shared loci are annotated. CHR, chromosome.
See this image and copyright information in PMC

References

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