| Title: | Bidirectional Mendelian Randomization and Multiphenotype GWAS Show Causality and Shared Pathophysiology Between Depression and Type 2 Diabetes |
| Journal: | Diabetes Care |
| Published: | 26 Jul 2023 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/37494602/ |
| DOI: | https://doi.org/10.2337/dc22-2373 |
| URL: | https://diabetesjournals.org/care/article-pdf/46/9/1707/733230/dc222373.pdf |
Publication 11650
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Abstract
OBJECTIVE: Depression is a common comorbidity of type 2 diabetes. We assessed the causal relationships and shared genetics between them.</p>
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.</p>
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.</p>
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.</p>
11 Authors
- Jared G. Maina
- Zhanna Balkhiyarova
- Arie Nouwen
- Igor Pupko
- Anna Ulrich
- Mathilde Boissel
- Amélie Bonnefond
- Philippe Froguel
- Amna Khamis
- Inga Prokopenko
- Marika Kaakinen
1 Application
| Application ID | Title |
|---|---|
| 35327 | Dissecting genetic relationships between type 2 diabetes, depression, and related phenotypes |
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