Bidirectional Mendelian Randomization and Multiphenotype GWAS Show Causality and Shared Pathophysiology Between Depression and Type 2 Diabetes.
Humans
Genome-Wide Association Study
/ methods
Diabetes Mellitus, Type 2
/ genetics
Depression
/ genetics
Depressive Disorder, Major
/ genetics
Mendelian Randomization Analysis
Polymorphism, Single Nucleotide
/ genetics
Membrane Proteins
/ genetics
Intracellular Signaling Peptides and Proteins
/ genetics
RNA-Binding Proteins
/ genetics
Journal
Diabetes care
ISSN: 1935-5548
Titre abrégé: Diabetes Care
Pays: United States
ID NLM: 7805975
Informations de publication
Date de publication:
01 09 2023
01 09 2023
Historique:
received:
07
12
2022
accepted:
21
06
2023
medline:
28
8
2023
pubmed:
26
7
2023
entrez:
26
7
2023
Statut:
ppublish
Résumé
Depression is a common comorbidity of type 2 diabetes. We assessed the causal relationships and shared genetics between them. 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. 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. 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.
Identifiants
pubmed: 37494602
pii: 153440
doi: 10.2337/dc22-2373
pmc: PMC10465984
doi:
Substances chimiques
SPRY2 protein, human
0
Membrane Proteins
0
Intracellular Signaling Peptides and Proteins
0
IGF2BP2 protein, human
0
RNA-Binding Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1707-1714Subventions
Organisme : Diabetes UK
ID : 20/0006307
Pays : United Kingdom
Informations de copyright
© 2023 by the American Diabetes Association.
Références
Curr Opin Psychiatry. 2013 Jan;26(1):60-5
pubmed: 23187087
Int J Epidemiol. 2012 Feb;41(1):161-76
pubmed: 22422451
Diabetes Care. 2009 Nov;32 Suppl 2:S157-63
pubmed: 19875544
J Affect Disord. 2021 Sep 1;292:311-318
pubmed: 34139403
Nat Genet. 2020 Apr;52(4):437-447
pubmed: 32231276
Stat Med. 2008 Apr 15;27(8):1133-63
pubmed: 17886233
Front Psychiatry. 2019 Feb 14;10:57
pubmed: 30837902
Mol Psychiatry. 2022 Jan;27(1):281-295
pubmed: 34079068
Curr Diabetes Rev. 2020;16(5):442-449
pubmed: 31657690
Nature. 2015 Feb 12;518(7538):197-206
pubmed: 25673413
Transl Psychiatry. 2021 Dec 13;11(1):633
pubmed: 34903730
PLoS Genet. 2022 May 13;18(5):e1010161
pubmed: 35560157
PLoS One. 2018 Mar 26;13(3):e0195002
pubmed: 29579109
Nat Genet. 2015 Mar;47(3):284-90
pubmed: 25642633
Diabet Med. 2004 Jun;21(6):515-23
pubmed: 15154933
J Psychiatr Res. 2014 Sep;56:106-11
pubmed: 24931850
Front Med. 2018 Dec;12(6):678-687
pubmed: 30446878
Gen Hosp Psychiatry. 2008 Mar-Apr;30(2):127-37
pubmed: 18291294
BMJ. 2021 Oct 26;375:n2233
pubmed: 34702754
Elife. 2018 May 30;7:
pubmed: 29846171
Psychosom Med. 2018 Apr;80(3):242-251
pubmed: 29280852
J Diabetes Complications. 2016 Jan-Feb;30(1):38-42
pubmed: 26604164
Am J Med Genet A. 2021 Sep;185(9):2719-2738
pubmed: 34087052
Front Immunol. 2019 Jul 19;10:1696
pubmed: 31379879
Genet Epidemiol. 2016 Nov;40(7):597-608
pubmed: 27625185
Diabetologia. 2008 Apr;51(4):597-601
pubmed: 18264689
Diabetes Care. 2007 Mar;30(3):542-8
pubmed: 17327318
Cell Rep. 2021 Oct 12;37(2):109807
pubmed: 34644572
Nat Genet. 2013 Jun;45(6):580-5
pubmed: 23715323
Diabetologia. 2020 Jul;63(7):1305-1311
pubmed: 32270255
Diabetologia. 2010 Dec;53(12):2480-6
pubmed: 20711716
Nature. 2018 Oct;562(7726):203-209
pubmed: 30305743
Nat Neurosci. 2019 Mar;22(3):343-352
pubmed: 30718901
Res Synth Methods. 2019 Dec;10(4):486-496
pubmed: 30861319
Nat Genet. 2018 Nov;50(11):1505-1513
pubmed: 30297969
Nat Genet. 2018 Feb;50(2):229-237
pubmed: 29292387
Epidemiol Psychiatr Sci. 2020 Jun 02;29:e134
pubmed: 32484148
J Clin Psychiatry. 2013 Jan;74(1):31-7
pubmed: 23419223
Curr Diabetes Rev. 2007 Nov;3(4):252-9
pubmed: 18220683
J Gen Intern Med. 2001 Sep;16(9):606-13
pubmed: 11556941