TABLE 1.

Direct phenotype causation: studies testing uni- or bi-directional phenotypic causation hypotheses of comorbid depression and type 2 diabetes

First author (year)	Study design, sample source, size, and characteristicsa	Depression assessment	Diabetes assessment	Genetic assessment and analytical approach	Findings and interpretationb
Tang (2020)32	Two-sample, bi-directional Mendelian randomization Summary statistics from multiple existing GWAS consortia: MD: UK Biobank + PGC N = 1 306 354 Type 2 diabetes: DIAGRAM N = 898 130	Lifetime MD UK Biobank GWAS defined MD as ever seeking treatment for ‘nerves, anxiety, tension or depression.’ PCG consists of multiple cohorts. All cohorts defined MD using DSM-IV criteria.	DIAGRAM consists of multiple cohorts, type 2 diabetes defined by self-report of type 2 diabetes, diabetes medication use, or diagnosis in medical chart.	Two-sample, two-directional Mendelian randomization using summary data: 1. Genetic liability of MD predicting odds of type 2 diabetes 2. Genetic liability of type 2 diabetes predicting odds of MD	Findings • Genetic liability for MD was associated with increased odds of type 2 diabetes (odds ratio: 1.26, 95% CI 1.10–1.43, P = 6×10−4). • Genetic liability for type 2 diabetes was not associated with odds of MD (odds ratio: 1.00, 95% CI 0.97–1.03, P = 0.948). Interpretation Findings are consistent with the hypothesis that MD causes type 2 diabetes, but not that type 2 diabetes causes MD.
Wehby (2018)26	Longitudinal population-based cohort Data source: Health and Retirement Study N = 7338 100% non-Hispanic white 57% female Age 65+ years	Current MD Instrument: CESD Type: Screening	Genetic liability for type 2 diabetes using existing GWAS estimates.	Whole-genome association testing of type 2 diabetes PRS with MD	Findings • No association between PRS of type 2 diabetes and depression (odds ratio: 0.97, 95% CI 0.82–1.16) or depressive symptoms (beta: −0.02, 95% CI −0.15 to 0.12). Interpretation Findings do not support the hypothesis that type 2 diabetes is causally related to risk of developing MD.
Xuan (2018)28	Cross-sectional, population-based sample Data source: Risk Evaluation of Cancers in Chinese Diabetic Individuals (REACTION) Study N = 11 506 Mean age: 57 years 78% female 100% Asian	Current MD Instrument: PHQ Type: Screening	Fasting plasma glucose	Approach 1: PRS of 34 type 2 diabetes-associated SNPs. Approach 2: Used Mendelian randomization to assess the association between this PRS and MD.	Findings • Approach 1: PRS type 2 diabetes was positively associated with depression (odds ratio: 1.21, 95% CI 1.07–1.37). • Approach 2: type 2 diabetes positively associated with odds of depression (odds ratio: 1.84, 95% CI 1.25–2.70). Interpretation Findings support the hypothesis that type 2 diabetes is causally related to risk of developing MD.
Clarke (2O17)20	Cross-sectional, population-based sample Data source: Generation Scotland, N = 19,858 Age 18+ 59% female 99% European Summary statistics from multiple existing GWAS consortia: DIAGRAM, AGEN-T2D, SAT2D, MAT2D, T2D-GENES	Lifetime MD Instrument: SCID: Type: Diagnostic	Self-report type 2 diabetes, diabetes medication use, or diagnosis in medical chart.	Approach 1: Used multiple PRS for type 2 diabetes to assess the bi-directional relationship between type 2 diabetes and MD. Approach 2: Used Mendelian randomization to assess the association between 11- SNP type 2 diabetes PRS and MD.	Findings • Approach 1: type 2 diabetes genetic liability was nominally associated with elevated risk of MD (type 2 diabetes PRS was associated with MD status at 3 out of 5 P value thresholds (beta: 0.007, P < 0.015; all betas nonsignificant after correcting for multiple testing). • Approach 2: Lower type 2 diabetes genetic liability was nominally associated with lower risk of MD (type 2 diabetes-protective SNP rs6808574 was also protective for MD: beta: −0.008, P = 0.02; non-significant after correcting for multiple testing). Interpretation Findings do not support the hypothesis that type 2 diabetes is causally related to risk of developing MD.
Wesolowska (2017) 27	Cross-sectional, population-based sample Data source: Cardiovascular Risk in Young Finns N = 1217 Mean age: 43 years 58.9% female 100% Finnish	Current MD Instrument: BDI Type: Screening	Fasting plasma glucose	PRS of 35 type 2 diabetes-associated SNPs. Used Mendelian randomization to assess the association between this PRS and MD.	Findings • Genetic liability for fasting glucose was inversely associated with depressive symptoms. PRS was positively associated with glucose (beta: 0.09, 95% CI 0.07, 0.12; P < 0.001) and negatively associated with depressive symptoms (beta: −0.04 95% CI −0.07, −0.005; P = 0.025). Interpretation Findings do not support the hypothesis that type 2 diabetes is causally related to risk of developing MD.
Mezuk (2015)17	Cross-sectional population-based study of MZ and DZ twins Data source: Screening Across the Lifespan Twin (SALT) N = 31 043 100% Swedish Mean age: 59 years	Lifetime MD Instrument: CIDI Type: Diagnostic	Self-report of physician diagnosis of type 2 diabetes	Twin modelling with comparison of direction of causation models to Cholesky decomposition (shared genetic/environmental cause)	Findings • MD was associated with risk of type 2 diabetes after accounting for genetic liability (hazard ratio for women: 1.74, 95% CI 1.09–2.79; hazard ratio for men: 1.08, 95% CI 0.70–1.67). • Type 2 diabetes was associated with risk of MD after accounting for genetic liability (hazard ratio for women: 1.49, 95% CI 1.04–2.12; hazard ratio for men: 1.21, 95% CI 0.83–1.78). Interpretation Findings are consistent with a bi-directional model of MD– type 2 diabetes.
Samaan (2015)	Cross-sectional, population-based sample Data source: EpiDREAM N = 17404 Mean age: 53 years 60.9% female 53.9% European, 18.9% Latin American, 15.8% South Asian, 7.2% African, 2.9 Native North American, 1.3% East Asian	Past year MD Instrument: Structured interview Type: Diagnostic	OGTT	PRS of 20 type 2 diabetes-associated SNPs. Assessed the relationship between this PRS with MD.	Findings • OGTT-identified impaired fasting glucose, impaired glucose tolerance, and type 2 diabetes were not significantly associated with past year MD (significance for all relationships: 0.30 ⩽ P ⩽ 0.65). • Genetic risk for type 2 diabetes: 12 of the 20 type 2 diabetes SNPs were significantly associated with type 2 diabetes. • Genetic risk for type 2 diabetes and MD: The 20 SNPs and resulting PRS were not associated with MD (P ⩾ 0.09). Interpretation Findings do not support the hypothesis that type 2 diabetes is causally related to risk of developing MD.

Abbreviations: AGEN-T2D, Asian Genetic Epidemiology Network Type 2 Diabetes; BDI, Beck Depression Inventory; CESD, Center for Epidemiologic Studies of Depression Scale; CIDI, Composite International Diagnostic Inventory; DIAGRAM, DIAbetes Genetics Replication And Meta-analysis Consortium; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders-IV; DZ, dizygotic (fraternal) twins; EpiDREAM, Diabetes REduction Assessment with ramipril and rosiglitazone Medication trial; GWAS, genome-wide association study; MAT2D, Mexican American Type 2 Diabetes Consortium; MD, major depression; MZ, monozygotic (identical) twins; OGTT, oral glucose tolerance test; PGC, Psychiatric Genetics Consortium; PHQ, Patient Health Questionnaire; PRS, polygenetic risk score; SALT, Screening Across the Lifespan Twin Study; SAT2D, South Asian Type 2 Diabetes Consortium; SCID, Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders; SNP, single nucleotide polymorphism; T2D-GENES, Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Multi-Ethnic Samples Consortium.

^aDetailed sample characteristics for GWAS consortia are not provided as these samples are generally used to generate aggregate summary statistics rather than for individual-level analysis. These samples are all publicly available on their respective websites. Unless specified otherwise, these GWAS consortia samples consist primarily of individuals of European descent.

^bThe quantitative measure of association provided in this table is the effect estimate each study’s authors indicated as the most representative of their conclusions; in instances where a study reported multiple representative estimates, this table reports the estimate with the lowest P value provided in the study.