Table 2.
Mendelian randomization in major depressive disorder
| Reference | Genetic instrument and exposure (P-value) | Main statistic test | Exclusion of pleiotropy | Outcome and findings | Outcome sample size |
|---|---|---|---|---|---|
| Maharjan et al., 2021 | 121 SNP associated with total testosterone | IVW | Yes | No causal association between genetic instruments for increased female testosterone or SHBG levels and MDD | 521 MDD cases |
| 91 with bioavailable testosterone | |||||
| 173 with serum SHBG protein | |||||
| 368 controls | |||||
| Lu et al., 2021 | 102 SNP associated with MDD (P < 5 × 10−8) | IVW | Yes | Genetic liability to MDD causally associated with higher CAD (OR, 1.14; 95% CI, 1.06–1.24; P = 1.0 × 10−3) and myocardial infarction (OR, 1.21; 95% CI, 1.11–1.33; P = 4.8 × 10−5) risks | 60 801 CAD cases, including 43 676 with myocardial infarction, |
| 123 504 controls | |||||
| Huang et al., 2020 | 32 SNP associated with Alzheimer’s Disease, and 65 SNP with MDD (P < 0.002) | IVW | Yes | No bidirectional causal association between Alzheimer’s Disease and MDD genetic instruments | 9240 MDD cases |
| 9519 controls | |||||
| Milaneschi et al., 2019 | 6 SNP associated with vitamin D | IVW | Yes | No bidirectional causal association between vitamin D or n3-PUFA and MDD genetic instruments | 1700 MDD cases |
| 347controls | |||||
| 7 with n3-PUFA | |||||
| 37 with MDD (P < 0.05) | |||||
| Gill et al., 2019 | 56 SNP associated with MDD (P < 5 × 10-8) | IVW | Yes | Genetic liability to MDD causally associated with functional outcome after ischemic stroke (OR of poor outcome per 1-SD increase in genetically determined risk of MDD, 1.81; 95% CI, 0.98–3.35; P = 0.06). | 60 341 ischemic stroke cases |
| 454 450 control subjects (MEGASTROKE consortium) | |||||
| Cai et al., 2019 | 72 SNP associated with MDD (P < 1 × 10−6) | IVW | Yes | Genetic liability to MDD: | 34 217 ischemic stroke cases |
| causally associated with higher risk of small vessel stroke, (OR, 1.33; 95% CI, 1.08–1.65; P = 0.009) | |||||
| 406 111 controls | |||||
| but not with large artery stroke, cardioembolic stroke, or all ischemic stroke | |||||
| Choi et al., 2019 | SNP associated with: | IVW | Yes | Genetic predisposition to higher accelerometer-based physical activity causally associated with reduced risk for MDD (IVW OR, 0.74 for MDD per 1-SD unit increase in mean acceleration; 95% CI, 0.59-0.92; P = 0.006) | 143 265 MDD |
| MDD (n = 17) (P < 1 × 10−6) | 91 084 accelerometer-based activity | ||||
| Accelerometer-based (n = 12) and self-reported (n = 25) physical activity (P < 1 × 10−7) | |||||
| 377 234 self-reported activity | |||||
| No causal association between genetic instruments for accelerometer-based activity and MDD | |||||
| No causal association between genetic instruments for self-reported activity and MDD | |||||
| Michalek et al., 2017 | 1 SNP associated with shorter leukocyte telomere lengths | Generalized linear model | NO | Genetic predisposition to shorter telomere lengths causally associated with: | 1628 MDD cases |
| 1140 controls | |||||
| Increased risk for childhood-onset MDD (P ≤ 0.05) | |||||
| Increased risk for childhood-onset MDD relative to adult-onset MDD cases (P ≤ 0.001) | |||||
| No association with adult-onset MDD | |||||
| Wium-Andersen et al., 2014 | 4 SNP associated with increased plasma CRP levels (P < 5.1 × 10−59) | Regression model | Yes | No causal association between genetic instruments for increased plasma CRP levels and MDD | 1183 MDD |
| 77 626 controls | |||||
| Sequeira et al., 2017 | 120 SNP associated with age at menarche (P < 0.0001) | Structural mean model | Yes | Genetic liability to early menarche: | 3920 girls (ALSPAC cohort) |
| Causally associated with higher levels of depressive symptoms at 14 years (OR, per risk allele 1.02; 95% CI, 1.005–1.04, n = 2404). | |||||
| No association with MDD after 14 years | |||||
| Kwok et al., 2016 | 3 SNP associated with coffee consumption (P < 5 × 10−8) | IVW | Yes | No causal association between genetic instruments for coffee consumption and MDD | 9240 MDD cases |
| 9519 controls (PGC) | |||||
| Clarke et al., 2017 | 10 SNP associated with T2D (P ≤ 5 × 10−8) | Mixed linear models | Yes | No causal association between genetic instruments for T2D and MDD | 2697 MDD cases |
| 20 800 controls (GS: SFHS) | |||||
| Hung et al., 2014 | 32 SNP associated with higher BMI (P < 5 × 10−8) | Maximum likelihood estimation model | Yes | No causal association between genetic instruments for higher BMI and MDD | 2430 MDD cases |
| 792 controls | |||||
| Wium-Andersen et al., 2015b | 1 SNP associated with smoking intensity | IVW | No | No causal association between genetic instruments for higher smoking intensity and MDD risk in any group | 1067 MDD cases |
| 40 014 ever-smokers and 23 282 never-smokers | |||||
| Wium-Andersen et al., 2015a | 2 SNP associated with alcohol consumption (P < 1 × 10−5) | IVW | No | Genetic predisposition to alcohol consumption causally associated with higher risk for hospitalization/death with MDD (OR, 4.52; 95% CI, 0.99–20.5; P = NG) | 4777 cases of hospitalization/death with MDD |
| 78 154 total participants |
Longitudinal Study of Parents and Children; CAD, coronary artery disease; CI, confidence interval; GS: SFHS, Generation Scotland: the Scottish Family Health Study; IVW, inverse variance–weighted; MDD, major depressive disorder; n3-PUFA, omega-3 polyunsaturated fatty acid; NG, not given; OR, odds ration; PGC, psychiatric genomic consortium; SHBG, sex-hormone-binding globulin; SNP, single-nucleotide polymorphisms; T2D, type 2 diabetes.