Table 1.
Mendelian randomization in schizophrenia
| References | Genetic instrument and exposure (P-value) | Main statistic test | Exclusion of pleiotropy | Outcome and findings | Outcome sample size |
|---|---|---|---|---|---|
| Andreu-Bernabeu et al., 2022 | 116 SNPs associated with SCZ (P < 5 × 10−8) | WM | Yes | Bidirectional causal effect between polygenic scores for loneliness/isolation and SCZ risk (WM−β (SE) = 1.37 (0.40); P = 6.14 × 10−4) | 35 476 SCZ cases |
| 19 SNPs associated with loneliness/social isolation (P < 5 × 10−6) | 46 839 controls (PGC) | ||||
| Chen et al., 2022 | 2422 SNPs associated with 41 systemic inflammatory regulators, 2788 SNPs associated with SCZ (P < 1 × 10−6) | IVW | Yes | Genetic predisposition to increased HGF, IL-17, IL-1ra, MCP3, TRAIL causally associated with higher SCZ risk (P < 5 × 10−2) | 36 989 SCZ cases |
| Genetic liability to SCZ causally associated with CTAK and RANTES (P < 3 × 10−2) | 11 3075 controls (PGC) | ||||
| Ni et al., 2022 | >700 SNPs associated with gut microbiota and 28 SNPs associated with SCZ (P < 1 × 10−5) | IVW | Yes | Genetic predisposition to increased class Actinobacteria causally associated with higher SCZ risk (P = 1.33 × 10−3) | 152 805 SCZ cases, 18 473 controls (MiBioGen) |
| No causal association between genetic instruments for SCZ and risk of different gut microbiota composition | |||||
| Perry et al., 2021b | 53 SNP associated with insulin resistance phenotype (P < 5 × 10−3) | IVW | Yes | No causal association between genetic instruments for insulin resistance and SCZ (IVW) | 40 675 SCZ cases |
| 58 SNP associated with CRP (P < 5 × 10−8) | MVMR | No significant association between inflammation-related SNP and SCZ after adjusting for genetic instruments for CRP (MVMR) | 64 643 controls | ||
| Kim et al., 2021 | 4 SNP associated with PD risk (P < 5 × 10−6) | IVW | Yes | Genetic predisposition to PD causally associated with higher SCZ risk (OR, 1.10; 95% CI, 1.05−1.15; P = 3.49 × 10−5) | 35 476 SCZ cases |
| 46 839 controls (PGC) | |||||
| Jin et al., 2021 | 93 SNP associated with PCOS (P < 5 × 10−8) | IVW, | Yes | No causal association between genetic instruments for PCOS predisposition and SCZ risk | 33 640 SCZ cases |
| 43 456 controls | |||||
| Chen et al., 2021 | 31 SNP associated with cigarette smoking (P < 1 × 10−5) | IVW, MR-Egger | Yes | No causal association between genetic instruments for smoking and SCZ | 7711 SCZ cases |
| 18 327 controls | |||||
| Yang et al., 2020 | 530 SNP associated with 2-methoxyacetaminophen sulfate levels (P < 1 × 10−5) | IVW | Yes | Genetic predisposition to higher 2-methoxyacetaminophen sulfate level causally associated with higher SCZ risk (P = 1.73 × 10−5) | 36 989 SCZ cases and 113 075 controls |
| Pasman et al., 2018 | 74 SNP associated with cannabis use (P < 1 × 10−5) | IVW | Yes | Genetic predisposition to cannabis use causally associated with higher SCZ risk (OR, 1.10; 95% CI, 0.99–1.21; P = 0.074) | 130 072 CZ cases |
| 109 with SCZ (P < 5 × 10−8) | Genetic liability to SCZ causally associated with cannabis use (OR, 1.16; 95% CI, 1.06–1.27; P = 0.001) | 180 934 cases of cannabis use | |||
| Zhuang et al., 2020 | 30 SNP associated with Enterobacteriaceae family and order (P = 3.72 × 10−11) | IVW | Yes | Genetic predisposition to increased: | 21 246 SCZ cases |
| Enterobacteriaceae family and order causally associated with higher SCZ risk (OR, 1.09; CI, 1.00–1.18; P = 0.048) | |||||
| Gammaproteobacteria class (OR, 0.90; CI, 0.83–0.98; P = 0.011) causally associated with lower SCZ risk | |||||
| 15 with Gammaproteobacteria class (P < 1.4 × 10−8) | Gut production of serotonin causally associated with higher SCZ risk (OR, 1.07; CI, 1.00–1.15; P = 0.047) | ||||
| 32 with increased gut production of serotonin (P < 8.96 × 10−6) | No causal associations with SCZ risk for other types of gut microbiota | 38 072 controls | |||
| Wootton et al., 2020 | 114 SNP associated with SCZ | IVW | Yes | Genetic predisposition to lifetime smoking causally associated with higher SCZ risk (OR, 2.27; 95% CI, 1.67–3.08; P < 0.001) | 36 989 SCZ cases |
| 126 with lifetime smoking (P < 5 × 10−8) | Genetic liability for SCZ causally associated with higher risk of lifetime smoking (β= 0.022; 95% CI, 0.005–0.038; P = 0.009) | 113 075 controls (PGC) | |||
| 213 372 ever-smokers and 249 318 never-smokers (UK Biobank) | |||||
| Peters et al., 2020 | 319 SNP associated with WHRadjBMI | IVW, MR-Egger | Yes | No causal association between genetic instruments for WHRadjBMI and SCZ risk | 40 675 SCZ cases |
| 64 643 controls (PGC) | |||||
| Kim et al., 2020 | 70 SNP associated with SCZ (P < 5 × 10−8) | IVW | Yes | Genetic liability to SCZ causally associated with higher breast cancer risk (OR, per log odds increase in SCZ risk, 1.069; 95% CI, 1.028–1.112; P < 0.001) | 82 315 SCZ cases (PGC) |
| 117, 146, 204 SNP associated with breast cancer (5 × 10−8, 5 × 10−7, 5 × 10−6respectively) | No causal association between genetic instruments for breast cancer and SCZ | 228 951 breast cancer cases (BCAC) | |||
| Jones et al., 2020 | 5 SNP associated with anxiety | IVW | Yes | Genetic liability to neuroticism (OR, 1.33; 95% CI, 1.12–1.59) and anxiety (OR, 1.10; 95% CI, 1.01–1.19) causally associated with higher SCZ risk | 33 640 SCZ cases |
| 116 with neuroticism (P < 5 × 10−8) | 43 456 controls (PGC) | ||||
| Jang et al., 2020 | 341 SNP associated with substance use phenotypes (smoking, alcohol, or cannabis use) | IVW, WM, MR-Egger; Latent Causal Variable model | Yes | No causal association between genetic instruments for substance use phenotypes and the risk SCZ | 105 318 SCZ cases |
| Song et al., 2021 | 1 SNP associated with pars triangularis volume (P < 5 × 10−8) | IVW | No | Genetic predisposition to lower pars triangularis volume causally associated with SCZ risk (OR, 0.48; 95% CI, 0.34-0.69; P = 5.9 × 10−5) | 40 675 SCZ cases |
| 64 643 controls (PGC) | |||||
| Luo et al., 2020 | 45 SNP associated with SCZ (P < 5 × 10−8) | IVW | Yes | Genetic liability to SCZ causally associated with higher serum uric acid risk (per 10-s% increase in SCZ risk: beta: −0.039, SE: 0.013; P = 0.003) | 35 476 SCZ cases |
| 26 SNP associated with serum uric acid (P < 5 × 10−8) | No causal association between genetic instruments for higher serum uric acid and SCZ | 46 839 controls (PGC) | |||
| Gao et al., 2019 | 110 SNP associated with insomnia (P < 5 × 10−8) | MR-Egger, GSMR | Yes | No causal association between genetic instruments for insomnia and SCZ | 33 426 SCZ cases |
| 32 541 controls | |||||
| Byrne et al., 2019 | 142 SNP associated with SCZ | GSMR | Yes | Genetic liability to SCZ causally associated with higher breast cancer risk (SE = 0.008; P = 2.2 × 10−4) | 40 675 SCZ cases and 64 643 controls (PGC) |
| 191 with breast cancer (P < 5 × 10−8) | No causal association between genetic instruments for breast cancer and SCZ | 122 977 breast cancer cases and 105 974 controls | |||
| Tomioka et al., 2018 | 1 SNP associated with serum pyridoxal levels (P = 0.006) | IVW | No | No causal association between genetic instruments for serum pyridoxal level and SCZ | 365 SCZ cases |
| 911 controls | |||||
| Polimanti et al. 2018 | 10 SNP associated with T2D (P < 5 × 10−8) | Instrumental variable analysis | Yes | No bidirectional causal associations between SCZ and T2D | 34 840 T2D cases and 114 981 controls (DIAGRAM consortium) |
| 108 SNP associated with SCZ (P < 5 × 10−8) | 34 241 SCZ cases and 45 604 controls (PGC) | ||||
| Arafat and Minica, 2018 | 60 SNP associated with birth weight (P < 5 × 10−8) | IVW | Yes | No causal association between genetic instruments for birth weight and SCZ | 34 241 SCZ cases |
| 45 604 controls (PGC) | |||||
| Li et al., 2018 | 13 SNP associated with fasting insulin levels | IVW | Yes | No causal effect of any of the genetic instruments on SCZ risk, nor in Europeans nor in East Asians, in the BMI-adjusted analysis | 84 514 SCZ cases |
| 30 with fasting glucose in Europeans, 14 in East Asians | 126 949 controls (PGC2, BIOX) | ||||
| 36 with HbA1c in Europeans, 27 in East Asians | |||||
| 140 with T2D (for Europeans, East Asians and trans-ancestry groups) (P < 5 × 10−8) | |||||
| Hartwig et al., 2017 | 18 SNP associated with CRP serum levels | IVW | Yes | Genetic predisposition to higher serum CRP causally associated with lower SCZ risk (OR, 0.90; 95% CI, 0.84-0.97; P = 0.005) | 36 989 SCZ cases |
| 1 associated with higher sIL-6R serum levels | Genetic predisposition to higher serum sIL-6R causally associated with higher SCZ risk (OR, 1.06; 95% CI, 1.01-1.12; P = 0.02) | ||||
| 2 associated with higher IL-1Ra serum levels (P < 5 × 10−5) | No causal association between genetic instruments for IL-1Ra and SCZ risk | 113 075 controls (PGC) | |||
| Gage et al., 2017a | 128 SNP associated with SCZ risk (P < 5 × 10−8) | IVW | Yes | Genetic liability to SCZ causally associated with risk for cannabis initiation (OR, 1.10 per doubling of the odds of SCZ; 95% CI, 1.05–1.14; P = 2.64 × 10−5) | 36 989 SCZ cases |
| 21 with cannabis initiation (P < 10−5) | Genetic predisposition to cannabis initiation causally associated with SCZ risk (OR, 1.04 per doubling odds of cannabis initiation; 95% CI, 1.01–1.07; P = 0.019) | 113 075 controls (PGC) | |||
| Gage et al., 2017b | 21 SNP associated with smoking initiation (P < 10−6) | IVW | Yes | Genetic predisposition to smoking initiation causally associated with SCZ risk (OR, 1.73; 95% CI, 1.30–2.25, P < 0.001) | 36 989 SCZ cases |
| 94 with SCZ risk (P < 5 × 10−8) | No causal association between genetic instruments for SCZ and risk for smoking initiation (OR, 1.01; 95% CI, 0.98–1.04; P = 0.32). | 113 075 controls (PGC) | |||
| 35 845 smokers (TAG consortium) | |||||
| Taylor et al., 2016 | 4 SNP associated with serum vitamin D levels (P < 6 × 10−10) | IVW | Yes | No causal association between genetic instruments for higher serum vitamin D and SCZ risk. | 36 989 SCZ cases |
| 113 075 controls (PGC) | |||||
| Prins et al., 2016 | 18 SNP associated with CRP levels (P < 1 × 10−4) | GRS IV | Yes | Genetic predisposition to higher serum CRP causally associated with reduced SCZ risk (per 10-s% increase in CRP level; OR, 0.86; 95% CI, 0.79–0.94; P < 0.0010) | 34 241 SCZ cases |
| 45 604 controls (PGC) | |||||
| Inoshita et al., 2016 | 15 SNP associated with CRP serum levels (P < 5 × 10−8) | IVW | Yes | Genetic predisposition to higher serum CRP causally associated with SCZ risk (OR, 1.10; 95% CI, 1.02–1.19; P = 0.015) | 418 SCZ cases |
| 1365 controls | |||||
| Wium-Andersen et al., 2015a | 1 SNP associated with smoking intensity | IVW | No | Genetic predisposition to higher smoking intensity causally associated with SCZ risk (OR, 1.06; 95% CI, 1.04–1.08) in ever- and never-smokers combined, but not in each group alone. | 67 SCZ cases |
| 40 014 ever-smokers and 23 282 never-smokers |
BCAC, Breast Cancer Association Consortium; BIOX, Bio-X Institutes; CI, confidence interval; CRP, C-reactive protein; CUD, cannabis use disorder; HGF, hepatocyte growth factor; CTACK, cutaneous T-cell attracting chemokine; GRS IV, Genetic risk score instrumental variable; (GS)MR, (Generalized Summary-based) Mendelian randomization; (s)IL-R, (soluble) interleukin receptor; IVW, inverse variance–weighted; MCP3, monocyte-specific chemokine 3; MVMR, multivariable Mendelian randomization; OR, odds ration; PGC, psychiatric genomic consortium; RANTES, regulated on Activation; SCZ, schizophrenia; SE, standard error; SNP, single-nucleotide polymorphisms; s%, symmetric percentage; TAG, Tobacco and Genetics Consortium; TRAIL, TNF-related apoptosis-inducing ligand; T2D, type 2 diabetes; WHRadjBMI, waist-to-hip ratio adjusted for BMI; WM, weighted median.