Genetically predisposed trauma was associated with overall psychiatric disorder risk in the UK Biobank (odds ratio [OR] = 1.02, 95% confidence interval [CI], 1.01–1.02, P = 2.32E-07). Although the Egger intercept did not indicate the presence of horizontal pleiotropy, significant heterogeneity (Cochran's Q P = 0.01) was observed for the inverse-variance weighted estimate. We had consistent findings using two other Mendelian randomization analysis methods (weighted median and weighted mode). However, using summary statistics from MR Base, we showed no association between genetically predisposed trauma and overall psychiatric disorder risk. See Table 1, Supplementary Table S2, and Supplementary Table S3.
Table 1
Mendelian randomization analyses of the causality between genetically predisposed trauma and psychiatric disorder risk.
Outcome | Outcome source | Consortium | Sample size | SNPs (N) | OR (95% CI) | P value | Heterogeneity Q tests P value | MR-Egger intercept test P value |
Psychiatric disorder | Gene ATLAS | UK Biobank | 452,264 | 66 | 1.02 (1.01–1.02) | 2.32E-07 | 0.01 | 0.05 |
| MR Base | NA | 94,402 | 49 | 0.81 (0.49–1.32) | 0.3907 | 0.2565 | 0.863 |
Mood disorder | Gene ATLAS | UK Biobank | 452,264 | 65 | 1.01 (1.00–1.01) | 6.11E-06 | 0.58 | 0.2 |
| MR Base | NA | 96,499 | 49 | 1.23 (1.03–1.48) | 0.02368 | 0.965 | 0.349 |
Depression | Gene ATLAS | UK Biobank | 452,264 | 66 | 1.02 (1.01–1.02) | 5.29E-08 | 0.02 | 0.07 |
| MR Base | NA | 180,866 | 49 | 1.10 (1.04–1.17) | 5.97E-04 | 7.54E-06 | 0.142 |
Bipolar disorder | Gene ATLAS | UK Biobank | 452,264 | 66 | 1.00 (1.00–1.00) | 0.19 | 0.13 | 0.66 |
| MR Base | Bipolar Disorder Working Group of the Psychiatric Genomics Consortium | 51,710 | 66 | 1.24 (1.04–1.49) | 0.02 | 7.97E-05 | 0.122 |
Anxiety disorder | MR Base | NA | 93,291 | 49 | 1.18 (0.92–1.53) | 0.1951 | 0.7287 | 0.677 |
PTSD | MR Base | NA | 89,058 | 49 | 0.77 (0.33–1.80) | 0.5392 | 0.9251 | 0.228 |
Sleep disorder | Gene ATLAS | UK Biobank | 452,264 | 66 | 1.00 (1.00–1.00) | 0.28 | 0.05 | 0.78 |
| MR Base | NA | 95,720 | 49 | 0.99 (0.78–1.26) | 0.9221 | 0.1047 | 0.906 |
Eating disorder | MR Base | NA | 96,499 | 49 | 1.19 (0.62–2.29) | 0.5919 | 0.2046 | 0.424 |
Schizophrenia | Gene ATLAS | UK Biobank | 452,264 | 66 | 1.00 (1.00–1.00) | 0.10 | 0.01 | 0.93 |
| MR Base | Schizophrenia Working Group of the Psychiatric Genomics Consortium | 77,096 | 66 | 1.47 (1.21–1.78) | 1.04E-04 | 3.98E-16 | 0.0455 |
CI: Confidence interval; NA: Not available; OR: Odds ratio; PTSD: Post-traumatic stress disorder; SNP: Single nucleotide polymorphism |
In particular, a positive association was observed between genetically predisposed trauma and the risk of mood disorder and depression in UK Biobank (OR = 1.01, 95% CI, 1.00-1.01, P = 6.11E-06; OR = 1.02, 95% CI, 1.01–1.02, P = 5.29E-08; respectively), as well as in data source from MR Base (OR = 1.23, 95% CI, 1.03–1.48, P = 0.02; OR = 1.10, 95% CI, 1.04–1.17, P = 5.97E-04; respectively). Egger intercept did not indicate the presence of horizontal pleiotropy, whereas significant heterogeneity (Cochran's Q P < 0.05) was observed for trauma and depression. However, other Mendelian randomization analysis methods were not support these findings, except for weighted median. Further investigations are thus warranted to elucidate these suggestive findings.
Besides, summary statistics from MR Base showed that genetically predisposed trauma increased risk of bipolar disorder (OR = 1.24, 95% CI, 1.04–1.49, P = 0.02) and schizophrenia (OR = 1.47, 95% CI, 1.21–1.78, P = 1.04E-04). However, no association was observed between genetically predisposed trauma and risk of post-traumatic stress disorder, anxiety disorder, sleep disorder, and eating disorder, with no evidence of effect heterogeneity or horizontal pleiotropy.
Leave-one-out analysis suggested that no single instrument was strongly driving the overall effect of trauma on psychiatric disorder, indicating that these results were not sensitive to SNP selection. Funnel plots, scatter plots and leave-one-out plots were shown in Fig. 1, and Supplementary Fig. S1-6 online.
Furthermore, we evaluated whether the correlation between trauma and psychiatric disorder was influenced by obesity, smoking status, alcohol consumption, diabetes mellitus, vitamin D use, or physical activity. The results demonstrated that genetically predisposed trauma was not causally associated with these potential confounders and mediators except obesity class 1 [body mass index(BMI):35-39.9 kg/m2] (OR = 1.24, 95% CI 1.07–1.43, P = 0.004). See Table 2.
Table 2
Causal effects between genetically predisposed trauma and potential confounders.
Trait | First author | Consortium | Sample size | OR (95% CI) | P value |
Obesity class 1 (BMI: 30-34.9 kg/m2) | Berndt SI | GIANT | 98,697 | 1.24 (1.07–1.43) | 0.004 |
Obesity class 2 (BMI: 35-39.9 kg/m2) | Berndt SI | GIANT | 72,546 | 1.18 (0.92–1.50) | 0.20 |
Obesity class 3 (BMI: ≥40 kg/m2) | Berndt SI | GIANT | 50,364 | 1.31 (0.87–1.97) | 0.20 |
Alcohol consumption | Clarke | UK Biobank | 112,117 | 0.99 (0.97–1.02) | 0.52 |
Smoking status (ever vs never) | Neale | Neale Lab | 336,024 | 1.02 (1.00–1.04) | 0.07 |
Physical activity | Ben Elsworth | MRC-IEU | 440,512 | 1.03 (0.97–1.09) | 0.30 |
Vitamin D use | Ben Elsworth | MRC-IEU | 64,949 | 0.99 (0.98–1.01) | 0.29 |
Diabetes mellitus | NA | NA | 96,499 | 1.17 (0.99–1.38) | 0.06 |
BMI: Body mass index; CI: Confidence interval; NA: Not available; OR: Odds ratio. |