Table 3.
Significant Associations Between Identified Metabolites and the Risk of Multiple Nonpsychiatric Diseases in the Phe-MR Analysis.
| PheCode | Outcome | SNPs | Disease chapter | IVW | Penalized IVW | MR-RAPS | Maximum likelihood | MR-Egger Intercept | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| OR (95% CI) | P value | OR (95% CI) | P value | OR (95% CI) | P value | OR (95% CI) | P value | P value | ||||
| 1-Arachidonoyl-GPC supplementation | ||||||||||||
| 208 | Benign neoplasm of colon | 5 | Neoplasms | 1.10 (1.06–1.13) | 4.47 × 10−10 | 1.10 (1.06–1.13) | 4.47 × 10−10 | 1.09 (1.06–1.13) | 1.88 × 10−9 | 1.09 (1.06–1.13) | 1.45 × 10−9 | 0.91 |
| 244.4 | Hypothyroidism NOS | 5 | Endocrine/metabolic | 1.09 (1.05–1.13) | 5.80 × 10−7 | 1.09 (1.05–1.13) | 6.34 × 10−6 | 1.09 (1.05–1.13) | 9.92 × 10−7 | 1.09 (1.05–1.13) | 9.29 × 10−7 | 0.87 |
| 244 | Hypothyroidism | 5 | Endocrine/metabolic | 1.09 (1.05–1.13) | 6.80 × 10−7 | 1.09 (1.05–1.13) | 2.00 × 10−6 | 1.09 (1.05–1.13) | 1.18 × 10−6 | 1.09 (1.05–1.13) | 1.08 × 10−6 | 0.90 |
| Glycoproteins supplementation | ||||||||||||
| 574 | Cholelithiasis and cholecystitis | 78 | Digestive | 0.86 (0.82–0.90) | 5.38 × 10−11 | 0.86 (0.83–0.90) | 2.57 × 10−11 | 0.86 (0.82–0.90) | 5.33 × 10−11 | 0.86 (0.82–0.90) | 8.24 × 10−11 | 0.30 |
| 574.1 | Cholelithiasis | 78 | Digestive | 0.85 (0.81–0.89) | 8.55 × 10−11 | 0.86 (0.82–0.90) | 3.70 × 10−11 | 0.85 (0.81–0.89) | 8.52 × 10−11 | 0.85 (0.81–0.89) | 1.36 × 10−10 | 0.52 |
| 454.11 | Varicose veins of lower extremity, symptomtic | 78 | Circulatory system | 1.92 (1.54–2.38) | 4.20 × 10−9 | 1.84 (1.50–2.26) | 4.20 × 10−9 | 1.90 (1.53–2.36) | 5.41 × 10−9 | 1.93 (1.55–2.40) | 3.83 × 10−9 | 0.21 |
| 426 | Cardiac conduction disorders | 78 | Circulatory system | 0.83 (0.77–0.89) | 3.20 × 10−8 | 0.84 (0.79–0.90) | 3.71 × 10−7 | 0.83 (0.78–0.89) | 3.22 × 10−8 | 0.83 (0.77–0.89) | 4.75 × 10−8 | 0.78 |
| 426.3 | Bundle branch block | 78 | Circulatory system | 0.79 (0.72–0.86) | 7.24 × 10−7 | 0.80 (0.73–0.88) | 1.31 × 10−6 | 0.79 (0.72–0.87) | 6.97 × 10−7 | 0.79 (0.72–0.87) | 1.01 × 10−6 | 0.88 |
| 577 | Diseases of pancreas | 78 | Digestive | 0.77 (0.69–0.85) | 9.47 × 10−7 | 0.78 (0.71–0.87) | 2.34 × 10−6 | 0.77 (0.69–0.85) | 9.84 × 10−7 | 0.77 (0.69–0.85) | 1.14 × 10−6 | 0.52 |
| 79 | Viral infection | 78 | Infectious diseases | 0.77 (0.70–0.86) | 1.04 × 10−6 | 0.79 (0.71–0.87) | 1.04 × 10−6 | 0.78 (0.70–0.86) | 1.16 × 10−6 | 0.77 (0.70–0.86) | 1.20 × 10−6 | 0.20 |
| 496 | Chronic airway obstruction | 78 | Respiratory | 1.14 (1.08–1.21) | 2.10 × 10−6 | 1.14 (1.08–1.20) | 1.22 × 10−6 | 1.14 (1.08–1.21) | 2.08 × 10−6 | 1.14 (1.08–1.21) | 2.08 × 10-6 | 0.54 |
| 414 | Other forms of chronic heart disease | 78 | Circulatory system | 0.73 (0.64–0.83) | 2.66 × 10−6 | 0.74 (0.65–0.84) | 3.71 × 10−6 | 0.73 (0.65–0.84) | 2.69 × 10−6 | 0.73 (0.64–0.84) | 3.40 × 10−6 | 0.37 |
| 727.5 | Rupture of synovium | 78 | Musculoskeletal | 0.60 (0.48–0.74) | 5.59 × 10−6 | 0.61 (0.50–0.76) | 7.19 × 10−6 | 0.60 (0.48–0.74) | 5.35 × 10−6 | 0.60 (0.48–0.75) | 7.75 × 10−6 | 0.32 |
| Glycine supplementation | ||||||||||||
| 79 | Viral infection | 9 | Infectious diseases | 0.74 (0.65–0.84) | 2.23 × 10−6 | 0.74 (0.65–0.84) | 4.77 × 10−6 | 0.74 (0.65–0.84) | 2.77 × 10−6 | 0.74 (0.65–0.84) | 2.60 × 10−6 | 0.20 |
| Docosahexaenoic acid supplementation | ||||||||||||
| 574.1 | Cholelithiasis | 152 | Digestive | 0.57 (0.50–0.66) | 2.57 × 10−15 | 0.52 (0.45–0.59) | 1.49 × 10−21 | 0.57 (0.51–0.63) | 4.35 × 10−26 | 0.57 (0.52–0.64) | 3.78 × 10−25 | 0.69 |
| 574 | Cholelithiasis and cholecystitis | 152 | Digestive | 0.61 (0.54–0.70) | 6.61 × 10−13 | 0.57 (0.51–0.64) | 1.40 × 10−19 | 0.61 (0.56–0.67) | 2.28 × 10−23 | 0.62 (0.56–0.68) | 1.76 × 10−22 | 0.25 |
| 743 | Osteoporosis, osteopenia and pathological fracture | 152 | Musculoskeletal | 1.44 (1.26–1.66) | 1.61 × 10−7 | 1.57 (1.31–1.87) | 7.86 × 10−7 | 1.44 (1.26–1.65) | 1.55 × 10−7 | 1.45 (1.26–1.66) | 1.50 × 10−7 | 0.63 |
| 172 | Skin cancer | 152 | Neoplasms | 1.37 (1.22–1.54) | 2.33 × 10−7 | 1.49 (1.29–1.71) | 4.84 × 10−8 | 1.37 (1.23–1.52) | 2.98 × 10−9 | 1.37 (1.24–1.52) | 3.27 × 10−9 | 0.08 |
| 195.1 | Malignant neoplasm, other | 152 | Neoplasms | 1.27 (1.16–1.40) | 5.54 × 10−7 | 1.34 (1.19–1.51) | 9.39 × 10−7 | 1.27 (1.16–1.40) | 5.57 × 10−7 | 1.27 (1.16–1.40) | 5.09 × 10−7 | 0.05 |
| 195 | Cancer, suspected or other | 152 | Neoplasms | 1.25 (1.14–1.38) | 1.45 × 10−6 | 1.32 (1.17–1.48) | 3.63 × 10−6 | 1.25 (1.14–1.38) | 1.44 × 10−6 | 1.26 (1.15–1.38) | 1.34 × 10−6 | 0.10 |
| 743.2 | Pathologic fracture | 152 | Musculoskeletal | 6.84 (4.07–11.47) | 3.43 × 10−13 | 9.90 (5.25–18.66) | 1.34 × 10−12 | 6.79 (4.05–11.38) | 3.95 × 10−13 | 6.88 (4.09–11.56) | 3.35 × 10−13 | 0.63 |
| 145 | Cancer of mouth | 152 | Neoplasms | 3.23 (2.03–5.12) | 6.79 × 10−7 | 4.34 (2.47–7.64) | 3.57 × 10−7 | 3.21 (2.03–5.10) | 7.05 × 10−7 | 3.23 (2.03–5.13) | 6.98 × 10−7 | 0.43 |
| 594.2 | Calculus of lower urinary tract | 152 | Genitourinary | 0.37 (0.25-0.57) | 5.16 × 10−6 | 0.30 (0.18–0.50) | 3.83 × 10−6 | 0.38 (0.25–0.57) | 5.27 × 10−6 | 0.37 (0.24–0.57) | 4.35 × 10−6 | 0.45 |
| 574.2 | Calculus of bile duct | 152 | Digestive | 0.56 (0.45–0.71) | 1.12 × 10−6 | 0.50 (0.37–0.66) | 1.76 × 10−6 | 0.57 (0.45–0.71) | 1.13 × 10−6 | 0.57 (0.45–0.71) | 1.36 × 10−6 | 0.21 |
| 611 | Abnormal findings on mammogram or breast exam | 152 | Genitourinary | 2.31 (1.64–3.27) | 2.00 × 10−6 | 2.96 (2.02–4.35) | 2.85 × 10−8 | 2.31 (1.72–3.11) | 2.88 × 10−8 | 2.32 (1.72–3.13) | 3.10 × 10−8 | 0.74 |
| 380 | Disorders of external ear | 152 | sense Organs | 0.48 (0.35–0.65) | 2.34 × 10−6 | 0.40 (0.28–0.59) | 2.34 × 10−6 | 0.48 (0.35–0.65) | 2.42 × 10−6 | 0.48 (0.35–0.65) | 2.61 × 10−6 | 0.63 |
| 384 | Other disorders of tympanic membrane | 152 | Sense organs | 0.38 (0.28–0.53) | 3.45 × 10−9 | 0.31 (0.21–0.46) | 1.18 × 10−8 | 0.38 (0.28–0.53) | 3.46 × 10−9 | 0.38 (0.28–0.53) | 3.60 × 10−9 | 0.82 |
| 384.4 | Perforation of tympanic membrane | 152 | Sense organs | 0.38 (0.27–0.55) | 2.14 × 10−7 | 0.30 (0.19–0.47) | 1.30 × 10−7 | 0.38 (0.27–0.55) | 2.22 × 10−7 | 0.38 (0.26–0.55) | 1.90 × 10−7 | 0.75 |
| 598 | Abnormal findings on examination of urine | 152 | Genitourinary | 0.63 (0.52–0.77) | 5.33 × 10−6 | 0.56 (0.44–0.71) | 2.90 × 10−6 | 0.63 (0.52–0.77) | 5.43 × 10−6 | 0.63 (0.52–0.77) | 6.01 × 10−6 | 0.72 |
| 803.2 | Fracture of radius and ulna | 152 | Injuries & Poisonings | 1.46 (1.24–1.73) | 6.27 × 10−6 | 1.63 (1.33–1.99) | 2.36 × 10−6 | 1.46 (1.24–1.72) | 6.33 × 10−6 | 1.46 (1.24–1.73) | 6.24 × 10−6 | 0.67 |
| 743.11 | Osteoporosis NOS | 152 | Musculoskeletal | 1.45 (1.23–1.70) | 6.44 × 10−6 | 1.62 (1.32–1.97) | 2.27 × 10−6 | 1.45 (1.23–1.70) | 6.32 × 10−6 | 1.45 (1.23–1.70) | 6.27 × 10−6 | 0.95 |
| Butyrylcarnitine inhibition | ||||||||||||
| 411.2 | Myocardial infarction | 25 | Circulatory system | 0.86 (0.82–0.91) | 6.42 × 10−8 | 0.86 (0.81–0.92) | 1.06 × 10−6 | 0.86 (0.82–0.91) | 5.75 × 10−8 | 0.86 (0.82–0.91) | 3.79 × 10−8 | 0.30 |
| 352 | Disorders of other cranial nerves | 25 | Neurological | 0.69 (0.59–0.80) | 8.97 × 10−7 | 0.69 (0.59–0.80) | 8.97 × 10−7 | 0.69 (0.59–0.80) | 9.76 × 10−7 | 0.69 (0.60–0.80) | 8.80 × 10−7 | 0.86 |
| 721.1 | Spondylosis without myelopathy | 25 | Musculoskeletal | 0.83 (0.77–0.90) | 6.13 × 10−6 | 0.83 (0.77–0.90) | 6.13 × 10−6 | 0.83 (0.77–0.90) | 6.44 × 10−6 | 0.83 (0.77–0.90) | 4.37 × 10−6 | 0.88 |
| Sphingomyelins inhibition | ||||||||||||
| 272 | Disorders of lipid metabolism | 185 | Endocrine/metabolic | 0.57 (0.51–0.62) | 2.67 × 10−30 | 0.65 (0.62–0.69) | 1.53 × 10−71 | 0.53 (0.52–0.55) | 1.00 × 10−99 | 0.55 (0.53–0.57) | 1.00 × 10−99 | 0.21 |
| 272.11 | Hypercholesterolemia | 185 | Endocrine/metabolic | 0.57 (0.51–0.62) | 3.01 × 10−30 | 0.67 (0.64–0.71) | 6.04 × 10−58 | 0.53 (0.52–0.55) | 1.00 × 10−99 | 0.54 (0.52–0.56) | 1.00 × 10−99 | 0.25 |
| 272.1 | Hyperlipidemia | 185 | Endocrine/metabolic | 0.57 (0.52–0.63) | 4.27 × 10−30 | 0.66 (0.63–0.69) | 4.62 × 10−69 | 0.53 (0.52–0.55) | 1.00 × 10−99 | 0.54 (0.53–0.56) | 1.00 × 10−99 | 0.21 |
| 411.4 | Coronary atherosclerosis | 185 | Circulatory system | 0.73 (0.67–0.80) | 1.33 × 10−11 | 0.75 (0.71–0.79) | 2.75 × 10−27 | 0.72 (0.69–0.75) | 5.56 × 10−73 | 0.72 (0.70–0.75) | 1.40 × 10−63 | 0.08 |
| 411 | Ischemic Heart Disease | 185 | Circulatory system | 0.79 (0.74–0.85) | 2.46 × 10−10 | 0.79 (0.75–0.82) | 1.31 × 10−30 | 0.79 (0.76–0.81) | 1.97 × 10−59 | 0.79 (0.77–0.81) | 8.80 × 10−52 | 0.06 |
| 411.2 | Myocardial infarction | 185 | Circulatory system | 0.75 (0.68–0.82) | 1.30 × 10−9 | 0.75 (0.71–0.79) | 4.28 × 10−24 | 0.74 (0.71–0.78) | 2.60 × 10−37 | 0.75 (0.71–0.78) | 3.64 × 10−34 | 0.20 |
| 785 | Abdominal pain | 185 | Symptoms | 1.06 (1.04–1.09) | 1.14 × 10−6 | 1.06 (1.03–1.08) | 3.50 × 10−6 | 1.06 (1.04–1.09) | 1.23 × 10−6 | 1.06 (1.04–1.09) | 1.34 × 10−6 | 0.77 |
| 550.2 | Diaphragmatic hernia | 185 | Digestive | 1.09 (1.05–1.13) | 4.84 × 10−6 | 1.08 (1.05–1.12) | 1.41 × 10−6 | 1.09 (1.06–1.12) | 2.46 × 10−8 | 1.09 (1.06–1.12) | 4.28 × 10−8 | 0.57 |
| 599.4 | Urinary incontinence | 185 | Genitourinary | 1.13 (1.07–1.19) | 4.96 × 10−6 | 1.12 (1.07–1.18) | 7.90 × 10−6 | 1.13 (1.07–1.19) | 4.86 × 10−6 | 1.13 (1.07–1.19) | 5.20 × 10−6 | 0.70 |
| 740.1 | Osteoarthritis; localized | 185 | Musculoskeletal | 1.12 (1.06–1.17) | 6.32 × 10−6 | 1.10 (1.05–1.14) | 5.73 × 10−6 | 1.12 (1.08–1.16) | 2.90 × 10−9 | 1.12 (1.08–1.16) | 6.50 × 10−9 | 0.21 |
| 1011 | Complications of surgical and medical procedures | 185 | Injuries & poisonings | 1.12 (1.07–1.18) | 7.34 × 10−6 | 1.12 (1.07–1.17) | 4.21 × 10−6 | 1.12 (1.07–1.18) | 7.41 × 10−6 | 1.12 (1.07–1.18) | 7.16 × 10−6 | 0.99 |
| 701.2 | Scar conditions and fibrosis of skin | 185 | Dermatologic | 0.75 (0.68–0.83) | 6.77 × 10−9 | 0.76 (0.69–0.84) | 1.34 × 10−8 | 0.75 (0.68–0.83) | 7.19 × 10−9 | 0.75 (0.68–0.83) | 7.42 × 10−9 | 0.26 |
| 381.1 | Otitis media | 185 | Sense organs | 1.33 (1.19–1.48) | 4.42 × 10−7 | 1.31 (1.18–1.46) | 7.41 × 10−7 | 1.33 (1.19–1.48) | 4.46 × 10−7 | 1.33 (1.19–1.49) | 4.49 × 10−7 | 0.24 |
| 381 | Otitis media and Eustachian tube disorders | 185 | Sense organs | 1.29 (1.17–1.42) | 5.12 × 10−7 | 1.28 (1.16–1.41) | 5.12 × 10−7 | 1.29 (1.17–1.42) | 5.35 × 10−7 | 1.29 (1.17–1.43) | 4.93 × 10−7 | 0.09 |
| 574.3 | Cholecystitis without cholelithiasis | 185 | Digestive | 1.40 (1.23–1.60) | 5.36 × 10−7 | 1.36 (1.24–1.49) | 2.05 × 10−11 | 1.40 (1.28–1.54) | 1.26 × 10−13 | 1.40 (1.28–1.53) | 4.88 × 10−13 | 0.98 |
| 411.1 | Unstable angina (intermediate coronary syndrome) | 185 | Circulatory system | 0.77 (0.70–0.85) | 1.65 × 10−7 | 0.77 (0.71–0.84) | 7.48 × 10−10 | 0.77 (0.72–0.82) | 3.11 × 10−15 | 0.77 (0.72–0.82) | 1.18 × 10−14 | 0.34 |
| 722.9 | Other and unspecified disc disorder | 185 | Musculoskeletal | 1.20 (1.12–1.29) | 6.34 × 10−7 | 1.18 (1.10–1.27) | 2.43 × 10−6 | 1.20 (1.12–1.29) | 6.27 × 10−7 | 1.20 (1.12–1.29) | 6.33 × 10−7 | 0.75 |
| 858 | Complication of internal orthopedic device | 185 | Injuries & poisonings | 1.25 (1.14-1.37) | 2.38 × 10−6 | 1.24 (1.13–1.35) | 2.22 × 10−6 | 1.25 (1.15–1.36) | 1.82 × 10−7 | 1.25 (1.15–1.36) | 2.08 × 10−7 | 0.38 |
Odds ratios (ORs) with their 95% confidence intervals (CIs) represent the effect estimates on the risk of multiple non-psychiatric diseases of per 10% reduction in risk for psychiatric disorders by targeting 1-arachidonoylglycerophosphocholine (1-arachidonoyl-GPC), glycoproteins, glycine, docosahexaenoic acid, butyrylcarnitine, and sphingomyelins, respectively. An observed 2-sided P < 9.54 × 10-6 was considered as statistically significant. A 2-sided P<0.05 was considered as suggestive evidence for directional pleiotropy in the MR-Egger regression.
Abbreviations: IVW, inverse-variance weighted; MR-RAPS, Mendelian randomization robust adjusted profile score; Phe-MR, phenome-wide Mendelian randomization.