Introduction
Materials and Methods
Exposure | SNP | Chr | Mapped genes | Effect allelea | Association with exposureb | Association with FN-BMDc | Association with LS-BMDc | Association with FA-BMDc | ||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Exposure effect (β) | p value | β (SE)d | p value | β (SE)d | p value | β (SE)d | p value | |||||
Schizophrenia | rs13240464 | 7 | IMMP2L | T | 0.0806 | 6.16E−13 | − 0.0131 (0.0079) | 0.1057 | − 0.0094 (0.0092) | 0.3211 | − 0.0158 (0.0166) | 0.3490 |
Schizophrenia | rs2945232 | 8 | FAM86B3P, ALG1L13P | T | − 0.0606 | 2.03E−08 | 0.0008 (0.0080) | 0.9203 | − 0.0096 (0.0095) | 0.3254 | 0.0093 (0.0184) | 0.6198 |
Schizophrenia | rs832187 | 3 | THOC7, C3orf49 | T | − 0.0607 | 2.58E−08 | 0.0055 (0.0078) | 0.4856 | 0.0063 (0.0090) | 0.4949 | − 0.0019 (0.0162) | 0.9097 |
Schizophrenia | rs75968099 | 3 | LINC02033, HSPD1P6 | T | 0.0790 | 3.39E−12 | − 0.0011 (0.0079) | 0.8941 | 0.0103 (0.0092) | 0.2710 | 0.0018 (0.0165) | 0.7522 |
Schizophrenia | rs2905426 | 19 | GATAD2A, MAU2 | T | − 0.0648 | 6.92E−09 | − 0.0009 (0.0079) | 0.9137 | − 0.0040 (0.0092) | 0.6749 | 0.0280 (0.0166) | 0.0977 |
Schizophrenia | rs2007044 | 12 | CACNA1C | A | − 0.0916 | 2.63E−17 | 0.0078 (0.0077) | 0.3241 | 0.0006 (0.0090) | 0.9471 | 0.0191 (0.0160) | 0.2421 |
Schizophrenia | rs7893279 | 10 | CACNB2 | T | 0.1131 | 3.56E−11 | − 0.0087 (0.0119) | 0.4769 | 0.0080 (0.0139) | 0.5729 | 0.0108 (0.0244) | 0.6646 |
Schizophrenia | rs11027857 | 11 | AC015771.1, RF00019 | A | 0.0626 | 3.21E−09 | 0.0067 (0.0075) | 0.3836 | 0.0170 (0.0087) | 0.0554 | − 0.0079 (0.0155) | 0.6158 |
Schizophrenia | rs16867576 | 5 | MEF2C-AS1 | A | 0.0958 | 1.36E−08 | − 0.0073 (0.0112) | 0.5225 | 0.0244 (0.0130) | 0.0670 | 0.0083 (0.0230) | 0.7247 |
Schizophrenia | rs17194490 | 3 | CNTN4 | T | 0.0971 | 4.87E−11 | 0.0049 (0.0101) | 0.6348 | − 0.0044 (0.0118) | 0.7170 | 0.0004 (0.0209) | 0.9854 |
Schizophrenia | rs2053079 | 19 | ZNF536 | A | − 0.0733 | 3.79E−09 | 0.0001 (0.0088) | 0.9898 | − 0.0027 (0.0103) | 0.8003 | − 0.0383 (0.0182) | 0.0385 |
Schizophrenia | rs4523957 | 17 | SRR | T | 0.0683 | 1.04E−09 | − 0.0118 (0.0084) | 0.1691 | − 0.0098 (0.0092) | 0.2976 | 0.0026 (0.0164) | 0.8761 |
Schizophrenia | rs8044995 | 16 | NFATC3 | A | 0.0777 | 3.27E−08 | − 0.0056 (0.0099) | 0.5788 | − 0.0100 (0.0116) | 0.3996 | − 0.0063 (0.0202) | 0.7588 |
Schizophrenia | rs2693698 | 14 | BCL11B | A | − 0.0630 | 1.38E−08 | 0.0014 (0.0075) | 0.8580 | − 0.0016 (0.0087) | 0.8581 | − 0.0059 (0.0156) | 0.7102 |
Schizophrenia | rs8139773 | 22 | CACNA1I | A | − 0.0710 | 1.36E−10 | − 0.0054 (0.0094) | 0.5749 | − 0.0184 (0.0107) | 0.0950 | − 0.0093 (0.0167) | 0.5859 |
Schizophrenia | rs7819570 | 8 | AC090578.1 | T | 0.0771 | 1.90E−08 | − 0.0016 (0.0141) | 0.9099 | − 0.0174 (0.0154) | 0.2706 | − 0.0085 (0.0294) | 0.7779 |
Schizophrenia | rs1702294 | 1 | MIR137HG | T | − 0.1157 | 2.79E−17 | − 0.0004 (0.0096) | 0.9668 | − 0.0146 (0.0111) | 0.1998 | − 0.0153 (0.0201) | 0.4549 |
Schizophrenia | rs6065094 | 20 | PPP1R16B | A | − 0.0742 | 5.52E−11 | − 0.0080 (0.0079) | 0.3225 | 0.0107 (0.0093) | 0.2573 | − 0.0054 (0.0167) | 0.7521 |
Schizophrenia | rs4648845 | 1 | PLCH2 | T | 0.0690 | 4.03E−09 | − 0.0047 (0.0080) | 0.5678 | − 0.0111 (0.0092) | 0.2382 | 0.0093 (0.0154) | 0.5533 |
Schizophrenia | rs12129573 | 1 | RN7SKP19, LINC01360 | A | 0.0694 | 2.35E−10 | 0.0017 (0.0079) | 0.8300 | 0.0045 (0.0093) | 0.6350 | 0.0132 (0.0170) | 0.4454 |
Schizophrenia | rs7432375 | 3 | STAG1 | A | − 0.0714 | 5.27E−11 | − 0.0025 (0.0077) | 0.7469 | 0.0022 (0.0090) | 0.8158 | 0.0053 (0.0164) | 0.7522 |
Schizophrenia | rs73036062 | 11 | IGSF9B | A | − 0.0897 | 2.14E−11 | 0.0028 (0.0093) | 0.7733 | 0.0068 (0.0108) | 0.5419 | − 0.0006 (0.0190) | 0.9742 |
Schizophrenia | rs4129585 | 8 | TSNARE1 | A | 0.0784 | 2.03E−13 | − 0.0013 (0.0076) | 0.8642 | − 0.0048 (0.0089) | 0.5997 | − 0.0138 (0.0158) | 0.3903 |
Schizophrenia | rs12887734 | 14 | APOPT1, AL139300.1, KLC1 | T | 0.0871 | 1.17E−13 | 0.0113 (0.0085) | 0.1926 | 0.0020 (0.0099) | 0.8428 | − 0.0151 (0.0175) | 0.3973 |
Schizophrenia | rs4391122 | 5 | ZSWIM6, LINC02057 | A | − 0.0789 | 1.73E−13 | 0.0060 (0.0076) | 0.4365 | − 0.0009 (0.0088) | 0.9216 | 0.0006 (0.0159) | 0.9703 |
Schizophrenia | rs34796896 | 3 | FXR1 | A | − 0.0864 | 6.23E−11 | 0.0041 (0.0092) | 0.6644 | − 0.0059 (0.0107) | 0.5866 | − 0.0052 (0.0195) | 0.7942 |
Schizophrenia | rs6430095 | 2 | Not reported | N | 0.0807 | 1.21E−08 | − 0.0104 (0.0100) | 0.3077 | − 0.0083 (0.0116) | 0.4861 | 0.0142 (0.0207) | 0.5003 |
Schizophrenia | rs301797 | 1 | RERE, RERE-AS1 | A | 0.0682 | 2.72E−09 | − 0.0196 (0.0081) | 0.0176 | − 0.0159 (0.0094) | 0.0986 | − 0.0488 (0.0168) | 0.0043 |
Schizophrenia | rs59979824 | 2 | AC092638.1, PCGEM1 | A | − 0.0664 | 1.08E−08 | 0.0018 (0.0080) | 0.8264 | − 0.0033 (0.0093) | 0.7295 | − 0.0141 (0.0169) | 0.4139 |
Schizophrenia | rs3798869 | 6 | SNAP91 | A | − 0.0648 | 1.15E−09 | − 0.0052 (0.0075) | 0.5014 | 0.0038 (0.0088) | 0.6759 | 0.0242 (0.0157) | 0.1314 |
Schizophrenia | rs6984242 | 8 | AC107934.2, AC107934.1 | A | − 0.0644 | 1.76E−09 | − 0.0030 (0.0102) | 0.7731 | − 0.0040 (0.0116) | 0.7362 | 0.0098 (0.0234) | 0.6815 |
Schizophrenia | rs7193419 | 16 | AC018846.1, AC138305.1 | T | 0.0597 | 1.59E−08 | 0.0149 (0.0074) | 0.0504 | 0.0214 (0.0086) | 0.0156 | 0.0040 (0.0154) | 0.7978 |
Schizophrenia | rs12903146 | 15 | AC104574.2 | A | 0.0648 | 1.04E−09 | − 0.0039 (0.0075) | 0.6123 | − 0.0046 (0.0088) | 0.6072 | − 0.0009 (0.0157) | 0.9566 |
Schizophrenia | rs1501357 | 5 | HCN1 | T | − 0.0765 | 1.24E−08 | 0.0201 (0.0099) | 0.0460 | 0.0011 (0.0115) | 0.9243 | 0.0117 (0.0206) | 0.5767 |
Schizophrenia | rs10520163 | 4 | CLCN3 | T | 0.0609 | 1.02E−08 | − 0.0036 (0.0075) | 0.6399 | − 0.0130 (0.0088) | 0.1494 | − 0.0097 (0.0158) | 0.5485 |
Schizophrenia | rs58120505 | 7 | MAD1L1 | T | 0.0807 | 6.43E−14 | − 0.0045 (0.0077) | 0.5665 | − 0.0042 (0.0089) | 0.6474 | − 0.0156 (0.0162) | 0.3453 |
Schizophrenia | rs2973155 | 5 | GRIA1, LINC01470 | T | − 0.0673 | 1.02E−09 | − 0.0014 (0.0084) | 0.8655 | 0.0015 (0.0091) | 0.8750 | − 0.0156 (0.0163) | 0.3485 |
Schizophrenia | rs3849046 | 5 | ETF1 | T | 0.0627 | 4.83E−09 | 0.0112 (0.0075) | 0.1464 | 0.0108 (0.0088) | 0.2263 | 0.0032 (0.0155) | 0.8392 |
Schizophrenia | rs140505938 | 1 | LOC105371427 | T | − 0.0908 | 9.34E−10 | 0.0004 (0.0101) | 0.9659 | 0.0061 (0.0118) | 0.6113 | 0.0006 (0.0212) | 0.9762 |
Schizophrenia | rs13217619 | 6 | ZSCAN31 | T | 0.2197 | 1.44E−29 | − 0.0007 (0.0135) | 0.9573 | − 0.0086 (0.0164) | 0.6086 | 0.0367 (0.0311) | 0.2460 |
Schizophrenia | rs3735025 | 7 | DGKI | T | 0.0637 | 7.75E−09 | 0.0102 (0.0078) | 0.1984 | 0.0035 (0.0091) | 0.7058 | 0.0120 (0.0162) | 0.4676 |
Schizophrenia | rs36068923 | 8 | AC090819.1, AC073023.1 | A | − 0.0840 | 1.05E−10 | − 0.0055 (0.0094) | 0.5671 | 0.0040 (0.0109) | 0.7207 | − 0.0180 (0.0194) | 0.3646 |
Schizophrenia | rs7951870 | 11 | DGKZ | T | − 0.0925 | 8.25E−11 | − 0.0372 (0.0109) | 0.0009 | − 0.0234 (0.0131) | 0.0810 | − 0.0065 (0.0210) | 0.7620 |
Schizophrenia | rs1106568 | 4 | GPM6A | A | − 0.0694 | 1.15E−08 | − 0.0074 (0.0088) | 0.4071 | 0.0068 (0.0102) | 0.5130 | 0.0037 (0.0179) | 0.8399 |
Bipolar disorder | rs10994397 | 10 | ANK3 | C | − 0.2979 | 5.54E−10 | − 0.0179 (0.0160) | 0.2746 | − 0.0359 (0.0186) | 0.0591 | − 0.0516 (0.0323) | 0.1172 |
Bipolar disorder | rs12576775 | 11 | TENM4 | A | − 0.1672 | 2.66E−08 | − 0.0137 (0.0098) | 0.1721 | − 0.0007 (0.0114) | 0.9492 | − 0.0410 (0.0204) | 0.0493 |
Bipolar disorder | rs9371601 | 6 | SYNE1 | G | − 0.1427 | 4.33E−09 | 0.0029 (0.0079) | 0.7208 | − 0.0111 (0.0092) | 0.2370 | − 0.0154 (0.0166) | 0.3630 |
Alzheimer’s disease | rs10792832 | 11 | RNU6-560P, AP003097.2 | A | − 0.1400 | 9.32E−26 | − 0.0060 (0.0077) | 0.4459 | − 0.0009 (0.0090) | 0.9245 | 0.0184 (0.0161) | 0.6118 |
Alzheimer’s disease | rs35349669 | 2 | INPP5D | T | 0.0755 | 3.17E−08 | 0.0074 (0.0076) | 0.3394 | − 0.0007 (0.0088) | 0.9409 | 0.0184 (0.0161) | 0.2628 |
Alzheimer’s disease | rs10948363 | 6 | CD2AP | G | 0.0954 | 5.20E−11 | 0.0111 (0.0089) | 0.2258 | − 0.0090 (0.0098) | 0.3706 | − 0.0219 (0.0175) | 0.2219 |
Alzheimer’s disease | rs11218343 | 11 | SORL1 | C | − 0.2620 | 9.73E−15 | − 0.0261 (0.0185) | 0.1683 | − 0.0437 (0.0214) | 0.0457 | − 0.0030 (0.0399) | 0.9407 |
Alzheimer’s disease | rs10498633 | 14 | SLC24A4 | T | − 0.0946 | 5.54E−09 | 0.0111 (0.0089) | 0.2258 | 0.0003 (0.0104) | 0.9774 | 0.0095 (0.0183) | 0.6118 |
Alzheimer’s disease | rs6656401 | 1 | CR1 | A | 0.1667 | 5.69E−24 | 0.0062 (0.0101) | 0.5587 | 0.0003 (0.0110) | 0.9756 | − 0.0117 (0.0194) | 0.5542 |
Alzheimer’s disease | rs190982 | 5 | MEF2C-AS1 | G | − 0.0759 | 3.23E−08 | − 0.0131 (0.0080) | 0.1068 | − 0.0050 (0.0092) | 0.5934 | 0.0023 (0.0160) | 0.8875 |
Alzheimer’s disease | rs1476679 | 7 | ZCWPW1 | C | − 0.0891 | 5.58E−10 | − 0.0003 (0.0083) | 0.9721 | 0.0023 (0.0098) | 0.8211 | 0.0046 (0.0172) | 0.7917 |
Alzheimer’s disease | rs7274581 | 20 | CASS4 | C | − 0.1323 | 2.46E−08 | − 0.0055 (0.0134) | 0.6861 | − 0.0050 (0.0156) | 0.7524 | − 0.0243 (0.0276) | 0.3877 |
Results
Causality Between Schizophrenia and BMD
Psychiatric disorders | MR methods | FN-BMD | LS-BMD | FA-BMD | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Number of SNPs | OR (95% CI) | SE | MR p value | MR-Steiger test | Number of SNPs | OR (95% CI) | SE | MR p value | MR-Steiger test | Number of SNPs | OR (95% CI) | SE | MR p value | MR-Steiger test | ||
Schizophrenia | MR-Egger | 44 | 0.9673 (0.8382 to 1.1163) | 0.0731 | 0.6519 | Direction: TRUE p value < 0.0001 | 44 | 0.9916 (0.8419 to 1.1678) | 0.0835 | 0.9195 | Direction: TRUE p value < 0.0001 | 44 | 1.2108 (0.8976 to 1.6334) | 0.1527 | 0.2173 | Direction: TRUE p value < 0.0001 |
Inverse variance weighted | 44 | 0.9954 (0.9624 to 1.0296) | 0.0172 | 0.7907 | 44 | 1.0040 (0.9667 to 1.0427) | 0.0193 | 0.8375 | 44 | 0.9944 (0.9294 to 1.0641) | 0.0345 | 0.8718 | ||||
Weighted median | 44 | 0.9870 (0.9424 to 1.0338) | 0.0236 | 0.5804 | 44 | 0.9753 (0.9231 to 1.0304) | 0.0280 | 0.3725 | 44 | 1.0257 (0.9319 to 1.1291) | 0.0490 | 0.6037 | ||||
Bipolar disorder | MR-Egger | 3 | 1.1355 (0.8870 to 1.4537) | 0.1260 | 0.4973 | Direction: TRUE p value < 0.0001 | 3 | 1.1819 (0.9073 to 1.5396) | 0.1349 | 0.4323 | Direction: TRUE p value < 0.0001 | 3 | 1.2457 (0.7879 to 1.9693) | 0.2337 | 0.5197 | Direction: TRUE p value < 0.0001 |
Inverse variance weighted | 3 | 1.0401 (0.9765 to 1.1079) | 0.0322 | 0.2218 | 3 | 1.0738 (0.9978 to 1.1555) | 0.0374 | 0.0572 | 3 | 1.1893 (1.0438 to 1.3552) | 0.0666 | 0.0092 | ||||
Weighted median | 3 | 1.0552 (0.9721 to 1.1453) | 0.0418 | 0.1993 | 3 | 1.0830 (0.9865 to 1.1890) | 0.0476 | 0.0941 | 3 | 1.1829 (1.0058 to 1.3938) | 0.0837 | 0.0448 | ||||
Alzheimer’s disease | MR-Egger | 9 | 1.0571 (0.9085 to 1.2299) | 0.0773 | 0.4960 | Direction: TRUE p value < 0.0001 | 9 | 1.1307 (0.9509 to 1.3445) | 0.0884 | 0.2070 | Direction: TRUE p value < 0.0001 | 9 | 0.9219 (0.6745 to 1.2601) | 0.1594 | 0.6258 | Direction: TRUE p value < 0.0001 |
Inverse variance weighted | 9 | 1.0478 (0.9951 to 1.1034) | 0.0263 | 0.0762 | 9 | 1.0207 (0.9620 to 1.0830) | 0.0302 | 0.4982 | 9 | 0.9514 (0.8561 to 1.0574) | 0.0539 | 0.3557 | ||||
Weighted median | 9 | 1.0438 (0.9756 to 1.1167) | 0.0345 | 0.2139 | 9 | 1.0038 (0.9286 to 1.0850) | 0.0397 | 0.9248 | 9 | 0.9334 (0.8142 to 1.0700) | 0.0697 | 0.3225 |
Psychiatric disorders | MR methods | FN-BMD | LS-BMD | FA-BMD | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Cochran Q statistic | I2 | Heterogeneity p value | MR-Egger | Cochran Q statistic | I2 | Heterogeneity p value | MR-Egger | Cochran Q statistic | I2 | Heterogeneity p value | MR-Egger | |||||
Intercept | Intercept p value | Intercept | Intercept p value | Intercept | Intercept p value | |||||||||||
Schizophrenia | MR-Egger | 46.1502 | 0.0899 | 0.3047 | 0.0023 | 0.6887 | 42.4492 | 0.0106 | 0.4516 | 0.0010 | 0.8789 | 30.5206 | < 0.0001 | 0.9057 | − 0.0156 | 0.1929 |
Inverse variance weighted | 46.3290 | 0.0719 | 0.3366 | 42.4729 | < 0.0001 | 0.4940 | 32.2717 | < 0.0001 | 0.8842 | |||||||
Maximum likelihood | 46.3274 | 0.0718 | 0.3367 | 42.4725 | < 0.0001 | 0.4940 | 32.2714 | < 0.0001 | 0.8843 | |||||||
Bipolar disorder | MR-Egger | 1.2019 | 0.1680 | 0.2729 | − 0.0163 | 0.6005 | 1.0253 | 0.0247 | 0.3113 | − 0.0178 | 0.5939 | 0.6131 | < 0.0001 | 0.4336 | − 0.0087 | 0.8703 |
Inverse variance weighted | 1.8344 | < 0.0001 | 0.3996 | 1.5886 | < 0.0001 | 0.4519 | 0.6558 | < 0.0001 | 0.7204 | |||||||
Maximum likelihood | 1.8075 | < 0.0001 | 0.4051 | 1.5346 | < 0.0001 | 0.4643 | 0.6157 | < 0.0001 | 0.7350 | |||||||
Alzheimer’s disease | MR-Egger | 5.5012 | < 0.0001 | 0.5990 | − 0.0011 | 0.9073 | 3.5194 | < 0.0001 | 0.8332 | − 0.0126 | 0.2573 | 4.4641 | < 0.0001 | 0.7250 | 0.0183 | 0.8396 |
Inverse variance weighted | 5.5158 | < 0.0001 | 0.7013 | 5.0401 | < 0.0001 | 0.7533 | 4.5082 | < 0.0001 | 0.8086 | |||||||
Maximum likelihood | 5.4805 | < 0.0001 | 0.7052 | 5.0350 | < 0.0001 | 0.7538 | 4.5001 | < 0.0001 | 0.8094 |