Table 3.
Mendelian randomization to estimate the causal effects of 15 genetically determined risk factors on hip fractures
| Trait or disease | Inverse variance weighted meta-analyses |
Egger regression |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Hip fractures |
Any fractures |
Power |
Intercept, p |
||||||||
| Hip |
Any |
Hip fractures | Any fractures | ||||||||
| OR | 95% CI | p | OR | 95% CI | p | OR 1.15, % | OR 1.20, % | OR 1.15, % | |||
| Continuous risk factors | |||||||||||
| BMD-related parameters | |||||||||||
| Decreased FN-BMD | 2.12 | (1.82–2.47) | 3.7 × 10−22a | 1.63 | (1.44–1.84) | 3.3 × 10−15a | 96 | 100 | 100 | 1.2 × 10−1 | 4.4 × 10−1 |
| Decreased LS-BMD | 1.66 | (1.38–2.00) | 9.9 × 10−8a | 1.56 | (1.39–1.76) | 7.2 × 10−14a | 97 | 100 | 100 | 5.5 × 10−4a | 4.1 × 10−1 |
| Decreased eBMD | 1.73 | (1.59–1.87) | 1.1 × 10−39a | 1.65 | (1.59–1.71) | 3.0 × 10−151a | 100 | 100 | 100 | 6.4 × 10−2 | 8.5 × 10−1 |
| Other risk markers | |||||||||||
| Early menopause | 0.95 | (0.87–1.04) | 3.0 × 10−1 | 1.07 | (1.03–1.12) | 9.0 × 10−4a | 96 | 100 | 100 | 2.3 × 10−1 | 8.8 × 10−1 |
| Only females | 1.01 | (0.88–1.16) | 8.5 × 10−1 | N/A | N/A | N/A | 75 | 95 | N/A | 9.6 × 10−2 | N/A |
| Late puberty | 1.13 | (1.01–1.27) | 3.3 × 10−2 | 1.07 | (1.01–1.13) | 2.5 × 10−2 | 69 | 91 | 99 | 3.2 × 10−2 | 8.5 × 10−1 |
| Only females | 1.18 | (1.02–1.38) | 2.8 × 10−2 | N/A | N/A | N/A | 40 | 65 | N/A | 2.5 × 10−1 | N/A |
| Only males | 1.02 | (0.83–1.24) | 8.7 × 10−1 | N/A | N/A | N/A | 22 | 37 | N/A | 4.1 × 10−3 | N/A |
| Decreased TSH | 1.01 | (0.91–1.11) | 8.6 × 10−1 | 0.99 | (0.95–1.03) | 6.2 × 10−1 | 95 | 100 | 100 | 4.8 × 10−1 | 8.1 × 10−1 |
| Decreased grip strength/BW | 1.06 | (0.87–1.30) | 5.6 × 10−1 | 1.21 | (1.09–1.34) | 3.4 × 10−4a | 48 | 74 | 91 | 3.8 × 10−1 | 2.4 × 10−1 |
| Low vitamin D levels | 0.98 | (0.87–1.10) | 7.1 × 10−1 | 0.99 | (0.94–1.04) | 5.9 × 10−1 | 99 | 100 | 100 | 3.8 × 10−1 | 1.8 × 10−1 |
| Binary risk factors | |||||||||||
| Alzheimer′s disease | 1.07 | (1.05–1.10) | 1.9 × 10−12a | 1.00 | (0.99–1.01) | 6.5 × 10−1 | 100 | 100 | 100 | 7.2 × 10−1 | 7.6 × 10−1 |
| Coronary heart disease | 1.01 | (0.95–1.08) | 6.7 × 10−1 | 1.01 | (0.99–1.03) | 4.3 × 10−1 | 95 | 100 | 100 | 4.0 × 10−1 | 2.6 × 10−1 |
| Rheumatoid arthritis | 1.00 | (0.97–1.02) | 9.3 × 10−1 | 1.01 | (1.00–1.02) | 1.0 × 10−1 | 95 | 100 | 100 | 6.3 × 10−1 | 4.3 × 10−1 |
| Inflammatory bowel disease | 1.01 | (1.00–1.03) | 1.2 × 10−1 | 1.00 | (0.99–1.01) | 7.8 × 10−1 | 99 | 100 | 100 | 3.6 × 10−1 | 8.9 × 10−1 |
| Type 1 diabetes | 1.00 | (0.98–1.02) | 8.6 × 10−1 | 1.00 | (0.99–1.00) | 6.6 × 10−1 | 98 | 100 | 100 | 5.5 × 10−1 | 8.4 × 10−1 |
| Type 2 diabetes | 1.03 | (0.99–1.06) | 1.8 × 10−1 | 1.00 | (0.98–1.03) | 6.3 × 10−1 | 95 | 100 | 100 | 2.2 × 10−1 | 7.6 × 10−2 |
| Ever smoked regularly | 1.08 | (1.03–1.13) | 2.3 × 10−3a | 1.05 | (1.03–1.07) | 1.4 × 10−4a | 61 | 96 | 97 | 7.6 × 10−1 | 2.3 × 10−1 |
Inverse variance weighted meta-analysis. Estimates for the association with hip fracture are from the present hip fracture GWAS, while the estimates from fractures at any bone site are from the summary statistics in Morris et al.11 Odds ratio (OR) is for the risk of fracture per standard deviation (SD) change in the risk factor for continuous trait or risk of fracture per doubling of odds (obtained by multiplying the causal estimate of log odds by ln(2) ≈ 0.69)19 of disease susceptibility for binary factors. For menopause and puberty, we used the estimated SD from the largest cohorts in the published GWAS (early menopause SD = 3.81 years in Breast Cancer Association Consortium;20 late puberty SD = 1.40 years in Women’s Genome Health Study21) to translate the effect unit from year to SD. For ever smoked regularly, the ORs are expressed per 0.5 unit increase in log odds of ever smoking regularly with a 1 SD increase in genetically predicted smoking initiation corresponding to a 10% increased risk of smoking.18,22 Estimates are displayed using a random effects model to account for possible heterogeneity. Statistical power is given to detect an odds ratio of 1.15 or 1.20 at α ≤ 3.3 × 10−3 (0.05/15 risk factors). Egger intercepts are given in this table, while Egger effect estimates are presented in Table S7.For risk factors including UK Biobank in the GWAS and displaying significant causal effects with hip fractures, sensitivity analyses were performed excluding UK Biobank in the hip fracture meta-analysis used for the mendelian randomization, revealing essentially similar effect estimates (results excluding UK Biobank in the hip fracture GWAS; decreased eBMD OR = 1.66, 95% CI: 1.54–1.79; ever smoked regularly OR = 1.07, 95% CI: 1.01–1.14). Grip strength is given as grip strength per body weight (BW). SD for grip strength is given for kg grip strength per kg in BW and was estimated in the UK Biobank to be 0.127. To achieve effect estimates not confounded by a possible minor dilution by diaphyseal and distal femur fractures and lack of adjustment for height and weight in the publicly available analyses of the FinnGen cohort, we replicated the significant causal associations for FN-BMD (OR 2.25, 95% CI 1.91–2.65), Alzheimer′s disease (OR 1.08, 95% CI 1.06–1.11), and ever smoked regularly (OR 1.06, 95% CI 1.00–1.12) in a meta-analysis excluding the FinnGen cohort, yielding similar effect estimates. N/A, not available; BMD, bone mineral density; TSH, thyroid-stimulating hormone; FN, femoral neck; LS, lumbar spine; eBMD, estimated BMD in the heel using ultrasound; CI, confidence interval.
Findings that remain significantly associated after correction for multiple testing (p < 0.05/15 = 3.3 × 10−3).