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Mendelian randomization in the bone field.

ABSTRACT: Identification of causative risk factors amenable for modification is essential for the prevention and treatment of osteoporosis. Observational studies have identified associations between several potentially modifiable risk factors and osteoporosis. However, observational studies are susceptible to confounding, reverse causation bias, and measurement error, all of which limit their ability to provide causal estimates of the effect of exposures on outcomes, thereby reducing their ability to inform prevention and treatment strategies against bone loss and fractures. In addition, not all risk factors are suitable for an analysis in a randomized clinical trial. Mendelian randomization is a genetic epidemiological method that exploits genetic variants as unbiased proxies for modifiable exposures (e.g., biomarkers, adiposity measures, dietary factors, and behaviors) to determine the causal relationships between exposures and health outcomes. This technique has been used to provide evidence of causal associations of serum estradiol concentrations, smoking, body mass index, and type 2 diabetes with bone mineral density and the lack of associations of serum thyroid stimulating hormone, urate, C-reactive protein, and 25?hydroxyvitamin D concentrations with bone mineral density in generally healthy populations. This review will briefly explain the concept of Mendelian randomization, the advantages and potential limitations of this study design, and give examples of how Mendelian randomization has been used to investigate questions relevant to osteoporosis.

SUBMITTER: Larsson SC

PROVIDER: S-EPMC6697532 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Mendelian randomization in the bone field.

Larsson Susanna C SC Michaëlsson Karl K Burgess Stephen S

Bone 20181012

Identification of causative risk factors amenable for modification is essential for the prevention and treatment of osteoporosis. Observational studies have identified associations between several potentially modifiable risk factors and osteoporosis. However, observational studies are susceptible to confounding, reverse causation bias, and measurement error, all of which limit their ability to provide causal estimates of the effect of exposures on outcomes, thereby reducing their ability to info ...[more]

PMID: 30321669

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Project description:Epidemiologic studies have replicated positive associations between obesity and bone health, but their mechanisms are still debatable. We aimed to scrutinize an association between bone health and obesity using genetic instrumental variables (IVs) with the distinction of general versus abdominal obesity. We selected independent IVs of body mass index (BMI) and BMI-adjusted waist circumference (aWC, a proxy of a central fat distribution) by combining novel genomewide searches from the Korean Genome Epidemiology Study (KoGES) consortium and existing reports. We evaluated the associations of obesity indices with bone health measures for weight-bearing and non-weight-bearing bones, applying standard Mendelian randomization analyses. The IVs for BMI and aWC selected from KoGES cohort studies (n = 14,389) explained its own trait only, negating the mutual correlation at the phenotypic level. Two-stage least squares analyses using an independent cohort study (n = 2507, mean age = 44.4 years, men = 44.3%) showed that BMI but not aWC was positively associated with bone mineral density (BMD for weight-bearing bones: 0.063 ± 0.016 g/cm2 per one standard deviation increase in BMI), implying the fat distribution might be neutral. The association was weaker for non-weight-bearing bones (BMI on BMD: 0.034 ± 0.011 g/cm2 ), and for postmenopausal women the association was absent. Obesity increased both bone area and bone mineral content (BMC) to a lesser degree, but the increase in BMC was not evident for menopausal women. When we stratified the weight into lean body mass and fat mass, the increase in BMD was more evident for lean body mass, and fat mass showed a beneficial role only for men and premenopausal women. Our findings suggest that bone health might gain little from obesity, if any, through its added weight, and other means to prevent bone loss would be essential for postmenopausal women. © 2019 American Society for Bone and Mineral Research.

Project description:BackgroundRecently, the association between inflammatory bowel disease (including ulcerative colitis and Crohn's disease) and BMD has attracted great interest in the research community. However, the results of the published epidemiological observational studies on the relationship between inflammatory bowel disease and BMD are still inconclusive. Here, we performed a two-sample Mendelian randomization analysis to investigate the causal link between inflammatory bowel disease and level of BMD using publically available GWAS summary statistics.MethodsA series of quality control steps were taken in our analysis to select eligible instrumental SNPs which were strongly associated with exposure. To make the conclusions more robust and reliable, we utilized several robust analytical methods (inverse-variance weighting, MR-PRESSO method, mode-based estimate method, weighted median, MR-Egger regression, and MR.RAPS method) that are based on different assumptions of two-sample MR analysis. The MR-Egger intercept test, Cochran's Q test, and "leave-one-out" sensitivity analysis were performed to evaluate the horizontal pleiotropy, heterogeneities, and stability of these genetic variants on BMD. Outlier variants identified by the MR-PRESSO outlier test were removed step-by-step to reduce heterogeneity and the effect of horizontal pleiotropy.ResultsOur two-sample Mendelian randomization analysis with two groups of exposure GWAS summary statistics and four groups of outcome GWAS summary statistics suggested a definitively causal effect of genetically predicted ulcerative colitis on TB-BMD and FA-BMD but not on FN-BMD or LS-BMD (after Bonferroni correction), and we merely determined a causal effect of Crohn's disease on FN-BMD but not on the others, which was somewhat inconsistent with many published observational researches. The causal effect of inflammatory bowel disease on TB-BMD was significant and robust but not on FA-BMD, FN-BMD, and LS-BMD, which might result from the cumulative effect of ulcerative colitis and Crohn's disease on BMDs.ConclusionsOur Mendelian randomization analysis supported the causal effect of ulcerative colitis on TB-BMD and FA-BMD. As to Crohn's disease, only the definitively causal effect of it on decreased FN-BMD was observed. Updated MR analysis is warranted to confirm our findings when a more advanced method to get less biased estimates and better precision or GWAS summary data with more ulcerative colitis and Crohn's disease patients was available.

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Mendelian randomization in the bone field.

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Mendelian randomization in the bone field.

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