Lipid Metabolism, Methylation Aberrant, and Osteoporosis: A Multi-omics Study Based on Mendelian Randomization

Observational studies have shown a causal association between dyslipidemia and osteoporosis, but the genetic causation and complete mechanism of which are uncertain. The disadvantage of previous observational studies is that they are susceptible to confounding factors and bias, that makes it difficult to infer a causal link between those two diseases. Abnormal epigenetic modifications, represented by DNA methylation, are important causes of many diseases. However, there are no studies showing a bridging role for methylation modifications in blood lipid metabolism and osteoporosis.

SNPs for lipid profile (Blood VLDL cholesterol (VLDL-C), blood LDL cholesterol (LDL-C), blood HDL cholesterol (HDL-C), blood triglycerides (TG), diagnosed pure hypercholesterolaemia, blood apolipoprotein B (Apo B), blood apolipoprotein A1(Apo A1)), and bone mineral density (BMD) in different body parts (Heel BMD, lumbar BMD, whole-body BMD, femoral neck BMD) were obtained from large meta-analyses of genome-wide association studies as instrumental variables for two-sample Mendelian randomization. Assessment of the genetic effects of lipid profile-associated methylation sites and bone mineral density was carried out using the summary-data-based Mendelian randomization (SMR) method.

Two-sample Mendelian randomization showed that there was a negative causal association between hypercholesterolaemia and heel BMD (p = 0.0103, OR = 0.4590), and total body BMD (p = 0.0002, OR = 0.2826). LDL-C had a negative causal association with heel BMD (p = 8.68E-05, OR = 0.9586). VLDL-C had a negative causal association with heel BMD (p = 0.035, OR = 0.9484), lumbar BMD (p = 0.0316, OR = 0.9356), and total body BMD (p = 0.0035, OR = 0.9484). HDL-C had a negative causal association with heel BMD (p = 1.25E-05, OR = 0.9548), lumbar BMD (p = 0.0129, OR = 0.9358), and total body BMD (p = 0.0399, OR = 0.9644). Apo B had a negative causal association with heel BMD (p = 0.0001, OR = 0.9647). Apo A1 had a negative causal association with heel BMD (p = 0.0132, OR = 0.9746) and lumbar BMD (p = 0.0058, OR = 0.9261). The p-values of all positive results corrected by the FDR method remained significant and sensitivity analysis showed that there was no horizontal pleiotropy in the results despite the heterogeneity in some results. SMR identified 3 methylation sites associated with lipid profiles in the presence of genetic effects on BMD: cg15707428(GREB1), cg16000331(SREBF2), cg14364472(NOTCH1).

Our study provides insights into the potential causal links and co-pathogenesis between dyslipidemia and osteoporosis. The genetic effects of dyslipidaemia on osteoporosis may be related to certain aberrant methylation genetic modifications.