Purpose A Disintegrin and Metalloproteinase (ADAM) and A Disintegrin and Metalloproteinase with Thrombospondin Motif (ADAMTS) have been reported potentially involved in bone metabolism and related to bone mineral density. This Mendelian Randomization (MR) analysis was performed to determine whether there are causal associations of serum ADAM/ADAMTS with BMD in rid of confounders. Methods The genome-wide summary statistics of four site-specific BMD measurements were obtained from studies in individuals of European ancestry, including forearm (n = 8,143), femoral neck (n = 32,735), lumbar spine (n = 28,498) and heel (n = 426,824). The genetic instrumental variables for circulating levels of ADAM12, ADAM19, ADAM23, ADAMTS5 and ADAMTS6 were retrieved from the latest genome-wide association study of European ancestry (n = 5336 ~ 5367). The estimated causal effect was given by the Wald ratio for each variant, the inverse-variance weighted model was used as the primary approach to combine estimates from multiple instruments, and sensitivity analyses were conducted to assess the robustness of MR results. The Bonferroni-corrected significance was set at P < 0.0025 to account for multiple testing, and a lenient threshold P < 0.05 was considered to suggest a causal relationship. Results The causal effects of genetically predicted serum ADAM/ADAMTS levels on BMD measurements at forearm, femoral neck and lumbar spine were not statistically supported by MR analyses. Although causal effect of ADAMTS5 on heel BMD given by the primary MR analysis (β = -0.006, -0.010 to 0.002, P = 0.004) failed to reach Bonferroni-corrected significance, additional MR approaches and sensitivity analyses indicated a robust causal relationship. Conclusion Our study provided suggestive evidence for the causal effect of higher serum levels of ADAMTS5 on decreased heel BMD, while there was no supportive evidence for the associations of ADAM12, ADAM19, ADAM23, and ADAMTS6 with BMD at forearm, femoral neck and lumbar spine in Europeans.

Purpose A Disintegrin and Metalloproteinase (ADAM) and A Disintegrin and Metalloproteinase with Thrombospondin Motif (ADAMTS) have been reported potentially involved in bone metabolism and related to bone mineral density. This Mendelian Randomization (MR) analysis was performed to determine whether there are causal associations of serum ADAM/ADAMTS with BMD in rid of confounders.Methods The genome-wide summary statistics of four site-specific BMD measurements were obtained from studies in individuals of European ancestry, including forearm (n = 8,143), femoral neck (n = 32,735), lumbar spine (n = 28,498) and heel (n = 426,824). The genetic instrumental variables for circulating levels of ADAM12, ADAM19, ADAM23, ADAMTS5 and ADAMTS6 were retrieved from the latest genome-wide association study of European ancestry (n = 5336 ~ 5367). The estimated causal effect was given by the Wald ratio for each variant, the inverse-variance weighted model was used as the primary approach to combine estimates from multiple instruments, and sensitivity analyses were conducted to assess the robustness of MR results. The Bonferroni-corrected significance was set at P < 0.0025 to account for multiple testing, and a lenient threshold P < 0.05 was considered to suggest a causal relationship.Results The causal effects of genetically predicted serum ADAM/ADAMTS levels on BMD measurements at forearm, femoral neck and lumbar spine were not statistically supported by MR analyses. Although causal effect of ADAMTS5 on heel BMD given by the primary MR analysis (β = -0.006, -0.010 to 0.002, P = 0.004) failed to reach Bonferroni-corrected significance, additional MR approaches and sensitivity analyses indicated a robust causal relationship.Conclusion Our study provided a suggestive evidence for the causal effect of higher serum levels of ADAMTS5 on decreased heel BMD, while there was no supportive evidence for the associations of ADAM12, ADAM19, ADAM23, and ADAMTS6 with BMD at forearm, femoral neck and lumbar spine in Europeans.

It has been previously postulated that blood neurotransmitters might affect risks of neurodegenerative diseases. Here, a Mendelian Randomization (MR) study was conducted to explore whether genetically predicted concentrations of glycine, glutamate and serotonin were associated with risks of Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). From three genome-wide association studies of European ancestry, single nucleotide polymorphisms strongly associated with glycine, glutamate and serotonin were selected as genetic instrumental variables. Corresponding summary statistics were also obtained from the latest genome-wide association meta-analyses of AD, PD and ALS. The inverse-variance weighted MR and multiple sensitivity analyses were performed to evaluate causal effects of genetically predicted levels of neurotransmitters on risks of neurodegenerative diseases. The statistical significance threshold was set at P &lt; 0.0056 using the Bonferroni-correction, while 0.0056 &lt; P &lt; 0.05 was considered suggestive evidence for a causal association. There was a causal association of elevated blood glutamate levels with higher AD risks. The odds ratio (OR) of AD was 1.311 [95% confidence interval (CI), 1.087–1.580; P = 0.004] per one standard deviation increase in genetically predicted glutamate concentrations. There was suggestive evidence in support of a protective effect of blood serotonin on AD (OR = 0.607; 95% CI, 0.396–0.932; P = 0.022). Genetically predicted glycine levels were not associated with the risk of AD (OR = 1.145; 95% CI, 0.939–1.396; P = 0.180). Besides, MR analyses indicated no causal roles of three blood neurotransmitters in PD or ALS. In conclusion, the MR study provided evidence supporting the association of elevated blood glutamate levels with higher AD risks and the association of increased blood serotonin levels with lower AD risks. Triangulating evidence across further study designs is still warranted to elucidate the role of blood neurotransmitters in risks of neurodegenerative diseases.