Mendelian randomization study of inflammatory bowel disease and bone mineral density

Wu, Fashuai; Huang, Yu; Hu, Jialu; Shao, Zhimin

doi:10.1186/s12916-020-01778-5

Cited by 220 publications

(170 citation statements)

References 44 publications

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“…First, SNPs with a p-value less than the locus-wide significance level (1 × 10 −5 ) were selected. Second, the genetic variations would be excluded if the minor allele frequency (MAF) is less than 0.01 (20). Third, in order to avoid the impact of linkage disequilibrium (LD) between the variables of interest on the results, the clumping process was performed, in which R 2 < 0.001 and clumping distance = 10,000 kb.…”

Section: Data Sources and Instrumental Variable Selectionmentioning

confidence: 99%

Genetically Predicted Causality of 28 Gut Microbiome Families and Type 2 Diabetes Mellitus Risk

Xiang

Zhang

et al. 2022

Front. Endocrinol.

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Mounting evidence indicates that gut microbiome may be involved in the pathogenesis of type 2 diabetes mellitus (T2DM). However, there is no consensus on whether there is a causal link between gut microbiome and T2DM risk. In the present study, the Mendelian randomization (MR) analysis was performed to investigate whether gut microbiome was causally linked to T2DM risk. The single nucleotide polymorphisms (SNPs) that were significantly related to exposure from published available genome-wide association study (GWAS) were selected as instrumental variables (IVs). The robust methods including inverse variance weighting (IVW), MR Egger, and weighted median were conducted to infer the causal links. Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) and MR-Egger regression were used to test whether there was horizontal pleiotropy and identify outlier SNPs. The estimates of IVW suggested that Streptococcaceae (odds ratio (OR) = 1.17, 95% confidence interval (CI), 1.04–1.31, p = 0.009) was associated with higher risk of T2DM in European population. In Asian population, the MR IVW estimates revealed that there was a causal link between Acidaminococcaceae and T2DM risk (OR = 1.17, 95% CI, 1.04–1.31, p = 0.008). There was no evidence of notable heterogeneity and horizontal pleiotropy. However, after false discovery rate (FDR) correction, the causal link between gut microbiome and T2DM was absent (FDR, p > 0.05). In summary, using genetic instruments, this study does not find evidence of association between the 28 gut microbiome families and T2DM risk. However, Streptococcaceae and Acidaminococcaceae may have a borderline positive correlation with T2DM risk.

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Section: Data Sources and Instrumental Variable Selectionmentioning

confidence: 99%

Genetically Predicted Causality of 28 Gut Microbiome Families and Type 2 Diabetes Mellitus Risk

Xiang

Zhang

et al. 2022

Front. Endocrinol.

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“…To ensure the robustness of estimates, we established a MR framework according to previous studies (Fig. 1B) (Burgess et al 2019;Burgess and Thompson 2017;Ference et al 2019;Wu et al 2020). Briefly, we first examined the horizontal pleiotropy that measured by MR-PRESSO global test and removed the outliers if the corresponding p value < 0.05.…”

Section: Mendelian Randomization and Sensitivity Analysesmentioning

confidence: 99%

Phenome-Wide Association Analysis Reveals Novel Links Between Genetically Determined Levels of Liver Enzymes and Disease Phenotypes

et al. 2022

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Serum liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], λ-glutamyl transferase [GGT] and alkaline phosphatase [ALP]) are the leading biomarkers to measure liver injury, and they have been reported to be associated with several intrahepatic and extrahepatic diseases in observational studies. We conducted a phenome-wide association study (PheWAS) to identify disease phenotypes associated with genetically predicted liver enzymes based on the UK Biobank cohort. Univariable and multivariable Mendelian randomization (MR) analyses were performed to obtain the causal estimates of associations that detected in PheWAS. Our PheWAS identified 40 out of 1,376 pairs (16, 17, three and four pairs for ALT, AST, GGT and ALP, respectively) of genotype-phenotype associations reaching statistical significance at the 5% false discovery rate threshold. A total of 34 links were further validated in Mendelian randomization analyses. Most of the disease phenotypes that associated with genetically determined ALT level were liver-related, including primary liver cancer and alcoholic liver damage. The disease outcomes associated with genetically determined AST involved a wide range of phenotypic categories including endocrine/metabolic diseases, digestive diseases, and neurological disorder. Genetically predicted GGT level was associated with the risk of other chronic non-alcoholic liver disease, abnormal results of function study of liver, and cholelithiasis. Genetically determined ALP level was associated with pulmonary heart disease, phlebitis and thrombophlebitis of lower extremities, and hypercholesterolemia. Our findings reveal novel links between liver enzymes and disease phenotypes providing insights into the full understanding of the biological roles of liver enzymes.

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“…We used the MR-PRESSO outlier test and other robust methods for the MR analysis, and no horizontal pleiotropy was detected in the results. The PhenoScanner database or the Ensembl Project would not necessarily distinguish between vertical and horizontal pleiotropy, and the former would not bias the MR analysis 87 . Furthermore, because the biological mechanisms and functions of numerous genetic variants are unknown, we did not use these variants to assess the IVs associated with potential confounding factors.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association and Mendelian randomization study of blood copper levels and 213 deep phenotypes in humans

Yang

Feng

et al. 2022

Commun Biol

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Metal elements are present in the human body, and their levels in the blood have important impacts on health. In this study, 2488 Chinese individuals were included in a genome-wide association study of 21 serum metal levels, with approximately 179,000 East Asian individuals in a bidirectional two-sample Mendelian randomization (MR) analysis, and 628,000 Europeans in a two-sample MR analysis. We identified two single nucleotide polymorphisms (SNPs) rs35691438 and rs671 that were significantly associated with serum copper levels (SCLs). The bidirectional two-sample MR analysis in the East Asian population showed that gamma-glutamyl transpeptidase levels have a causal effect on SCLs. SCLs have causal effects on six outcomes, namely risks of esophageal varix, glaucoma, sleep apnea syndrome, and systemic lupus erythematosus, white blood cell count, and usage of drugs affecting bone structure and mineralization. The two-sample MR analyses in the European population showed causal effects of erythrocyte copper levels on risks of carpal tunnel syndrome and compression fracture. Our results provide original insights into the causal relationship between blood metal levels and multiple human phenotypes.

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Mendelian randomization study of inflammatory bowel disease and bone mineral density

Cited by 220 publications

References 44 publications

Genetically Predicted Causality of 28 Gut Microbiome Families and Type 2 Diabetes Mellitus Risk

Genetically Predicted Causality of 28 Gut Microbiome Families and Type 2 Diabetes Mellitus Risk

Phenome-Wide Association Analysis Reveals Novel Links Between Genetically Determined Levels of Liver Enzymes and Disease Phenotypes

Genome-wide association and Mendelian randomization study of blood copper levels and 213 deep phenotypes in humans

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