The metabolomic profiling of total fat and fat distribution in a multi-cohort study of women and men

Zheng, Rui; Michaëlsson, Karl; Fall, Tove; Elmståhl, Sölve; Lind, Lars

doi:10.1038/s41598-023-38318-z

Cited by 3 publications

References 57 publications

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A combined observational and Mendelian randomization investigation reveals NMR-measured analytes to be risk factors of major cardiovascular diseases

Zheng,

Lind

2024

Sci Rep

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Dyslipidaemias is the leading risk factor of several major cardiovascular diseases (CVDs), but there is still a lack of sufficient evidence supporting a causal role of lipoprotein subspecies in CVDs. In this study, we comprehensively investigated several lipoproteins and their subspecies, as well as other metabolites, in relation to coronary heart disease (CHD), heart failure (HF) and ischemic stroke (IS) longitudinally and by Mendelian randomization (MR) leveraging NMR-measured metabolomic data from 118,012 UK Biobank participants. We found that 123, 110 and 36 analytes were longitudinally associated with myocardial infarction, HF and IS (FDR < 0.05), respectively, and 25 of those were associated with all three outcomes. MR analysis suggested that genetically predicted levels of 70, 58 and 7 analytes were associated with CHD, HF and IS (FDR < 0.05), respectively. Two analytes, ApoB/ApoA1 and M-HDL-C were associated with all three CVD outcomes in the MR analyses, and the results for M-HDL-C were concordant in both observational and MR analyses. Our results implied that the apoB/apoA1 ratio and cholesterol in medium size HDL were particularly of importance to understand the shared pathophysiology of CHD, HF and IS and thus should be further investigated for the prevention of all three CVDs.

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A combined observational and Mendelian randomization investigation reveals NMR-measured analytes to be risk factors of major cardiovascular diseases

Zheng,

Lind

2024

Sci Rep

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Genetic Architecture and Analysis Practices of Circulating Metabolites in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program

Wang,

Ockerman,

Zhou

et al. 2024

Preprint

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Circulating metabolite levels partly reflect the state of human health and diseases, and can be impacted by genetic determinants. Hundreds of loci associated with circulating metabolites have been identified; however, most findings focus on predominantly European ancestry or single study analyses. Leveraging the rich metabolomics resources generated by the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program, we harmonized and accessibly cataloged 1,729 circulating metabolites among 25,058 ancestrally-diverse samples. We provided recommendations for outlier and imputation handling to process metabolite data, as well as a general analytical framework. We further performed a pooled analysis following our practical recommendations and discovered 1,778 independent loci associated with 667 metabolites. Among 108 novel locus-metabolite pairs, we detected not only novel loci within previously implicated metabolite associated genes, but also novel genes (such as GAB3 and VSIG4 located in the X chromosome) that have putative roles in metabolic regulation. In the sex-stratified analysis, we revealed 85 independent locus-metabolite pairs with evidence of sexual dimorphism, including well-known metabolic genes such as FADS2, D2HGDH, SUGP1, UTG2B17, strongly supporting the importance of exploring sex difference in the human metabolome. Taken together, our study depicted the genetic contribution to circulating metabolite levels, providing additional insight into the understanding of human health.

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Genetic prediction of blood metabolites mediating the relationship between gut microbiota and Alzheimer’s disease: a Mendelian randomization study

Chen,

Jin,

Chu

et al. 2024

Front. Microbiol.

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BackgroundObservational studies have suggested an association between gut microbiota and Alzheimer’s disease (AD); however, the causal relationship remains unclear, and the role of blood metabolites in this association remains elusive.PurposeTo elucidate the causal relationship between gut microbiota and AD and to investigate whether blood metabolites serve as potential mediators.Materials and methodsUnivariable Mendelian randomization (UVMR) analysis was employed to assess the causal relationship between gut microbiota and AD, while multivariable MR (MVMR) was utilized to mitigate confounding factors. Subsequently, a two-step mediation MR approach was employed to explore the role of blood metabolites as potential mediators. We primarily utilized the inverse variance-weighted method to evaluate the causal relationship between exposure and outcome, and sensitivity analyses including Contamination mixture, Maximum-likelihood, Debiased inverse-variance weighted, MR-Egger, Bayesian Weighted Mendelian randomization, and MR pleiotropy residual sum and outlier were conducted to address pleiotropy.ResultsAfter adjustment for reverse causality and MVMR correction, class Actinobacteria (OR: 1.03, 95% CI: 1.01–1.06, p = 0.006), family Lactobacillaceae (OR: 1.03, 95% CI: 1.00–1.05, p = 0.017), genus Lachnoclostridium (OR: 1.03, 95% CI: 1.00–1.06, p = 0.019), genus Ruminiclostridium9 (OR: 0.97, 95% CI: 0.94–1.00, p = 0.027) and genus Ruminiclostridium6 (OR: 1.03, 95% CI: 1.01–1.05, p = 0.009) exhibited causal effects on AD. Moreover, 1-ribosyl-imidazoleacetate levels (−6.62%), Metabolonic lactone sulfate levels (2.90%), and Nonadecanoate (19:0) levels (−12.17%) mediated the total genetic predictive effects of class Actinobacteria on AD risk. Similarly, 2-stearoyl-GPE (18:0) levels (−9.87%), Octadecanedioylcarnitine (C18-DC) levels (4.44%), 1-(1-enyl-stearoyl)-2-oleoyl-GPE (p-18:0/18:1) levels (38.66%), and X-23639 levels (13.28%) respectively mediated the total genetic predictive effects of family Lactobacillaceae on AD risk. Furthermore, Hexadecanedioate (C16-DC) levels (5.45%) mediated the total genetic predictive effects of genus Ruminiclostridium 6 on AD risk; Indole-3-carboxylate levels (13.91%), X-13431 levels (7.08%), Alpha-ketoglutarate to succinate ratio (−13.91%), 3-phosphoglycerate to glycerate ratio (15.27%), and Succinate to proline ratio (−14.64%) respectively mediated the total genetic predictive effects of genus Ruminiclostridium 9 on AD risk.ConclusionOur mediation MR analysis provides genetic evidence suggesting the potential mediating role of blood metabolites in the causal relationship between gut microbiota and AD. Further large-scale randomized controlled trials are warranted to validate the role of blood metabolites in the specific mechanisms by which gut microbiota influence AD.

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The metabolomic profiling of total fat and fat distribution in a multi-cohort study of women and men

Cited by 3 publications

References 57 publications

A combined observational and Mendelian randomization investigation reveals NMR-measured analytes to be risk factors of major cardiovascular diseases

A combined observational and Mendelian randomization investigation reveals NMR-measured analytes to be risk factors of major cardiovascular diseases

Genetic Architecture and Analysis Practices of Circulating Metabolites in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program

Genetic prediction of blood metabolites mediating the relationship between gut microbiota and Alzheimer’s disease: a Mendelian randomization study

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