Metabolome-wide Mendelian randomization characterizes heterogeneous and shared causal effects of metabolites on human health

Yin, Xianyong; Li, Jack; Bose, Debraj; Okamoto, Jeffrey; Kwon, Annie; Jackson, Anne; Silva, Lilian Fernandes; Oravilahti, Anniina; Stringham, Heather M.; Ripatti, Samuli; Daly, Mark J.; Palotie, Aarno; Scott, Laura J.; Burant, Charles F.; Fauman, Eric B.; Wen, Xiaoquan; Boehnke, Michael; Laakso, Markku; Morrison, Jean

doi:10.1101/2023.06.26.23291721

Cited by 4 publications

(2 citation statements)

References 42 publications

(67 reference statements)

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“…Takebayashi et al demonstrated that the quenching of free radicals by ascorbic acid 2-sulfate was comparable to or greater than that of ascorbic acid over a prolonged period [52]. In the current study, it was found that ascorbic acid 2-sulfate has an impact on a wide range of diseases, including cardiomyopathy [53]. This compound may play a protective role in the kidneys of ACF rats.…”

Section: Discussionsupporting

confidence: 56%

Metabolomics Assessment of Volume Overload-Induced Heart Failure and Oxidative Stress in the Kidney

Tang,

Huang,

Tsau

et al. 2023

Metabolites

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The incidence of heart failure (HF) is increasing and is associated with a poor prognosis. Moreover, HF often coexists with renal dysfunction and is associated with a worsened outcome. In many experimental studies on cardiac dysfunction, the function of other organs was either not addressed or did not show any decline. Until now, the exact mechanisms for initiating and sustaining this interaction are still unknown. The objective of this study is to use volume overload to induce cardiac hypertrophy and HF in aortocaval fistula (ACF) rat models, and to elucidate how volume overload affects metabolic changes in the kidney, even with normal renal function, in HF. The results showed the metabolic changes between control and ACF rats, including taurine metabolism; purine metabolism; glycine, serine, and threonine metabolism; glycerophospholipid metabolism; and histidine metabolism. Increasing the downstream purine metabolism from inosine to uric acid in the kidneys of ACF rats induced oxidative stress through xanthine oxidase. This result was consistent with HK-2 cells treated with xanthine and xanthine oxidase. Under oxidative stress, taurine accumulation was observed in ACF rats, indicating increased activity of the hypotaurine–taurine pathway as a defense mechanism against oxidative stress in the kidney. Another antioxidant, ascorbic acid 2-sulfate, showed lower levels in ACF rats, indicating that the kidneys experience elevated oxidative stress due to volume overload and HF. In summary, metabolic profiles are more sensitive than clinical parameters in reacting to damage to the kidney in HF.

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Section: Discussionsupporting

confidence: 56%

Metabolomics Assessment of Volume Overload-Induced Heart Failure and Oxidative Stress in the Kidney

Tang,

Huang,

Tsau

et al. 2023

Metabolites

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“…The limited prediction of metabolite profiles may be related to the uncertain causal role in modulating T2D risk, a question investigated using Mendelian randomization (MR) 12 . One particular example is BCAAs, for which some studies have described a causal effect of valine, leucine and/or isoleucine on T2D [13][14][15] , while more recent evidence has shown no causal effect of BCAAs on T2D risk in the UK Biobank (UKBB) cohort 16 . Conversely, increasing evidence of a causal effect of T2D liability on metabolite profiles has been shown, with increased alanine levels caused by increased T2D liability being consistently reported 13,17,18 .…”

Section: Introductionmentioning

confidence: 99%

Insights into the metabolic consequences of type 2 diabetes

Bocher,

Singh,

Huang

et al. 2024

Preprint

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Circulating metabolite levels have been associated with type 2 diabetes (T2D), but the extent to which these are affected by T2D and the involvement of genetics in mediating these relationships remain to be elucidated. In this study, we investigate the interplay between genetics, metabolomics and T2D risk in the UK Biobank dataset. We find 79 metabolites with a causal association to T2D, mostly spanning lipid-related classes, while twice as many metabolites are causally affected by T2D liability, including branched-chain amino acids. Secondly, using an interaction quantitative trait locus (QTL) analysis, we describe four metabolites, consistently replicated in an independent dataset from the Estonian Biobank, for which genetic loci in two different genomic regions show attenuated regulation in T2D cases compared to controls. The significant variants from the interaction QTL analysis are significant QTLs for the corresponding metabolites in the general population, but are not associated with T2D risk, pointing towards consequences of T2D on the genetic regulation of metabolite levels. Finally, we find 165 metabolites associated with microvascular, macrovascular, or both types of T2D complications, with only a few discriminating between complication classes. Of the 165 metabolites, 40 are not causally linked to T2D in either direction, suggesting biological mechanisms specific to the occurrence of complications. Overall, this work provides a map of the metabolic consequences of T2D and of the genetic regulation of metabolite levels and enable to better understand the trajectory of T2D leading to complications.

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Mediation-adjusted multivariable Mendelian randomisation study identified novel metabolites related to mental health

Freuer,

Meisinger

2024

BMJ Ment Health

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BackgroundFrom the pathway perspective, metabolites have the potential to improve knowledge about the aetiology of psychiatric diseases. Previous studies suggested a link between specific blood metabolites and mental disorders, but some Mendelian randomisation (MR) studies in particular are insufficient for various reasons.ObjectiveThis study focused on bias assessment due to interdependencies between metabolites and psychiatric mediation effects.MethodsIn a multistep framework containing network and multivariable MR, direct effects of 21 mutually adjusted metabolites on 8 psychiatric disorders were estimated based on summary statistics of genome-wide association studies from multiple resources. Robust inverse-variance weighted models were used in primary analyses. Several sensitivity analyses were performed to assess different patterns of pleiotropy and weak instrument bias. Estimates for the same phenotypes from different resources were pooled using fixed effect meta-analysis models.FindingsAfter adjusting for mediation effects, genetically predicted metabolite levels of six metabolites of lipid, amino acid and cofactors pathways were directly associated with overall six mental disorders (attention-deficit/hyperactivity disorder, bipolar disorder, anorexia nervosa, depression, post-traumatic stress disorder and schizophrenia). Point estimates ranged from −0.45 (95% CI −0.67; −0.24, p=1.0×104) to 1.78 (95% CI 0.85; 2.71, p=0.006). No associations were found with anxiety and suicide attempt.ConclusionsThis study provides insights into new metabolic pathways that seems to be causally related to certain mental disorders.Clinical implicationsFurther studies are needed to investigate whether the identified associations are effects of the metabolites itself or the biochemical pathway regulating the metabolites.

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Metabolome-wide Mendelian randomization characterizes heterogeneous and shared causal effects of metabolites on human health

Cited by 4 publications

References 42 publications

Metabolomics Assessment of Volume Overload-Induced Heart Failure and Oxidative Stress in the Kidney

Metabolomics Assessment of Volume Overload-Induced Heart Failure and Oxidative Stress in the Kidney

Insights into the metabolic consequences of type 2 diabetes

Mediation-adjusted multivariable Mendelian randomisation study identified novel metabolites related to mental health

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