Mendelian randomization linking metabolites with enzymes reveals pathway regulation and therapeutic avenues.

Adriaan van der Graaf, Sadegh Rizi, Chiara Auwerx, Zoltán Kutalik

Abstract read

In one paragraph

Article in American journal of human genetics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it

0cells of the map it votes in

1citing papers in PubMed

–field-weighted citation impact

1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

Genetic evidence for potential causal associations between gut microbiota and site-specific urolithiasis risk: a two-sample mendelian randomization study.Urolithiasis · 2026
Article

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

4 authors.

Adriaan van der GraafDepartment of Computational Biology, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland.

Sadegh RiziUniversity of Maastricht, Maastricht, the Netherlands.

Chiara AuwerxDepartment of Computational Biology, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland; Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; University Center for Primary Care and Public Health, Lausanne, Switzerland.

Zoltán KutalikDepartment of Computational Biology, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland; University Center for Primary Care and Public Health, Lausanne, Switzerland. Electronic address: zoltan.kutalik@unil.ch.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Reactions between metabolites are catalyzed by enzymes. These biochemical reactions form complex metabolic networks, which are only partially characterized in humans and whose regulation remains poorly understood. Here, we assess human biochemical reactions and regulation using Mendelian randomization (MR), a genetic observational causal inference technique, to understand the methods' strengths and weaknesses in identifying metabolic reactions and regulation. We combine four metabolite and two protein quantitative trait locus (QTL) studies to determine how well MR recovers 945 curated canonical enzyme-substrate/product relationships. Using genetic variants from an enzyme's transcribed (cis) region as instrumental variables, MR-inferred estimates have high precision (35%-47%) but low recall (3.2%-4.6%) for identifying the substrates and products of an enzyme. Testing reverse causality from metabolites to enzymes using genome-wide instruments yields lower precision (1.8%-8.5%) and recall (1.0%-1.9%) due to an increased multiple-testing burden. Literature review of 106 Bonferroni-significant results identifies 45 links (43%) confirmed by different degrees of evidence, including bidirectional links between linoleate and cytochrome P450 3A4 (CYP3A4) levels (p = 8.6 × 10

Indexed as

EnzymesMendelian Randomization AnalysisMetabolic Networks and PathwaysQuantitative Trait LociGenome-Wide Association StudyHumansEnzymesenzymesMendelian randomizationmetabolic regulationmetabolismproteomics

Identifiers

PMID41650937

DOI10.1016/j.ajhg.2025.12.013

PMCPMC13087421

What OpenQuestion holds

Textmetadata

Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.