Metabolomic studies are increasingly used for both etiological and predictive research, but frequently report missing values. We hypothesized that interindividual genetic variation may account for part of this missingness. Therefore, we performed a GWAS of missingness in measured metabolite levels using an untargeted mass spectrometry-based platform in the Netherlands Epidemiology of Obesity Study (N=594) and the Rhineland Study (N=4,165). We considered metabolites missing in 10%-90% of individuals in both cohorts (N=224). GWAS meta-analyses of these metabolites' probability of missingness revealed 55 metabolome-wide significant associations, including 42 novel ones (p<1.58x10-10), involving 28 metabolites and 41 lead SNPs. Despite considerable pleiotropy, the majority of identified SNP-"missing metabolite" associations were biologically plausible, relating to beta-oxidation, bile acids, steroids, and xenobiotics metabolism. These findings suggest that missing values in metabolomics are nonrandom and partly reflect genetic variation, accounting for which is important for both clinical and epidemiological studies, especially nutritional and pharmacogenetics studies.

The authors have declared no competing interest.

The NEO study is supported by the participating Departments, Division, and Board of Directors of the Leiden University Medical Center, and by the Leiden University, Research Profile Area Vascular and Regenerative Medicine. D.O. Mook-Kanamori. is supported by Dutch Science Organization (ZonMW-VENI Grant No. 916.14.023). D. van Heemst. and R. Noordam were supported by a grant of the VELUX Stiftung [grant number 1156]. T.O. Faquih was supported by the King Abdullah Scholarship Program and King Faisal Specialist Hospital & Research Center [No. 1012879283]. The Rhineland Study is funded by the German Center for Neurodegenerative Diseases (DZNE). The work was further partly supported by the German Research Foundation (DFG) under Germany's Excellence Strategy (EXC2151-390873048) and SFB1454-project number 432325352; the Federal Ministry of Education and Research under the Diet-Body-Brain Competence Cluster in Nutrition Research (grant numbers 01EA1410C and FKZ:01EA1809C) and in the framework "PreBeDem-Mit Prävention und Behandlung gegen Demenz" (FKZ: 01KX2230); and the Helmholtz Association under the Initiative and Networking Fund (No. RA-285/19) and the 2023 Innovation Pool. N.A. Aziz is partly supported by a European Research Council Starting Grant (#101041677).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The NEO study was approved by the medical ethical committee of the Leiden University Medical Centre (LUMC) and all participants gave their written informed consent. The ethics committee of the medical faculty of the University of Bonn approved the undertaking of the Rhineland Study and it was carried out according to the recommendations of the "International Council for Harmonisation Good Clinical Practice" standards. Written informed consent was acquired from all participants per the Declaration of Helsinki in both the NEO and Rhineland Study.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

To protect participant privacy and comply with legal regulations, the NEO study data is not publicly accessible. Qualified researchers can request access by contacting the NEO Executive Board at https://www.lumc.nl/org/neo-studie/contact/. Similarly, the Rhineland Study data used in this manuscript is restricted to public access due to data protection laws. Researchers seeking access to these datasets can submit requests to RS-DUAC@dzne.de, providing evidence of their qualifications and adherence to the respective study's data use policies. All authors had full access to the data from their respective studies and are responsible for the accuracy and integrity of the data and analysis.