Multi-trait genome-wide association study in 34,394 Chinese women reveals the genetic architecture of plasma metabolites during pregnancy

Metabolites are important indicators of individual health and can serve as crucial targets for therapy. However, the genetic basis of many metabolites remains largely unexplored, especially among underrepresented East Asians and during critical periods such as pregnancy. In this study, we utilized genetic information obtained from non-invasive prenatal testing to conduct a genome-wide association analysis of 84 metabolites, including 37 amino acids, 10 vitamins, 24 metal elements, and 13 hormones, among 34,394 Chinese pregnant women. Of these metabolites, 52 and 11 had not previously been studied in East Asians or globally. We identified 30 novel metabolite-gene associations. We also observed substantial differences in the genetic effects on hormones between pregnancy and non-pregnancy periods, suggesting effect modifications in response to physiological changes. Furthermore, we uncovered pervasive pleiotropic effects for 50.94% of the genetic associations among metabolites, as well as between six metabolites and eight pregnancy biomarkers. Using mendelian randomization, we identified potential causal relationships between plasma folate and ischemic stroke, vitamin D3 and Graves' disease, copper and open-angle glaucoma, and androstenedione and rheumatoid arthritis. These discoveries provide invaluable genetic insights into human metabolism, laying the foundation for future mechanistic studies and the development of new therapeutic targets, particularly for underrepresented East Asians. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The study was supported by National Natural Science Foundation of China (31900487, 81830041), Natural Science Foundation of Guangdong Province, China (2017A030306026), Shenzhen Key Laboratory of Genomics (CXB200903110066A) and Guangdong Enterprise Key Laboratory of Human Disease Genomics (2011A060906007), Guangdong Provincial Key Laboratory of Genome Read and Write(2017B030301011) and Guangdong Provincial Academician Workstation of BGI Synthetic Genomics(2017B090904014). ### Author Declarations 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 study was reviewed and approved by the Institutional Review Board of BGI (BGI-IRB21184) in strict compliance with regulations regarding ethical considerations and personal data protection. 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 The summary statistics of the metal meta-analysis outcome and the MTAG outcome have been deposited into CNGB Sequence Archive of CNGBdb with accession number CNP0003025.