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

Abstract

SummaryMetabolites 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.