Artem Khan¹, Gokhan Unlu¹, Phillip Lin², Yuyang Liu¹, Ece Kilic¹, Timothy C. Kenny¹, Kıvanç Birsoy^1*, and Eric R. Gamazon^2,3*

1 Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, NY, USA 2 Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA 3 Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA

*Correspondence: kbirsoy@rockefeller.edu, eric.gamazon@vumc.org

Organisms maintain metabolic homeostasis through the combined functions of small molecule transporters and enzymes. While many of the metabolic components have been well-established, a substantial number remains without identified physiological substrates. To bridge this gap, we have leveraged large-scale plasma metabolome genome-wide association studies (GWAS) to develop a multiomic Gene-Metabolite Associations Prediction (GeneMAP) discovery platform. GeneMAP can generate accurate predictions and even pinpoint genes that are distant from the variants implicated by GWAS. In particular, our analysis identified SLC25A48 as a genetic determinant of plasma choline levels. Mechanistically, SLC25A48 loss strongly impairs mitochondrial choline import and synthesis of its downstream metabolite, betaine. Integrative rare variant and polygenic score analyses provide strong evidence that the SLC25A48 causal effects on human disease may in part be mediated by the effects of choline. Altogether, our study provides a discovery platform for metabolic gene function and proposes SLC25A48 as a mitochondrial choline transporter.