A Genome-Wide Association Study of Circulating Serum Choline, Betaine, Dimethylglycine, and Their Ratios

Background/Objectives: Genetic variation has been thought to alter the human dietary requirement for choline and subsequent circulating levels of its metabolites betaine and dimethylglycine (DMG). The aim of this genome-wide association study (GWAS) was to identify single nucleotide polymorphisms (SNPs) associated with serum choline, betaine, and dimethylglycine (DMG) as well as choline-to-betaine and betaine-to-DMG ratios. Methods: Data from the Collaborative Study of Genes, Nutrients and Metabolites (CSGNM; n = 2402) were used to model individual associations of choline, betaine, and DMG circulating metabolites and their ratios with 680,975 SNPs, using linear regression. Models were unadjusted (model 1), adjusted for age and sex (model 2), and further adjusted for selected principal components (model 3) and B₁₂, B₉, B₆, and holotranscobalamin (model 4). Statistical significance was set at p < 5.0 × 10^-5. Affected SNPs in the dbSNP (database of Single Nucleotide Polymorphisms) were then identified. Results: GWAS revealed both intuitive and novel results, including the recently described SLC25A48, several intronic variants in the gene encoding LYPLAL1, and a pair of SNPs present in the intronic region of PID1 related to serum choline. SNPs related to betaine and DMG included SLCA12, BHMT, DMGDH, and additional SLC family transporters that require further validation. While exploratory, GWAS of the choline-to-betaine and betaine-to-DMG ratios revealed common targets with direct links to choline and one-carbon metabolism. Conclusions: These results suggest that metabolic handling of choline has genetic determinants not formerly recognized in the scientific literature. Replication is needed in larger cohorts due to low statistical power.