Genome-wide association study of circulating folate one-carbon metabolites

Experimental, observational, and clinical trials support a critical role of folate one-carbon metabolism (FOCM) in colorectal cancer (CRC) development. In this report, we focus on understanding the relationship between common genetic variants and metabolites of FOCM. We conducted a genome-wide association study of FOCM biomarkers among 1,788 unaffected (without CRC) individuals of European ancestry from the Colon Cancer Family Registry. Twelve metabolites, including 5-methyltetrahydrofolate, vitamin B₂ (flavin mononucleotide and riboflavin), vitamin B₆ (4-pyridoxic acid, pyridoxal, and pyridoxamine), total homocysteine, methionine, S-adenosylmethionine, S-adenosylhomocysteine, cystathionine, and creatinine were measured from plasma using liquid chromatography-mass spectrometry (LC-MS) or LC-MS/MS. For each individual biomarker, we estimated genotype array-specific associations followed by a fixed-effect meta-analysis. We identified the variant rs35976024 (at 2p11.2 and intronic of ATOH8) associated with total homocysteine (p = 4.9 × 10^-8 ). We found a group of six highly correlated variants on chromosome 15q14 associated with cystathionine (all p < 5 × 10^-8 ), with the most significant variant rs28391580 (p = 2.8 × 10^-8 ). Two variants (rs139435405 and rs149119426) on chromosome 14q13 showed significant (p < 5 × 10^-8 ) associations with S-adenosylhomocysteine. These three biomarkers with significant associations are closely involved in homocysteine metabolism. Furthermore, when assessing the principal components (PCs) derived from seven individual biomarkers, we identified the variant rs12665366 (at 6p25.3 and intronic of EXOC2) associated with the first PC (p = 2.3 × 10^-8 ). Our data suggest that common genetic variants may play an important role in FOCM, particularly in homocysteine metabolism.