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

Abstract

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 B 2 (flavin mononucleotide and riboflavin), vitamin B 6 (4-pyridoxic acid, pyridoxal, and pyridoxamine), total homocysteine, methionine, S-adenosylmethionine, Sadenosylhomocysteine, 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