Genome-Wide Association Study Identifies Genetic Polymorphisms for Folate-Related Biomarkers in Chinese Preconception Women.

Background: Single-nucleotide polymorphism (SNP) allele frequencies, dietary habits, and folate status and their associations vary across ethnic populations. Little is known about the SNPs accounting for variations of folate-related biomarkers for Chinese preparing-for-pregnant females.

Objectives: We aimed to identify SNPs contributing to RBC and serum folate, vitamin B-12, and homocysteine concentrations in Chinese female preconception population.

Methods: A genome-wide association study was conducted on 1000 randomly selected preconception Chinese women from the Shanghai Preconception Cohort. SNPs were genotyped using Illumina chips, and associations with biomarkers were assessed using simple linear regression models under the assumption of an additive genetic model. Genome-wide significance was considered at P < 10^-7.

Results: The MTHFR rs1801133 was the major genetic coding variant contributing to RBC folate, serum folate, and homocysteine concentrations (P = 2.28 × 10^-16; P = 8.85 × 10^-8, and P = 2.46 × 10^-13, repsectively). It is associated with increased RBC folate (β: 0.154 per additional risk allele after log transform), decreased serum folate (β: -0.951 per additional risk allele), and increased serum homocysteine concentrations (β: 1.153 per additional risk allele). The predominant SNP associated with serum folate was rs147162222 in NTRK2 (P = 2.55 × 10^-8), although that associated with homocysteine was rs77025184 located between PDE7B and LINC00271 (P = 4.91 × 10^-17). For vitamin B-12, FUT2 rs1047781 was the dominant genetic variant (P = 1.59 × 10^-10). The numbers of signals with a P value of <10^-7 for RBC folate, serum folate, vitamin B-12, and homocysteine were 12, 18, 8, and 614, respectively.

Conclusions: This study represents the first genome-wide association study focusing on folate-related biomarkers in a Chinese preparing-for-pregnant female population. The contributions of dominent SNPs to each biomarker are partly different from other populations. The rs1801133 (C677T) in MTHFR is the predominant genetic variant contributing to RBC folate and rs1047781 (A385T) in FUT2 as the primary one explaining vitamin B-12. Notably, the intronic rs147162222 and noncoding rs77025184 are the predominant SNPs for serum folate and homocysteine, respectively.