Novel associations of CPS1, MUT, NOX4, and DPEP1 with plasma homocysteine in a healthy population: a genome-wide evaluation of 13 974 participants in the Women's Genome Health Study

Abstract

Background: Homocysteine is a sulfur amino acid whose plasma concentration has been associated with the risk of cardiovascular diseases, neural tube defects, and loss of cognitive function in epidemiological studies. Although genetic variants of MTHFR and CBS are known to influence homocysteine concentration, common genetic determinants of homocysteine remain largely unknown.

Methods and results: To address this issue comprehensively, we performed a genome-wide association analysis, testing 336 469 single-nucleotide polymorphisms in 13 974 healthy white women. Although we confirm association with MTHFR (1p36.22; rs1801133; P=8.1 x 10(-35)) and CBS (21q22.3; rs6586282; P=3.2 x 10(-10)), we found novel associations with CPS1 (2q34; rs7422339; P=1.9 x 10(-11)), MUT (6p12.3; rs4267943; P=2.0 x 10(-9)), NOX4 (11q14.3; rs11018628; P=9.6 x 10(-12)), and DPEP1 (16q24.3; rs1126464; P=1.2 x 10(-12)). The associations at MTHFR, DPEP1, and CBS were replicated in an independent sample from the PROCARDIS study, whereas the association at CPS1 was only replicated among the women.

Conclusions: These associations offer new insight into the biochemical pathways involved in homocysteine metabolism and provide opportunities to better delineate the role of homocysteine in health and disease.

Figure 1. Genetic Context of Significant Associations

Genomic context for each of six loci with significant association with homocysteine concentration. (A) MTHFR locus (1p36.22); (B) CPS1 locus (2q34); (C) MUT locus (6p12.3); (D) NOX4 locus (11q14.3); (E) DPEP1 locus (16q24.3); (F) CBS locus (21q22.3). Upper panel: Genes from RefSeq release 25. Only one isoform is shown when multiple splicing variants are known. Lower Panel: SNPs are shown according to their physical location and − log₁₀ P-values for association with homocysteine (red dots). The red line represents the genome-wide significance threshold of 5 × 10⁻⁸. Also shown is the genetic distance in cM from the lowest P-value SNP (light grey line) along with the position of recombination hotspots (light grey vertical bars). Recombination rates and hotspots are based on HapMap data, as described by McVean et al. and Winckler et al.

Figure 2. Quantile-Quantile plot of Homocysteine Association P-Values

The quantile-quantile plot of homocysteine association P-values is shown on the left. On the right, the same quantile-quantile plot is shown, but after adjusting homocysteine values for the 7 SNPs retained by the model selection algorithm (see text for details).