Plasma glycine levels are associated with a missense variant in Carbamoyl-Phosphate Synthase 1 (CPS1) in Nigerians

Authors

  • Bin Jalloh
  • Ayo Doumatey
  • Gua Chen
  • Jie Zhou
  • Lin Lei
  • Cha Rotimi
  • Ade Adeyemo

Abstract

Low circulating glycine levels and other disorders of glycine metabolism are associated with metabolic disorders. Mechanisms that have been implicated include decreased gut absorption, increased catabolism, increased urine excretion and/or decreased biosynthesis. Importantly, these mechanisms are influenced by host genetics. Given rising prevalence of metabolic disorders and current limited data on the genetic underpinnings of circulating glycine and related chemical entities in populations of African ancestry, we established this investigation to identify genetic variants associated with plasma glycine in Africans. We performed a genome-wide association study (GWAS) of plasma glycine in 579 adult Nigerians from the Africa America Diabetes Study (AADM). Glycine was measured as part of an untargeted metabolomics using RP-HPLC-MS/MS on the Metabolon Platform. We identified 3 glycine metQTL (rs1047891, rs7684, rs715) at a significance threshold of p< 6.7x1011 within Carbamoyl-Phosphate Synthase 1 (CPS1). The most significant metQTLocus, rs1047891 (Chr2:210675783, MAF=.0.36), p= 1.52x10-34), is a missense variant in CPS1, a gene that encodes the enzyme responsible for the rate-limiting step of the urea cycle, which is responsible for the detoxification of ammonia, a breakdown product of glycine. Notably, rs1047891 is not in near complete LD (r2=0.36; D’ =0.89) with the lead glycine-associated SNP (rs715) reported in European ancestry populations. Previous studies in European populations have implicated CPS1 in low glycine levels associated with T2D risk and in higher risk of coronary heart disease. Our findings refined observations in European populations and provided insights into genetic control of glycine levels in an African population.

Scientific Focus Area: Genetics and Genomics

This page was last updated on Tuesday, August 6, 2024