Phenome-wide association study of genetically predicted B vitamins and homocysteine biomarkers with multiple health and disease outcomes: analysis of the UK Biobank

Lijuan Wang, Xue Li, Azita Montazeri, Amanda J. MacFarlane, Franco Momoli, Susan J Duthie, Marjanne Senekal, Ines Mesa Eguiagaray, Ronald G Munger, Derrick Bennett, Harry Campbell, Michele Rubini, Helene McNulty, Julian Little, Evropi Theodoratou*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Background: Although a number of health outcomes such as cardiovascular diseases, metabolic-related outcomes, neurological disorders, pregnancy outcomes and cancers have been identified in relation to B vitamins, evidence is of uneven quality and volume, and there is uncertainty about putative causal relationships.

Objectives: To explore the effects of B vitamins and homocysteine on a wide range of health outcomes based on a large biorepository linking biological samples and electronic medical records.

Methods: First, we performed a phenome-wide association study (PheWAS) to investigate associations of genetically predicted plasma concentrations (genetic component of the circulating concentrations) of folate, vitamin B6, vitamin B12 and their metabolite homocysteine with a wide range of disease outcomes (including both prevalent and incident events) among 385,917 individuals in the UK Biobank. Second, two-sample Mendelian randomization (MR) analysis was used to replicate any observed associations and detect causality. We considered MR p
Results: In total 1,117 phenotypes were tested in each PheWAS analysis. After multiple correction, 32 phenotypic associations of B vitamins and homocysteine were identified. Two-sample MR analysis supported that three of them were causal, including associations of higher plasma vitamin B6 with lower risk of calculus of kidney (OR: 0.64; 95% CI: 0.42, 0.97; P=0.033); higher homocysteine concentration with higher risk of hypercholesterolemia (OR: 1.28, 95% CI: 1.04, 1.56; P=0.018) and chronic kidney disease (OR: 1.32, 95% CI: 1.06, 1.63; P=0.012). Significant nonlinear dose-response relationships were observed for the associations of folate with anemia, vitamin B12 with vitamin B-complex deficiencies, anemia and cholelithiasis, and homocysteine with cerebrovascular disease.

Conclusions: This study provides strong evidence for the associations of B vitamins and homocysteine with endocrine/metabolic and genitourinary disorders.

Keywords: B vitamins, Homocysteine, PheWAS, Mendelian randomization
Original languageEnglish
Pages (from-to)564-575
JournalThe American Journal of Clinical Nutrition (AJCN)
Issue number3
Early online date13 Jan 2023
Publication statusPublished - 1 Mar 2023

Keywords / Materials (for Non-textual outputs)

  • Biological Specimen Banks
  • Biomarkers
  • Female
  • Folic Acid
  • Homocysteine
  • Humans
  • Mendelian Randomization Analysis
  • Pregnancy
  • United Kingdom
  • Vitamin A
  • Vitamin B 12
  • Vitamin B 6
  • Vitamin B Complex
  • Vitamin K


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