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 Duthie, Marjanne Senekal, Ines Mesa Eguiagaray, Ron Munger, Derrick Bennett, Harry Campbell, Michele Rubini, Helene Mcnulty, Julian Little, Evropi Theodoratou

Research output: Contribution to journalArticlepeer-review

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Abstract

Background: Although a number of health outcomes such as CVDs, 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 the 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, 2-sample Mendelian randomization (MR) analysis was used to replicate any observed associations and detect causality. We considered MR P <0.05 as significant for replication. Third, dose-response, mediation, and bioinformatics analyses were carried out to examine any nonlinear trends and to disentangle the underlying mediating biological mechanisms for the identified associations. Results: In total, 1117 phenotypes were tested in each PheWAS analysis. After multiple corrections, 32 phenotypic associations of B vitamins and homocysteine were identified. Two-sample MR analysis supported that 3 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.

Original languageEnglish
Pages (from-to)564-575
Number of pages12
JournalThe American Journal of Clinical Nutrition
Volume117
Issue number3
Early online date13 Jan 2023
DOIs
Publication statusPublished online - 13 Jan 2023

Bibliographical note

Funding Information:
LW is supported by a Darwin Trust PhD studentship . ET is supported by a Cancer Research UK Career Development Fellowship (C31250/A22804). This work was in part supported by the Canadian Institutes of Health Research (CIHR)-Funding Reference Number: 175263.

Publisher Copyright:
© 2023 American Society for Nutrition

Keywords

  • B vitamins
  • homocysteine
  • phenome-wide association study
  • Mendelian randomization

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