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

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


Lijuan Wang

Xue Li

Azita Montazeri

Amanda J. MacFarlane

Franco Momoli

Marjanne Senekal

Ines Mesa Eguiagaray

Ron Munger

Derrick Bennett

Harry Campbell

Michele Rubini

Helene McNulty

Julian Little

Evropi Theodoratou


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. The objective of the study was 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. 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 <0.05 as significant for replication. Third, dose-response, mediation and bioinformatics analyses were carried out to examine any non-linear trends and to disentangle the underlying mediating biological mechanisms for the identified associations. 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. This study provides strong evidence for the associations of B vitamins and homocysteine with endocrine/metabolic and genitourinary disorders.


WANG, L., LI, X., MONTAZERI, A., MACFARLANE, A.J., MOMOLI, F., DUTHIE, S., SENEKAL, M., EGUIAGARAY, I.M., MUNGER, R., BENNETT, D., CAMPBELL, H., RUBINI, M., MCNULTY, H., LITTLE, J. and THEODORATOU, E. 2023. Phenome-wide association study of genetically predicted B vitamins and homocysteine biomarkers with multiple health and disease outcomes: analysis of the UK Biobank. American journal of clinical nutrition [online], 117(3), pages 564-575. Available from:

Journal Article Type Article
Acceptance Date Jan 9, 2023
Online Publication Date Jan 13, 2023
Publication Date Mar 31, 2023
Deposit Date Jan 13, 2023
Publicly Available Date Jan 14, 2024
Journal American journal of clinical nutrition
Print ISSN 0002-9165
Electronic ISSN 1938-3207
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 117
Issue 3
Pages 564-575
Keywords B vitamins; Homocysteine; PheWAS; Mendelian randomization
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