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

doi:10.1016/j.ajcnut.2023.01.005

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 journal › Article › peer-review

Abstract

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 language	English
Pages (from-to)	564-575
Journal	The American Journal of Clinical Nutrition (AJCN)
Volume	117
Issue number	3
Early online date	13 Jan 2023
DOIs	https://doi.org/10.1016/j.ajcnut.2023.01.005
Publication status	Published - 1 Mar 2023

Keywords

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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10.1016/j.ajcnut.2023.01.005

Phenome-wide association study of genetically predicted B vitamins and homocysteine biomarkers with multiple health and disease outcomes - analysis of the UK BiobankAccepted author manuscript, 974 KB

Colorectal cancer reduction through risk stratification of screening, follow-up and treatment
Theodoratou, E.
UK-based charities
1/05/17 → 30/04/23
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Wang, L., Li, X., Montazeri, A., MacFarlane, A. J., Momoli, F., Duthie, S. J., Senekal, M., Mesa Eguiagaray, I., Munger, R. G., Bennett, D., Campbell, H., Rubini, M., McNulty, H., Little, J., & 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. The American Journal of Clinical Nutrition (AJCN), 117(3), 564-575. https://doi.org/10.1016/j.ajcnut.2023.01.005

@article{8ee3d4994039474ca383e663a5c2c373,

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

abstract = "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",

keywords = "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",

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

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: {\textcopyright} 2023 American Society for Nutrition",

year = "2023",

month = mar,

day = "1",

doi = "10.1016/j.ajcnut.2023.01.005",

language = "English",

volume = "117",

pages = "564--575",

journal = "The American Journal of Clinical Nutrition (AJCN)",

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Wang, L, Li, X, Montazeri, A, MacFarlane, AJ, Momoli, F, Duthie, SJ, Senekal, M, Mesa Eguiagaray, I, Munger, RG, Bennett, D, Campbell, H, Rubini, M, McNulty, H, Little, J & 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', The American Journal of Clinical Nutrition (AJCN), vol. 117, no. 3, pp. 564-575. https://doi.org/10.1016/j.ajcnut.2023.01.005

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 et al.

In: The American Journal of Clinical Nutrition (AJCN), Vol. 117, No. 3, 01.03.2023, p. 564-575.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Phenome-wide association study of genetically predicted B vitamins and homocysteine biomarkers with multiple health and disease outcomes

T2 - analysis of the UK Biobank

AU - Wang, Lijuan

AU - Li, Xue

AU - Montazeri, Azita

AU - MacFarlane, Amanda J.

AU - Momoli, Franco

AU - Duthie, Susan J

AU - Senekal, Marjanne

AU - Mesa Eguiagaray, Ines

AU - Munger, Ronald G

AU - Bennett, Derrick

AU - Campbell, Harry

AU - Rubini, Michele

AU - McNulty, Helene

AU - Little, Julian

AU - Theodoratou, Evropi

N1 - 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

PY - 2023/3/1

Y1 - 2023/3/1

N2 - 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

AB - 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

KW - Biological Specimen Banks

KW - Biomarkers

KW - Female

KW - Folic Acid

KW - Homocysteine

KW - Humans

KW - Mendelian Randomization Analysis

KW - Pregnancy

KW - United Kingdom

KW - Vitamin A

KW - Vitamin B 12

KW - Vitamin B 6

KW - Vitamin B Complex

KW - Vitamin K

U2 - 10.1016/j.ajcnut.2023.01.005

DO - 10.1016/j.ajcnut.2023.01.005

M3 - Article

C2 - 36811473

VL - 117

SP - 564

EP - 575

JO - The American Journal of Clinical Nutrition (AJCN)

JF - The American Journal of Clinical Nutrition (AJCN)

SN - 0002-9165

IS - 3

ER -

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

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Keywords

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Colorectal cancer reduction through risk stratification of screening, follow-up and treatment

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