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Evaluation of genetic markers as instruments for Mendelian randomization studies on vitamin D.
PLoS One. 2012; 7(5):e37465.Plos

Abstract

BACKGROUND

Mendelian randomization (MR) studies use genetic variants mimicking the influence of a modifiable exposure to assess and quantify a causal association with an outcome, with an aim to avoid problems with confounding and reverse causality affecting other types of observational studies.

AIM

We evaluated genetic markers that index differences in 25-hydroxyvitamin D (25(OH)D) as instruments for MR studies on vitamin D.

METHODS AND FINDINGS

We used data from up-to 6,877 participants in the 1958 British birth cohort with information on genetic markers and 25(OH)D. As potential instruments, we selected 20 single nucleotide polymorphisms (SNP) which are located in the vitamin D metabolism pathway or affect skin pigmentation/tanning, including 4 SNPs from genome-wide association (GWA) meta-analyses on 25(OH)D. We analyzed SNP associations with 25(OH)D and evaluated the use of allele scores dividing genes to those affecting 25(OH)D synthesis (DHCR7, CYP2R1) and metabolism (GC, CYP24A1, CYP27B1). In addition to the GWA SNPs, only two SNPs (CYP27B1, OCA2) showed evidence for association with 25(OH)D, with the OCA2 association abolished after lifestyle adjustment. Per allele differences varied between -0.02 and -0.08 nmol/L (P≤0.02 for all), with a 6.1 nmol/L and a 10.2 nmol/L difference in 25(OH)D between individuals with highest compared lowest number of risk alleles in synthesis and metabolism allele scores, respectively. Individual SNPs but not allele scores showed associations with lifestyle factors. An exception was geographical region which was associated with synthesis score. Illustrative power calculations (80% power, 5% alpha) suggest that approximately 80,000 participants are required to establish a causal effect of vitamin D on blood pressure using the synthesis allele score.

CONCLUSIONS

Combining SNPs into allele scores provides a more powerful instrument for MR analysis than a single SNP in isolation. Population stratification and the potential for pleiotropic effects need to be considered in MR studies on vitamin D.

Authors+Show Affiliations

Centre for Paediatric Epidemiology and Biostatistics, UCL Institute of Child Health, London, United Kingdom.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22629401

Citation

Berry, Diane J., et al. "Evaluation of Genetic Markers as Instruments for Mendelian Randomization Studies On Vitamin D." PloS One, vol. 7, no. 5, 2012, pp. e37465.
Berry DJ, Vimaleswaran KS, Whittaker JC, et al. Evaluation of genetic markers as instruments for Mendelian randomization studies on vitamin D. PLoS One. 2012;7(5):e37465.
Berry, D. J., Vimaleswaran, K. S., Whittaker, J. C., Hingorani, A. D., & Hyppönen, E. (2012). Evaluation of genetic markers as instruments for Mendelian randomization studies on vitamin D. PloS One, 7(5), e37465. https://doi.org/10.1371/journal.pone.0037465
Berry DJ, et al. Evaluation of Genetic Markers as Instruments for Mendelian Randomization Studies On Vitamin D. PLoS One. 2012;7(5):e37465. PubMed PMID: 22629401.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Evaluation of genetic markers as instruments for Mendelian randomization studies on vitamin D. AU - Berry,Diane J, AU - Vimaleswaran,Karani S, AU - Whittaker,John C, AU - Hingorani,Aroon D, AU - Hyppönen,Elina, Y1 - 2012/05/21/ PY - 2012/01/03/received PY - 2012/04/20/accepted PY - 2012/5/26/entrez PY - 2012/5/26/pubmed PY - 2012/12/18/medline SP - e37465 EP - e37465 JF - PloS one JO - PLoS One VL - 7 IS - 5 N2 - BACKGROUND: Mendelian randomization (MR) studies use genetic variants mimicking the influence of a modifiable exposure to assess and quantify a causal association with an outcome, with an aim to avoid problems with confounding and reverse causality affecting other types of observational studies. AIM: We evaluated genetic markers that index differences in 25-hydroxyvitamin D (25(OH)D) as instruments for MR studies on vitamin D. METHODS AND FINDINGS: We used data from up-to 6,877 participants in the 1958 British birth cohort with information on genetic markers and 25(OH)D. As potential instruments, we selected 20 single nucleotide polymorphisms (SNP) which are located in the vitamin D metabolism pathway or affect skin pigmentation/tanning, including 4 SNPs from genome-wide association (GWA) meta-analyses on 25(OH)D. We analyzed SNP associations with 25(OH)D and evaluated the use of allele scores dividing genes to those affecting 25(OH)D synthesis (DHCR7, CYP2R1) and metabolism (GC, CYP24A1, CYP27B1). In addition to the GWA SNPs, only two SNPs (CYP27B1, OCA2) showed evidence for association with 25(OH)D, with the OCA2 association abolished after lifestyle adjustment. Per allele differences varied between -0.02 and -0.08 nmol/L (P≤0.02 for all), with a 6.1 nmol/L and a 10.2 nmol/L difference in 25(OH)D between individuals with highest compared lowest number of risk alleles in synthesis and metabolism allele scores, respectively. Individual SNPs but not allele scores showed associations with lifestyle factors. An exception was geographical region which was associated with synthesis score. Illustrative power calculations (80% power, 5% alpha) suggest that approximately 80,000 participants are required to establish a causal effect of vitamin D on blood pressure using the synthesis allele score. CONCLUSIONS: Combining SNPs into allele scores provides a more powerful instrument for MR analysis than a single SNP in isolation. Population stratification and the potential for pleiotropic effects need to be considered in MR studies on vitamin D. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/22629401/Evaluation_of_genetic_markers_as_instruments_for_Mendelian_randomization_studies_on_vitamin_D_ L2 - https://dx.plos.org/10.1371/journal.pone.0037465 DB - PRIME DP - Unbound Medicine ER -