Exploring a causal role of DNA methylation in the relationship between maternal vitamin B12 during pregnancy and child’s IQ at age 8, cognitive performance and educational attainment: a two-step Mendelian randomization study

Human Molecular Genetics

Volumn 26, Issue 15, 2017, Pages 3001-3013

  Caramaschi, Doretta ^a   Sharp, Gemma C ^a,b   Nohr, Ellen A ^c   Berryman, Katie ^a   Lewis, Sarah J ^a   Smith, George Davey ^a   Relton, Caroline L ^a  

^a UNIVERSITY OF BRISTOL   (United Kingdom)

^b UNIVERSITY OF BRISTOL   (United Kingdom)

^c UNIVERSITY OF SOUTHERN DENMARK   (Denmark)

Author keywords

[No Author keywords available]

Indexed keywords

CYANOCOBALAMIN; FUCOSYLTRANSFERASE 2; TRANSFERASE; UNCLASSIFIED DRUG;

ARTICLE; BODY MASS; CHILD HEALTH; COGNITION; CONCEPTION; CPG ISLAND; DNA METHYLATION; EDUCATIONAL STATUS; EPIGENETICS; FEMALE; GENETIC ASSOCIATION; GENOME-WIDE ASSOCIATION STUDY; GENOTYPE; HETEROZYGOSITY; HUMAN; MALE; MENDELIAN RANDOMIZATION ANALYSIS; MENTAL PERFORMANCE; PREGNANCY; SINGLE NUCLEOTIDE POLYMORPHISM; SMOKING; UMBILICAL CORD BLOOD; VITAMIN BLOOD LEVEL; WECHSLER INTELLIGENCE SCALE FOR CHILDREN; ADULT; CHILD; COMPARATIVE STUDY; DRUG EFFECTS; FAMILY; FETUS BLOOD; GENETIC EPIGENESIS; GENETICS; INTELLIGENCE; INTELLIGENCE TEST; LONGITUDINAL STUDY; METABOLISM; PHYSIOLOGY; PRENATAL EXPOSURE; RANDOMIZATION;

ADULT; CHILD; COGNITION; DNA METHYLATION; EPIGENESIS, GENETIC; FAMILY; FEMALE; FETAL BLOOD; GENOTYPE; HUMANS; INTELLIGENCE; INTELLIGENCE TESTS; LONGITUDINAL STUDIES; MALE; MENDELIAN RANDOMIZATION ANALYSIS; PREGNANCY; PRENATAL EXPOSURE DELAYED EFFECTS; RANDOM ALLOCATION; VITAMIN B 12;

EID: 85032335608     PISSN: 09646906     EISSN: 14602083     Source Type: Journal    
DOI: 10.1093/hmg/ddx164     Document Type: Article

References (76)

1. Rush, E.C., Katre, P. and Yajnik, C.S. (2014) Vitamin B12: one carbon metabolism, fetal growth and programming for chronic disease. Eur. J. Clin. Nutr., 68, 2–7.
2. Relton, C.L., Wilding, C.S., Laffling, A.J., Jonas, P.A., Burgess, T., Binks, K., Tawn, E.J. and Burn, J. (2004) Low erythrocyte folate status and polymorphic variation in folate-related genes are associated with risk of neural tube defect pregnancy. Mol. Genet. Metab., 81, 273–281.
3. Hibbard, B.M., Hibbard, E.D. and Jeffcoate, T.N. (1965) Folic acid and reproduction. Acta Obstet. Gynecol. Scand., 44, 375–400.
4. MRC Vitamin Study Research Group(1991) Prevention of neural tube defects: results of the Medical Research Council vitamin study. Lancet, 338, 131–137.
5. Mulinare, J., Cordero, J.F., Erickson, J.D. and Berry, R.J. (1988) Periconceptional use of multivitamins and the occurrence of neural tube defects. JAMA, 260, 3141–3145.
6. Czeizel, A.E. and Dudas, I. (1992) Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N. Engl. J. Med., 327, 1832–1835.
7. Roth, C., Magnus, P., Schjolberg, S., Stoltenberg, C., Suren, P., McKeague, I.W., Davey Smith, G., Reichborn-Kjennerud, T. and Susser, E. (2011) Folic acid supplements in pregnancy and severe language delay in children. JAMA, 306, 1566–1573.
8. Suren, P., Roth, C., Bresnahan, M., Haugen, M., Hornig, M., Hirtz, D., Lie, K.K., Lipkin, W.I., Magnus, P., Reichborn-Kjennerud, T. et al. (2013) Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children. JAMA, 309, 570–577.
9. Molloy, A.M., Kirke, P.N., Troendle, J.F., Burke, H., Sutton, M., Brody, L.C., Scott, J.M. and Mills, J.L. (2009) Maternal vitamin B12 status and risk of neural tube defects in a population with high neural tube defect prevalence and no folic Acid fortification. Pediatrics, 123, 917–923.
10. Bhate, V., Deshpande, S., Bhat, D., Joshi, N., Ladkat, R., Watve, S., Fall, C., de Jager, C.A., Refsum, H. and Yajnik, C. (2008) Vitamin B12 status of pregnant Indian women and cognitive function in their 9-year-old children. Food Nutr. Bull., 29, 249–254.
11. Villamor, E., Rifas-Shiman, S.L., Gillman, M.W. and Oken, E. (2012) Maternal intake of methyl-donor nutrients and child cognition at 3 years of age. Paediatr. Perinat. Epidemiol., 26, 328–335.
12. del Rio Garcia, C., Torres-Sanchez, L., Chen, J., Schnaas, L., Hernandez, C., Osorio, E., Portillo, M.G. and Lopez-Carrillo, L. (2009) Maternal MTHFR 677C>T genotype and dietary intake of folate and vitamin B(12): their impact on child neurodevelopment. Nutr. Neurosci., 12, 13–20.
13. Bonilla, C., Lawlor, D.A., Taylor, A.E., Gunnell, D.J., Ben-Shlomo, Y., Ness, A.R., Timpson, N.J., St Pourcain, B., Ring, S.M., Emmett, P.M. et al. (2012) Vitamin B-12 status during pregnancy and child’s IQ at age 8: a Mendelian randomization study in the Avon longitudinal study of parents and children. PLoS One, 7, e51084.
14. McKay, J.A., Groom, A., Potter, C., Coneyworth, L.J., Ford, D., Mathers, J.C. and Relton, C.L. (2012) Genetic and non-genetic influences during pregnancy on infant global and site specific DNA methylation: role for folate gene variants and vitamin B12. PLoS One, 7, e33290.
15. Ba, Y., Yu, H., Liu, F., Geng, X., Zhu, C., Zhu, Q., Zheng, T., Ma, S., Wang, G., Li, Z. et al. (2011) Relationship of folate, vitamin B12 and methylation of insulin-like growth factor-II in maternal and cord blood. Eur. J. Clin. Nutr., 65, 480–485.
16. Wang, L., Wang, F., Guan, J., Le, J., Wu, L., Zou, J., Zhao, H., Pei, L., Zheng, X. and Zhang, T. (2010) Relation between hypomethylation of long interspersed nucleotide elements and risk of neural tube defects. Am. J. Clin. Nutr., 91, 1359–1367.
17. Relton, C.L. and Davey Smith, G. (2012) Two-step epigenetic Mendelian randomization: a strategy for establishing the causal role of epigenetic processes in pathways to disease. Int. J. Epidemiol., 41, 161–176.
18. Lewis, S.J., Araya, R., Smith, G.D., Freathy, R., Gunnell, D., Palmer, T. and Munafo, M. (2011) Smoking is associated with, but does not cause, depressed mood in pregnancy–a mendelian randomization study. PLoS One, 6, e21689.
19. Bonilla, C., Lawlor, D.A., Ben-Shlomo, Y., Ness, A.R., Gunnell, D., Ring, S.M., Smith, G.D. and Lewis, S.J. (2012) Maternal and offspring fasting glucose and type 2 diabetes-associated genetic variants and cognitive function at age 8: a Mendelian randomization study in the Avon longitudinal study of parents and children. BMC Med. Genet., 13, 90.
20. Zuccolo, L., Lewis, S.J., Smith, G.D., Sayal, K., Draper, E.S., Fraser, R., Barrow, M., Alati, R., Ring, S., Macleod, J. et al. (2013) Prenatal alcohol exposure and offspring cognition and school performance. A ‘Mendelian randomization’ natural experiment. Int. J. Epidemiol., 42, 1358–1370.
21. Lewis, S.J., Bonilla, C., Brion, M.J., Lawlor, D.A., Gunnell, D., Ben-Shlomo, Y., Ness, A. and Smith, G.D. (2014) Maternal iron levels early in pregnancy are not associated with offspring IQ score at age 8, findings from a Mendelian randomization study. Eur. J. Clin. Nutr., 68, 496–502.
22. 0: can genetic epidemiology contribute to understanding environmental determinants of disease? Int. J. Epidemiol., 32, 1–22.
23. Davey Smith, G. and Hemani, G. (2014) Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum. Mol. Genet., 23, R89–R98.
24. Hazra, A., Kraft, P., Selhub, J., Giovannucci, E.L., Thomas, G., Hoover, R.N., Chanock, S.J. and Hunter, D.J. (2008) Common variants of FUT2 are associated with plasma vitamin B12 levels. Nat. Genet., 40, 1160–1162.
25. Hazra, A., Kraft, P., Lazarus, R., Chen, C., Chanock, S.J., Jacques, P., Selhub, J. and Hunter, D.J. (2009) Genome-wide significant predictors of metabolites in the one-carbon metabolism pathway. Hum. Mol. Genet., 18, 4677–4687.
26. Grarup, N., Sulem, P., Sandholt, C.H., Thorleifsson, G., Ahluwalia, T.S., Steinthorsdottir, V., Bjarnason, H., Gudbjartsson, D.F., Magnusson, O.T., Sparso, T. et al. (2013) Genetic architecture of vitamin B12 and folate levels uncovered applying deeply sequenced large datasets. PLoS Genet., 9, e1003530.
27. Tanaka, T., Scheet, P., Giusti, B., Bandinelli, S., Piras, M.G., Usala, G., Lai, S., Mulas, A., Corsi, A.M., Vestrini, A. et al. (2009) Genome-wide association study of vitamin B6, vitamin B12, folate, and homocysteine blood concentrations. Am. J. Hum. Genet., 84, 477–482.
28. Lin, X., Lu, D., Gao, Y., Tao, S., Yang, X., Feng, J., Tan, A., Zhang, H., Hu, Y., Qin, X. et al. (2012) Genome-wide association study identifies novel loci associated with serum level of vitamin B12 in Chinese men. Hum. Mol. Genet., 21, 2610–2617.
29. Ars, C.L., Nijs, I.M., Marroun, H.E., Muetzel, R., Schmidt, M., Steenweg-de Graaff, J., van der Lugt, A., Jaddoe, V.W., Hofman, A., Steegers, E.A. et al. (2016) Prenatal folate, homocysteine and vitamin B12 levels and child brain volumes, cognitive development and psychological functioning: the Generation R Study. Br. J. Nutr., 22, 1–9.
30. Srinivasan, K., Thomas, T., Kapanee, A.R., Ramthal, A., Bellinger, D.C., Bosch, R.J., Kurpad, A.V. and Duggan, C. (2016) Effects of maternal vitamin B12 supplementation on early infant neurocognitive outcomes: a randomized controlled clinical trial. Matern. Child. Nutr., 13, e12325.
31. Richmond, R.C., Hemani, G., Tilling, K., Davey Smith, G. and Relton, C.L. (2016) Challenges and novel approaches for investigating molecular mediation. Hum. Mol. Genet., 25, R149–R156.
32. Pavlides, J.M., Zhu, Z., Gratten, J., McRae, A.F., Wray, N.R. and Yang, J. (2016) Predicting gene targets from integrative analyses of summary data from GWAS and eQTL studies for 28 human complex traits. Genome. Med., 8, 84.
33. Zhu, Z., Zhang, F., Hu, H., Bakshi, A., Robinson, M.R., Powell, J.E., Montgomery, G.W., Goddard, M.E., Wray, N.R., Visscher, P.M. et al. (2016) Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets. Nat. Genet., 48, 481–487.
34. Boyd, A., Golding, J., Macleod, J., Lawlor, D.A., Fraser, A., Henderson, J., Molloy, L., Ness, A., Ring, S. and Davey Smith, G. (2013) Cohort Profile: the ‘children of the 90s’–the index offspring of the Avon longitudinal study of parents and children. Int. J. Epidemiol., 42, 111–127.
35. Fraser, A., Macdonald-Wallis, C., Tilling, K., Boyd, A., Golding, J., Davey Smith, G., Henderson, J., Macleod, J., Molloy, L., Ness, A. et al. (2013) Cohort profile: the Avon longitudinal study of parents and children: ALSPAC mothers cohort. Int. J. Epidemiol., 42, 97–110.
36. Rietveld, C.A., Esko, T., Davies, G., Pers, T.H., Turley, P., Benyamin, B., Chabris, C.F., Emilsson, V., Johnson, A.D., Lee, J.J. et al. (2014) Common genetic variants associated with cognitive performance identified using the proxy-phenotype method. Proc. Natl. Acad Sci. U. S. A, 111, 13790–13794.
37. Rietveld, C.A., Medland, S.E., Derringer, J., Yang, J., Esko, T., Martin, N.W., Westra, H.J., Shakhbazov, K., Abdellaoui, A., Agrawal, A. et al. (2013) GWAS of 126,559 individuals identifies genetic variants associated with educational attainment. Science, 340, 1467–1471.
38. Benyamin, B., Pourcain, B., Davis, O.S., Davies, G., Hansell, N.K., Brion, M.J., Kirkpatrick, R.M., Cents, R.A., Franic, S., Miller, M.B. et al. (2014) Childhood intelligence is heritable, highly polygenic and associated with FNBP1L. Mol. Psychiatry, 19, 253–258.
39. Martin, Y., Cabrera, E., Amoedo, H., Hernandez-Perez, S., Dominguez-Kelly, R. and Freire, R. (2015) USP29 controls the stability of checkpoint adaptor Claspin by deubiquitination. Oncogene, 34, 1058–1063.
40. Huffman, J.E., Albrecht, E., Teumer, A., Mangino, M., Kapur, K., Johnson, T., Kutalik, Z., Pirastu, N., Pistis, G., Lopez, L.M. et al. (2015) Modulation of genetic associations with serum urate levels by body-mass-index in humans. PLoS One, 10, e0119752.
41. Mimmack, M.L., Ryan, M., Baba, H., Navarro-Ruiz, J., Iritani, S., Faull, R.L., McKenna, P.J., Jones, P.B., Arai, H., Starkey, M. et al. (2002) Gene expression analysis in schizophrenia: reproducible up-regulation of several members of the apolipoprotein L family located in a high-susceptibility locus for schizophrenia on chromosome 22. Proc. Natl. Acad. Sci. U. S. A, 99, 4680–4685.
42. Bostrom, M.A., Lu, L., Chou, J., Hicks, P.J., Xu, J., Langefeld, C.D., Bowden, D.W. and Freedman, B.I. (2010) Candidate genes for non-diabetic ESRD in African Americans: a genome-wide association study using pooled DNA. Hum. Genet., 128, 195–204.
43. Binder, A.M. and Michels, K.B. (2013) The causal effect of red blood cell folate on genome-wide methylation in cord blood: a Mendelian randomization approach. BMC Bioinformatics, 14, 353.
44. Relton, C.L., Wilding, C.S., Pearce, M.S., Laffling, A.J., Jonas, P.A., Lynch, S.A., Tawn, E.J. and Burn, J. (2004) Gene-gene interaction in folate-related genes and risk of neural tube defects in a UK population. J. Med. Genet., 41, 256–260.
45. Pierce, B.L. and Burgess, S. (2013) Efficient design for Mendelian randomization studies: subsample and 2-sample instrumental variable estimators. Am. J. Epidemiol., 178, 1177–1184.
46. Welter, D., MacArthur, J., Morales, J., Burdett, T., Hall, P., Junkins, H., Klemm, A., Flicek, P., Manolio, T., Hindorff, L. et al. (2014) The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic. Acids. Res., 42, D1001–D1006.
47. Davies, M.N., Volta, M., Pidsley, R., Lunnon, K., Dixit, A., Lovestone, S., Coarfa, C., Harris, R.A., Milosavljevic, A., Troakes, C. et al. (2012) Functional annotation of the human brain methylome identifies tissue-specific epigenetic variation across brain and blood. Genome. Biol., 13, R43.
48. Provencal, N., Suderman, M.J., Guillemin, C., Massart, R., Ruggiero, A., Wang, D., Bennett, A.J., Pierre, P.J., Friedman, D.P., Cote, S.M. et al. (2012) The signature of maternal rearing in the methylome in rhesus macaque prefrontal cortex and T cells. J. Neurosci., 32, 15626–15642.
49. Wang, D., Szyf, M., Benkelfat, C., Provencal, N., Turecki, G., Caramaschi, D., Cote, S.M., Vitaro, F., Tremblay, R.E. and Booij, L. (2012) Peripheral SLC6A4 DNA methylation is associated with in vivo measures of human brain serotonin synthesis and childhood physical aggression. PLoS One, 7, e39501.
50. Provencal, N., Suderman, M.J., Guillemin, C., Vitaro, F., Cote, S.M., Hallett, M., Tremblay, R.E. and Szyf, M. (2014) Association of childhood chronic physical aggression with a DNA methylation signature in adult human T cells. PLoS One, 9, e89839.
51. Cummings, E.M., George, M.R., Koss, K.J. and Davies, P.T. (2013) Parental depressive symptoms and adolescent adjustment: responses to children’s distress and representations of attachment as explanatory mechanisms. Parent. Sci. Pract., 13, doi: 10.1080/15295192.2013.832568.
52. Wong, C.C., Meaburn, E.L., Ronald, A., Price, T.S., Jeffries, A.R., Schalkwyk, L.C., Plomin, R. and Mill, J. (2014) Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits. Mol. Psychiatry, 19, 495–503.
53. Montano, C., Taub, M.A., Jaffe, A., Briem, E., Feinberg, J.I., Trygvadottir, R., Idrizi, A., Runarsson, A., Berndsen, B., Gur, R.C. et al. (2016) Association of DNA methylation differences with schizophrenia in an epigenome-wide association study. JAMA Psychiatry, 73, 506–514.
54. Jaffe, A.E. and Kleinman, J.E. (2016) Genetic and epigenetic analysis of schizophrenia in blood-a no-brainer? Genome Med., 8.
55. Bakulski, K.M., Halladay, A., Hu, V.W., Mill, J. and Fallin, M.D. (2016) Epigenetic research in neuropsychiatric disorders: the “tissue issue”. Curr. Behav. Neurosci. Rep., 3, 264–274.
56. Hannon, E., Dempster, E., Viana, J., Burrage, J., Smith, A.R., Macdonald, R., St Clair, D., Mustard, C., Breen, G., Therman, S. et al. (2016) An integrated genetic-epigenetic analysis of schizophrenia: evidence for co-localization of genetic associations and differential DNA methylation. Genome Biol., 17, 176.
57. Obeid, R., Munz, W., Jager, M., Schmidt, W. and Herrmann, W. (2005) Biochemical indexes of the B vitamins in cord serum are predicted by maternal B vitamin status. Am. J. Clin. Nutr., 82, 133–139.
58. Jacquemyn, Y., Ajaji, M., Karepouan, N., Jacquemyn, N. and Van Sande, H. (2014) Vitamin B12 and folic acid status of term pregnant women and newborns in the Antwerp region, Belgium. Clin. Exp. Obstet. Gynecol., 41, 141–143.
59. Khulan, B., Cooper, W.N., Skinner, B.M., Bauer, J., Owens, S., Prentice, A.M., Belteki, G., Constancia, M., Dunger, D. and Affara, N.A. (2012) Periconceptional maternal micronutrient supplementation is associated with widespread gender related changes in the epigenome: a study of a unique resource in the Gambia. Hum. Mol. Genet., 21, 2086–2101.
60. Zhang, J. and Liu, Q. (2015) Cholesterol metabolism and homeostasis in the brain. Protein Cell, 6, 254–264.
61. Genomes Project, C., Abecasis, G.R., Auton, A., Brooks, L.D., DePristo, M.A., Durbin, R.M., Handsaker, R.E., Kang, H.M., Marth, G.T. and McVean, G.A. (2012) An integrated map of genetic variation from 1,092 human genomes. Nature, 491, 56–65.
62. Relton, C.L., Gaunt, T., McArdle, W., Ho, K., Duggirala, A., Shihab, H., Woodward, G., Lyttleton, O., Evans, D.M., Reik, W. et al. (2015) Data Resource Profile: Accessible Resource for Integrated Epigenomic Studies (ARIES). Int. J. Epidemiol., 44, 1181–1190.
63. Du, P., Zhang, X., Huang, C.C., Jafari, N., Kibbe, W.A., Hou, L. and Lin, S.M. (2010) Comparison of Beta-value and M-value methods for quantifying methylation levels by microarray analysis. BMC Bioinformatics, 11, 587.
64. Pidsley, R., Wong, C.C.Y., Volta, M., Lunnon, K., Mill, J. and Schalkwyk, L.C. (2013) A data-driven approach to preprocessing Illumina 450K methylation array data. BMC Genomics, 14,
65. Touleimat, N. and Tost, J. (2012) Complete pipeline for Infinium((R)) Human Methylation 450K BeadChip data processing using subset quantile normalization for accurate DNA methylation estimation. Epigenomics, 4, 325–341.
66. Joinson, C., Heron, J., Butler, R., Von Gontard, A., Butler, U., Emond, A. and Golding, J. (2007) A United Kingdom population-based study of intellectual capacities in children with and without soiling, daytime wetting, and bed-wetting. Pediatrics, 120, e308–e316.
67. Wechsler, D. (1991) Manual for the Wechsler Intelligence Scale for Children. 3rd ed., San Antonio, TX.
68. Paternoster, L., Evans, D.M., Nohr, E.A., Holst, C., Gaborieau, V., Brennan, P., Gjesing, A.P., Grarup, N., Witte, D.R., Jorgensen, T. et al. (2011) Genome-wide population-based association study of extremely overweight young adults–the GOYA study. PLoS One, 6, e24303.
69. Nohr, E.A., Timpson, N.J., Andersen, C.S., Davey Smith, G., Olsen, J. and Sorensen, T.I. (2009) Severe obesity in young women and reproductive health: the Danish National Birth Cohort. PLoS One, 4, e8444.
70. Thomas, D.C., Lawlor, D.A. and Thompson, J.R. (2007) Re: Estimation of bias in nongenetic observational studies using “Mendelian triangulation” by Bautista et al. Ann. Epidemiol., 17, 511–513.
71. Barfield, R.T., Kilaru, V., Smith, A.K. and Conneely, K.N. (2012) CpGassoc: an R function for analysis of DNA methylation microarray data. Bioinformatics, 28, 1280–1281.
72. Bakulski, K.M., Feinberg, J.I., Andrews, S.V., Yang, J., Brown, S., S, L.M., Witter, F., Walston, J., Feinberg, A.P. and Fallin, M.D. (2016) DNA methylation of cord blood cell types: Applications for mixed cell birth studies. Epigenetics, 11, 354–362.
73. Ashburner, M., Ball, C.A., Blake, J.A., Botstein, D., Butler, H., Cherry, J.M., Davis, A.P., Dolinski, K., Dwight, S.S., Eppig, J.T. et al. (2000) Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat. Genet., 25, 25–29.
74. Gaunt, T.R., Shihab, H.A., Hemani, G., Min, J.L., Woodward, G., Lyttleton, O., Zheng, J., Duggirala, A., McArdle, W.L., Ho, K. et al. (2016) Systematic identification of genetic influences on methylation across the human life course. Genome Biol., 17, 61.
75. Taylor, A.E., Davies, N.M., Ware, J.J., VanderWeele, T., Smith, G.D. and Munafo, M.R. (2014) Mendelian randomization in health research: using appropriate genetic variants and avoiding biased estimates. Econ. Hum. Biol., 13, 99–106.
76. Burgess, S. and Thompson, S.G. (2013) Use of allele scores as instrumental variables for Mendelian randomization. Int. J. Epidemiol., 42, 1134–1144.